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Sample records for bile acid conjugates

  1. The synthesis of taurine-conjugated bile acids and bile acid sulfates labeled with 14C or 3H in the taurine moiety

    International Nuclear Information System (INIS)

    Jie Zhang; Griffiths, W.J.; Sjoevall, Jan

    1997-01-01

    Studies of bile acid transport systems require radio-labeled taurine-conjugated bile acids with high specific activity. An established procedure was optimized to provide mild, fast, and effective conjugation of radio-labeled taurine with different types of bile acids, including those with labile 7α-hydroxy-3-oxo-Δ 4 or 3β, 7α-dihydroxy-Δ 5 structures. Taurine labeled with 14 C or 3 H was reacted with excess bile acid anhydride formed from the tributylamine salt and ethylchloroformate (2/1 M/M) in aqueous dioxane for 15 min at room temperature. The yields were higher than 95% and less than 2% side products were formed. Bile acid sulfates were conjugated with 14 C- or 3 H-labeled taurine by using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline as the coupling reagent. The products were effectively purified by chromatography of the sodium salts on Sephadex LH-20. The yields of taurine-conjugated bile acid sulfates were 65-70%. (author)

  2. Profiles of bile acids and their glucuronide and sulphate conjugates in the serum, urine and bile from patients undergoing bile drainage.

    OpenAIRE

    Takikawa, H; Beppu, T; Seyama, Y

    1985-01-01

    Bile acid profiles in serum, urine, and bile from patients undergoing bile drainage and the changes of serum bile acids after bile drainage were studied. Bile acids were separated into non-glucuronidate-non-sulphate, glucuronidated, and sulphated fractions and were measured by mass fragmentography using conjugates of deuterium labelled bile acids as internal standards. Glucuronidated and sulphated bile acids contribute 14-32% and 16-44% of serum bile acids, 4-11% and 61-82% of urine bile acid...

  3. The synthesis of taurine-conjugated bile acids and bile acid sulfates labeled with {sup 14}C or {sup 3}H in the taurine moiety

    Energy Technology Data Exchange (ETDEWEB)

    Jie Zhang; Griffiths, W.J.; Sjoevall, Jan [Karolinska Inst., Medical Biochemistry and Biophysics Dept., Stockholm (Sweden)

    1997-02-01

    Studies of bile acid transport systems require radio-labeled taurine-conjugated bile acids with high specific activity. An established procedure was optimized to provide mild, fast, and effective conjugation of radio-labeled taurine with different types of bile acids, including those with labile 7{alpha}-hydroxy-3-oxo-{Delta}{sup 4} or 3{beta}, 7{alpha}-dihydroxy-{Delta}{sup 5} structures. Taurine labeled with {sup 14}C or {sup 3}H was reacted with excess bile acid anhydride formed from the tributylamine salt and ethylchloroformate (2/1 M/M) in aqueous dioxane for 15 min at room temperature. The yields were higher than 95% and less than 2% side products were formed. Bile acid sulfates were conjugated with {sup 14}C- or {sup 3}H-labeled taurine by using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline as the coupling reagent. The products were effectively purified by chromatography of the sodium salts on Sephadex LH-20. The yields of taurine-conjugated bile acid sulfates were 65-70%. (author).

  4. Specific bile acid radioimmunoassays for separate determinations of unconjugated cholic acid, conjugated cholic acid and conjugated deoxycholic acid in serum and their clinical application

    International Nuclear Information System (INIS)

    Matern, S.; Gerok, W.

    1977-01-01

    Specific radioimmunoassays for separate determinations of serum unconjugated cholic, conjugated cholic and conjugated deoxycholic acids have been developed. Prior to the radioimmunoassay, extraction of serum bile acids was performed with Amberlite XAD-2. Unconjugated cholic acid was separated from glyco- and taurocholic acids by thin-layer chromatography. At 50% displacement of bound labeled glyco[ 3 H]cholic acid using antiserum obtained after immunization with cholic acid-bovine serum albumin-conjugate the cross-reactivity of taurocholic acid was 100%, cholic acid 80%, glycochenodeoxycholic acid 10%, chenodeoxycholic acid 7%, conjugated deoxycholic acid 3%, and conjugated lithocholic acid 3 H]cholic acid was linear on a logit-log plot from 5 to 80 pmol of unlabeled glycocholic acid. Fasting serum conjugated cholic acid in healthy subjects was 0.68 +- 0.34 μmol/l. Unconjugated cholic acid was determined by a solid phase radioimmunoassay using the cholic acid antibody chemically bound to Sepharose. The displacement curve of [ 3 H]cholic acid in the solid phase radioimmunoassay was linear on a logit-log plot from 5 to 200 pmol of unlabeled cholic acid. The coefficient of variation between samples was 5%. Fasting serum conjugated deoxycholic acid concentrations in 10 healthy subjects ranged from 0.18 to 0.92 μmol/l determined by a radioimmunoassay using antiserum obtained after immunization with deoxycholic acid-bovine serum albumin-conjugate. The clinical application of these bile acid radioimmunoassays is shown by an 'oral cholate tolerance test' as a sensitive indicator of liver function and by an 'oral cholyglycine tolerance test' as a useful test for bile acid absorption. (orig.) [de

  5. Novel two-step synthesis of gold nanoparticles capped with bile acid conjugates

    International Nuclear Information System (INIS)

    Noponen, Virpi; Bhat, Shreedhar; Sievaenen, Elina; Kolehmainen, Erkki

    2008-01-01

    Bile acids and their conjugates are physiologically important molecules. Syntheses and structure elucidation combined with investigation of properties and applications of bile acids and their derivatives are of academic interest. The concept of using bile acids and their conjugates in nanoscience is a novel idea, which opens up fascinating prospects. In this article, an easy and simple route for obtaining N-lithocholyl-L-(cysteine ethyl ester) (3), capable of effectively capping and stabilizing metal nanoparticles, is described. The whole synthetic route needs only two steps giving a moderate to good yield. The gold NPs are characterized by elemental analysis, UV spectroscopy, and TEM. Additionally, 13 C CP/MAS NMR studies for different ligand/Au ratios have been performed

  6. Hepatic uptake of conjugated bile acids is mediated by both sodium taurocholate cotransporting polypeptide and organic anion transporting polypeptides and modulated by intestinal sensing of plasma bile acid levels in mice.

    Science.gov (United States)

    Slijepcevic, Davor; Roscam Abbing, Reinout L P; Katafuchi, Takeshi; Blank, Antje; Donkers, Joanne M; van Hoppe, Stéphanie; de Waart, Dirk R; Tolenaars, Dagmar; van der Meer, Jonathan H M; Wildenberg, Manon; Beuers, Ulrich; Oude Elferink, Ronald P J; Schinkel, Alfred H; van de Graaf, Stan F J

    2017-11-01

    The Na + -taurocholate cotransporting polypeptide (NTCP/SLC10A1) is believed to be pivotal for hepatic uptake of conjugated bile acids. However, plasma bile acid levels are normal in a subset of NTCP knockout mice and in mice treated with myrcludex B, a specific NTCP inhibitor. Here, we elucidated which transport proteins mediate the hepatic uptake of conjugated bile acids and demonstrated intestinal sensing of elevated bile acid levels in plasma in mice. Mice or healthy volunteers were treated with myrcludex B. Hepatic bile acid uptake kinetics were determined in wild-type (WT), organic anion transporting polypeptide (OATP) knockout mice (lacking Slco1a/1b isoforms), and human OATP1B1-transgenic mice. Effects of fibroblast growth factor 19 (FGF19) on hepatic transporter mRNA levels were assessed in rat hepatoma cells and in mice by peptide injection or adeno-associated virus-mediated overexpression. NTCP inhibition using myrcludex B had only moderate effects on bile acid kinetics in WT mice, but completely inhibited active transport of conjugated bile acid species in OATP knockout mice. Cholesterol 7α-hydroxylase Cyp7a1 expression was strongly down-regulated upon prolonged inhibition of hepatic uptake of conjugated bile acids. Fgf15 (mouse counterpart of FGF19) expression was induced in hypercholanemic OATP and NTCP knockout mice, as well as in myrcludex B-treated cholestatic mice, whereas plasma FGF19 was not induced in humans treated with myrcludex B. Fgf15/FGF19 expression was induced in polarized human enterocyte-models and mouse organoids by basolateral incubation with a high concentration (1 mM) of conjugated bile acids. NTCP and OATPs contribute to hepatic uptake of conjugated bile acids in mice, whereas the predominant uptake in humans is NTCP mediated. Enterocytes sense highly elevated levels of (conjugated) bile acids in the systemic circulation to induce FGF15/19, which modulates hepatic bile acid synthesis and uptake. (Hepatology 2017;66:1631-1643).

  7. Radiosynthesis of N-¹¹C-Methyl-Taurine-Conjugated Bile Acids and Biodistribution Studies in Pigs by PET/CT.

    Science.gov (United States)

    Schacht, Anna Christina; Sørensen, Michael; Munk, Ole Lajord; Frisch, Kim

    2016-04-01

    During cholestasis, accumulation of conjugated bile acids may occur in the liver and lead to hepatocellular damage. Inspired by our recent development of N-(11)C-methyl-glycocholic acid-that is, (11)C-cholylsarcosine-a tracer for PET of the endogenous glycine conjugate of cholic acid, we report here a radiosynthesis of N-(11)C-methyl-taurine-conjugated bile acids and biodistribution studies in pigs by PET/CT. A radiosynthesis of N-(11)C-methyl-taurine-conjugated bile acids was developed and used to prepare N-(11)C-methyl-taurine conjugates derived from cholic, chenodeoxycholic, deoxycholic, ursodeoxycholic, and lithocholic acid. The lipophilicity of these new tracers was determined by reversed-phase thin-layer chromatography. The effect of lipophilicity and structure on the biodistribution was investigated in pigs by PET/CT using the tracers derived from cholic acid (3α-OH, 7α-OH, 12α-OH), ursodeoxycholic acid (3α-OH, 7β-OH), and lithocholic acid (3α-OH). The radiosyntheses of the N-(11)C-methyl-taurine-conjugated bile acids proceeded with radiochemical yields of 61% (decay-corrected) or greater and radiochemical purities greater than 99%. PET/CT in pigs revealed that the tracers were rapidly taken up by the liver and secreted into bile. There was no detectable radioactivity in urine. Significant reflux of N-(11)C-methyl-taurolithocholic acid into the stomach was observed. We have successfully developed a radiosynthesis of N-(11)C-methyl-taurine-conjugated bile acids. These tracers behave in a manner similar to endogenous taurine-conjugated bile acids in vivo and are thus promising for functional PET of patients with cholestatic diseases. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

  8. Improved synthesis of glycine, taurine and sulfate conjugated bile acids as reference compounds and internal standards for ESI-MS/MS urinary profiling of inborn errors of bile acid synthesis.

    Science.gov (United States)

    Donazzolo, Elena; Gucciardi, Antonina; Mazzier, Daniela; Peggion, Cristina; Pirillo, Paola; Naturale, Mauro; Moretto, Alessandro; Giordano, Giuseppe

    2017-04-01

    Bile acid synthesis defects are rare genetic disorders characterized by a failure to produce normal bile acids (BAs), and by an accumulation of unusual and intermediary cholanoids. Measurements of cholanoids in urine samples by mass spectrometry are a gold standard for the diagnosis of these diseases. In this work improved methods for the chemical synthesis of 30 BAs conjugated with glycine, taurine and sulfate were developed. Diethyl phosphorocyanidate (DEPC) and diphenyl phosphoryl azide (DPPA) were used as coupling reagents for glycine and taurine conjugation. Sulfated BAs were obtained by sulfur trioxide-triethylamine complex (SO 3 -TEA) as sulfating agent and thereafter conjugated with glycine and taurine. All products were characterized by NMR, IR spectroscopy and high resolution mass spectrometry (HRMS). The use of these compounds as internal standards allows an improved accuracy of both identification and quantification of urinary bile acids. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. [Correlations of bile acids in the bile of rats in conditions of alloxan induced diabetes melitus].

    Science.gov (United States)

    Danchenko, N M; Vesel'skyĭ, S P; Tsudzevych, B O

    2014-01-01

    The ratio of bile acids in the bile of rats with alloxan diabetes was investigated using the method of thin-layer chromatography. Changes of coefficients of conjugation and hydroxylation of bile acids were calculated and analyzed in half-hour samples of bile obtained during the 3-hour experiment. It has been found that the processes of conjugation of cholic acid with glycine and taurine are inhibited in alloxan diabetes. At the same time a significant increase of free threehydroxycholic and dixydroxycholic bile acids and conjugates of the latter ones with taurine has been registered. Coefficients of hydroxylation in alloxan diabetes show the domination of "acidic" pathway in bile acid biosynthesis that is tightly connected with the activity of mitochondrial enzymes.

  10. Radioimmunoassay of conjugated cholic acid, chenodeoxycholic acid, and deoxycholic acid from human serum, with use of 125I-labeled ligands

    International Nuclear Information System (INIS)

    Maeentausta, O.; Jaenne, O.

    1979-01-01

    We describe a method for radioimmunoassay of conjugated cholic acid, chenodeoxycholic acid, and deoxycholic acid in serum. In the method, 125 I-labeled bile acid conjugates are used as the tracers along with antibodies raised against individual bile acid-bovine serum albumin conjugates. Antibody-bound and free bile acids were separated by polyethylene glycol precipitation (final concentration, 125 g/L). The lowest measurable amounts of the bile acids, expressed as pmol/tube, were: cholic acid conjugates, 2; chenodeoxycholic acid conjugates, 0.5; and deoxycholic acid conjugates, 2. Analytical recovery of bile acids added to bile acid-free serum ranged from 85 to 110%; intra-assay and inter-assay CVs ranged from 8.3 to 5.3% and from 5.3 to 12.2%, respectively. Concentrations (mean +- SD) of the bile acid conjugates in serum from apparently healthy women and men (in μmol/L) were: cholic acid conjugates, 0.43 +- 0.17 (n=126); chenodeoxycholic acid conjugates, 0.47 +- 0.23 (n=111); and deoxycholic acid conjugates, 0.33 +- 0.11 (n=96). The values for primary bile acids were greatly increased in patients with various hepatobiliary diseases

  11. Effects of Bariatric Surgery on Serum Bile Acid Composition and Conjugation in a Diabetic Rat Model.

    Science.gov (United States)

    Wu, Qunzheng; Zhang, Xiang; Zhong, Mingwei; Han, Haifeng; Liu, Shaozhuang; Liu, Teng; Wei, Meng; Guo, Wei; Xie, Haibin; Hu, Sanyuan; Zhang, Guangyong

    2016-10-01

    Serum bile acids (BAs) are elevated following bariatric surgery and have emerged as a potential glucose-lowering beneficial factor. The change of BA components and its underlying mechanisms may be of great significance during bariatric surgery. The aim of this study is to investigate the effects of different bariatric procedures on serum BA composition and explore the potential mechanisms using a diabetic rat model. Duodenal-jejunal bypass (DJB), sleeve gastrectomy (SG), and sham operation were performed in diabetic rats induced by high-fat diet (HFD) and streptozotocin (STZ). Body weight, food intake, oral glucose tolerance test (OGTT), and insulin tolerance test (ITT) were measured at indicated time points. Serum BAs composition and the expression of cholesterol 7α hydroxylase (CYP7A1), bile acid: CoA synthase (BACS) and bile acid-CoA: amino acid N-acyltransferase (BAAT) at both transcriptional and protein levels in the liver were evaluated at 12 weeks postoperatively. Compared with sham group, DJB and SG both achieved rapid and sustained improvements in glucose tolerance and insulin sensitivity. They also resulted in increased serum BAs, especially the taurine-conjugated BAs by elevated conjugation. No obvious difference was detected between DJB and SG except that SG achieved decreased weight gain and food intake. The preferentially elevated serum taurine-conjugated BAs were similar after different bariatric surgeries, and the enhanced conjugation of BAs in the liver might account for the changed serum BAs profiles.

  12. Bile acids induce arrhythmias in human atrial myocardium--implications for altered serum bile acid composition in patients with atrial fibrillation.

    Science.gov (United States)

    Rainer, Peter P; Primessnig, Uwe; Harenkamp, Sandra; Doleschal, Bernhard; Wallner, Markus; Fauler, Guenter; Stojakovic, Tatjana; Wachter, Rolf; Yates, Ameli; Groschner, Klaus; Trauner, Michael; Pieske, Burkert M; von Lewinski, Dirk

    2013-11-01

    High bile acid serum concentrations have been implicated in cardiac disease, particularly in arrhythmias. Most data originate from in vitro studies and animal models. We tested the hypotheses that (1) high bile acid concentrations are arrhythmogenic in adult human myocardium, (2) serum bile acid concentrations and composition are altered in patients with atrial fibrillation (AF) and (3) the therapeutically used ursodeoxycholic acid has different effects than other potentially toxic bile acids. Multicellular human atrial preparations ('trabeculae') were exposed to primary bile acids and the incidence of arrhythmic events was assessed. Bile acid concentrations were measured in serum samples from 250 patients and their association with AF and ECG parameters analysed. Additionally, we conducted electrophysiological studies in murine myocytes. Taurocholic acid (TCA) concentration-dependently induced arrhythmias in atrial trabeculae (14/28 at 300 µM TCA, pursodeoxycholic acid did not. Patients with AF had significantly decreased serum levels of ursodeoxycholic acid conjugates and increased levels of non-ursodeoxycholic bile acids. In isolated myocytes, TCA depolarised the resting membrane potential, enhanced Na(+)/Ca(2+) exchanger (NCX) tail current density and induced afterdepolarisations. Inhibition of NCX prevented arrhythmias in atrial trabeculae. High TCA concentrations induce arrhythmias in adult human atria while ursodeoxycholic acid does not. AF is associated with higher serum levels of non-ursodeoxycholic bile acid conjugates and low levels of ursodeoxycholic acid conjugates. These data suggest that higher levels of toxic (arrhythmogenic) and low levels of protective bile acids create a milieu with a decreased arrhythmic threshold and thus may facilitate arrhythmic events.

  13. Identification of quinone imine containing glutathione conjugates of diclofenac in rat bile.

    Science.gov (United States)

    Waldon, Daniel J; Teffera, Yohannes; Colletti, Adria E; Liu, Jingzhou; Zurcher, Danielle; Copeland, Katrina W; Zhao, Zhiyang

    2010-12-20

    High-resolution accurate MS with an LTQ-Orbitrap was used to identify quinone imine metabolites derived from the 5-hydroxy (5-OH) and 4 prime-hydroxy (4'-OH) glutathione conjugates of diclofenac in rat bile. The initial quinone imine metabolites formed by oxidation of diclofenac have been postulated to be reactive intermediates potentially involved in diclofenac-mediated hepatotoxicity; while these metabolites could be formed using in vitro systems, they have never been detected in vivo. This report describes the identification of secondary quinone imine metabolites derived from 5-OH and 4'-OH diclofenac glutathione conjugates in rat bile. To verify the proposed structures, the diclofenac quinone imine GSH conjugate standards were prepared synthetically and enzymatically. The novel metabolite peaks displayed the identical retention times, accurate mass MS/MS spectra, and the fragmentation patterns as the corresponding authentic standards. The formation of these secondary quinone metabolites occurs only under conditions where bile salt homeostasis was experimentally altered. Standard practice in biliary excretion experiments using bile duct-cannulated rats includes infusion of taurocholic acid and/or other bile acids to replace those lost due to continuous collection of bile; for this experiment, the rats received no replacement bile acid infusion. High-resolution accurate mass spectrometry data and comparison with chemically and enzymatically prepared quinone imines of diclofenac glutathione conjugates support the identification of these metabolites. A mechanism for the formation of these reactive quinone imine containing glutathione conjugates of diclofenac is proposed.

  14. Ultrastructural changes in the isolated rat kidney induced by conjugated bilirubin and bile acids.

    Science.gov (United States)

    Gollan, J L; Billing, B H; Huang, S N

    1976-10-01

    The effects of bilirubin and bile acids on the ultrastructure of proximal renal tubules have been studied using an isolated rat kidney preparation, perfused with a protein-free dextran medium. Control kidneys perfused for 1 h had a normal glomerular filtration rate and effective renal plasma flow; the ultrastructure of proximal tubular cells was well preserved, with normal mitochondria, nuclear and plasma membranes, and microvilli of the brush border. When conjugated bilirubin, prepared from human hepatic bile, was added to the perfusion medium (5-0-7-5 mg/100 ml), marked alterations were observed in some cells, particularly with regard to the mitochondria and plasma membranes. These changes were greatly diminished by the inclusion of bovine albumin in the medium, indicating that the unbound fraction was primarily responsible for the tubular damage. The addition of taurocholate (450 muM), taurochenodeoxycholate (550 muM) or taurolithocholate (250 muM, bound to albumin) also produced plasma membrane changes, but only slight abnormalities were seen in the mitochondria and other structures. These ultrastructural observations support the concept that the elevated plasma levels of conjugated bilirubin and to a lesser extent bile acids are related to the renal failure associated with obstructive jaundice.

  15. Biliary Bile Acids in Primary Biliary Cirrhosis: Effect of Ursodeoxycholic Acid

    Science.gov (United States)

    Combes, Burton; Carithers, Robert L.; Maddrey, Willis C.; Munoz, Santiago; Garcia-Tsao, Guadalupe; Bonner, Gregory F.; Boyer, James L.; Luketic, Velimir A.; Shiffman, Mitchell L.; Peters, Marion G.; White, Heather; Zetterman, Rowen K.; Risser, Richard; Rossi, Stephen S.; Hofmann, Alan F.

    2014-01-01

    Bile acid composition in fasting duodenal bile was assessed at entry and at 2 years in patients with primary biliary cirrhosis (PBC) enrolled in a randomized, double-blind, placebo-controlled trial of ursodeoxycholic acid (UDCA) (10–12 mg/kg/d) taken as a single bedtime dose. Specimens were analyzed by a high-pressure liquid chromatography method that had been validated against gas chromatography. Percent composition in bile (mean ± SD) for 98 patients at entry for cholic (CA), chenodeoxycholic (CDCA), deoxycholic (DCA), lithocholic (LCA), and ursodeoxycholic (UDCA) acids, respectively, were 57.4 ± 18.6, 31.5 ± 15.5, 8.0 ± 9.3, 0.3 ± 1.0, and 0.6 ± 0.9. Values for CA were increased, whereas those for CDCA, DCA, LCA, and UDCA were decreased when compared with values in normal persons. Bile acid composition of the major bile acids did not change after 2 years on placebo medication. By contrast, in patients receiving UDCA for 2 years, bile became enriched with UDCA on average to 40.1%, and significant decreases were noted for CA (to 32.2%) and CDCA (to 19.5%). No change in percent composition was observed for DCA and LCA. Percent composition at entry and changes in composition after 2 years on UDCA were similar in patients with varying severity of PBC. In patients whose bile was not enriched in UDCA (entry and placebo-treated specimens), CA, CDCA, DCA, and the small amount of UDCA found in some of these specimens were conjugated to a greater extent with glycine (52%–64%) than with taurine (36%–48%). Treatment with UDCA caused the proportion of all endogenous bile acids conjugated with glycine to increase to 69% to 78%, while the proportion conjugated with taurine (22%–31%) fell (P < .05). Administered UDCA was also conjugated predominantly with glycine (87%). PMID:10347103

  16. In Vitro Antibacterial Activity of Unconjugated and Conjugated Bile Salts on Staphylococcus aureus

    Directory of Open Access Journals (Sweden)

    Thippeswamy H. Sannasiddappa

    2017-08-01

    Full Text Available Bile salts are potent antimicrobial agents and are an important component of innate defenses in the intestine, giving protection against invasive organisms. They play an important role in determining microbial ecology of the intestine and alterations in their levels can lead to increased colonization by pathogens. We have previously demonstrated survival of the opportunistic pathogen Staphylococcus aureus in the human colonic model. Thus investigating the interaction between S. aureus and bile salts is an important factor in understanding its ability to colonize in the host intestine. Harnessing bile salts may also give a new avenue to explore in the development of therapeutic strategies to control drug resistant bacteria. Despite this importance, the antibacterial activity of bile salts on S. aureus is poorly understood. In this study, we investigated the antibacterial effects of the major unconjugated and conjugated bile salts on S. aureus. Several concentration-dependent antibacterial mechanisms were found. Unconjugated bile salts at their minimum inhibitory concentration (cholic and deoxycholic acid at 20 and 1 mM, respectively killed S. aureus, and this was associated with increased membrane disruption and leakage of cellular contents. Unconjugated bile salts (cholic and deoxycholic acid at 8 and 0.4 mM, respectively and conjugated bile salts (glycocholic and taurocholic acid at 20 mM at their sub inhibitory concentrations were still able to inhibit growth through disruption of the proton motive force and increased membrane permeability. We also demonstrated that unconjugated bile salts possess more potent antibacterial action on S. aureus than conjugated bile salts.

  17. Effect of ursodeoxycholic acid on bile acid profiles and intestinal detoxification machinery in primary biliary cirrhosis and health.

    Science.gov (United States)

    Dilger, Karin; Hohenester, Simon; Winkler-Budenhofer, Ursula; Bastiaansen, Barbara A J; Schaap, Frank G; Rust, Christian; Beuers, Ulrich

    2012-07-01

    Ursodeoxycholic acid (UDCA) exerts anticholestatic, antifibrotic and antiproliferative effects in primary biliary cirrhosis (PBC) via mechanisms not yet fully understood. Its adequate biliary enrichment is considered mandatory for therapeutic efficacy. However, precise determination of biliary enrichment of UDCA is not possible in clinical practice. Therefore, we investigated (i) the relationship between biliary enrichment and plasma pharmacokinetics of UDCA, (ii) the effect of UDCA on plasma and biliary bile acid composition and conjugation patterns, and (iii) on the intestinal detoxification machinery in patients with PBC and healthy controls. In 11 PBC patients and 11 matched healthy subjects, cystic bile and duodenal tissue were collected before and after 3 weeks of administration of UDCA (15 mg/kg/day). Extensive pharmacokinetic profiling of bile acids was performed. The effect of UDCA on the intestinal detoxification machinery was studied by quantitative PCR and Western blotting. The relative fraction of UDCA and its conjugates in plasma at trough level[x] correlated with their biliary enrichment[y] (r=0.73, p=0.0001, y=3.65+0.49x). Taurine conjugates of the major hydrophobic bile acid, chenodeoxycholic acid, were more prominent in bile of PBC patients than in that of healthy controls. Biliary bile acid conjugation patterns normalized after treatment with UDCA. UDCA induced duodenal expression of key export pumps, BCRP and P-glycoprotein. Biliary and trough plasma enrichment of UDCA are closely correlated in PBC and health. Taurine conjugation may represent an adaptive mechanism in PBC against chenodeoxycholic acid-mediated bile duct damage. UDCA may stabilize small intestinal detoxification by upregulation of efflux pumps. Copyright © 2012. Published by Elsevier B.V.

  18. 125I radioimmunoassay for primary conjugated bile salts

    International Nuclear Information System (INIS)

    Spenney, J.G.; Johnson, B.J.; Hirschowitz, B.I.; Mihas, A.A.; Gibson, R.

    1977-01-01

    Cholylglycylhistamine, a derivative of cholic acid, has been synthesized and characterized. This derivative has been iodinated using Na125I and chloramine-T and purified free from unlabeled cholylglycylhistamine. Application of this iodinated bile salt derivative to radioimmunoassay of bile salts in human serum is reported. Antibody titers have uniformly increased over titers used in tritium-based assays; some antibodies are usable in dilutions of 1 : 80,000. The radioimmunoassay described here was found to measure predominantly the primary conjugated bile salts. Sensitivity has been maintained, with the least detectable amount being 0.5 pmoles per assay tube. Normal values in human serum are 3.47 +- 2.16 (SD) nmoles per ml

  19. Bile salt tolerance of Lactococcus lactis is enhanced by expression of bile salt hydrolase thereby producing less bile acid in the cells.

    Science.gov (United States)

    Bi, Jie; Liu, Song; Du, Guocheng; Chen, Jian

    2016-04-01

    Changes of bile salt tolerance, morphology and amount of bile acid within cells were studied to evaluate the exact effects of bile salt hydrolase (BSH) on bile salt tolerance of microorganism. The effect of BSHs on the bile salt tolerance of Lactococcus lactis was examined by expressing two BSHs (BSH1 and BSH2). Growth of L. lactis expressing BSH1 or BSH2 was better under bile salt stress compared to wild-type L. lactis. As indicated by transmission electron microscopy, bile acids released by the action of BSH induced the formation of micelles around the membrane surface of cells subject to conjugated bile salt stress. A similar micelle containing bile acid was observed in the cytoplasm by liquid chromatography-mass spectrometry. BSH1 produced fewer bile acid micelles in the cytoplasm and achieved better cell growth of L. lactis compared to BSH2. Expression of BSH improved bile salt tolerance of L. lactis but excessive production by BSH of bile acid micelles in the cytoplasm inhibited cell growth.

  20. Novel, major 2α- and 2β-hydroxy bile alcohols and bile acids in the bile of Arapaima gigas, a large South American river fish.

    Science.gov (United States)

    Sato née Okihara, Rika; Saito, Tetsuya; Ogata, Hiroaki; Nakane, Naoya; Namegawa, Kazunari; Sekiguchi, Shoutaro; Omura, Kaoru; Kurabuchi, Satoshi; Mitamura, Kuniko; Ikegawa, Shigeo; Raines, Jan; Hagey, Lee R; Hofmann, Alan F; Iida, Takashi

    2016-03-01

    Bile alcohols and bile acids from gallbladder bile of the Arapaima gigas, a large South American freshwater fish, were isolated by reversed-phase high-performance liquid chromatography. The structures of the major isolated compounds were determined by electrospray-tandem mass spectrometry and nuclear magnetic resonance using (1)H- and (13)C-NMR spectra. The novel bile salts identified were six variants of 2-hydroxy bile acids and bile alcohols in the 5α- and 5β-series, with 29% of all compounds having hydroxylation at C-2. Three C27 bile alcohols were present (as ester sulfates): (24ξ,25ξ)-5α-cholestan-2α,3α,7α,12α,24,26-hexol; (25ξ)-5β-cholestan-2β,3α,7α,12α,26,27-hexol, and (25ξ)-5α-cholestan-2α,3α,7α,12α,26,27-hexol. A single C27 bile acid was identified: (25ξ)-2α,3α,7α,12α-tetrahydroxy-5α-cholestan-26-oic acid, present as its taurine conjugate. Two novel C24 bile acids were identified: the 2α-hydroxy derivative of allochenodeoxycholic acid and the 2β-hydroxy derivative of cholic acid, both occurring as taurine conjugates. These studies extend previous work in establishing the natural occurrence of novel 2α- and 2β-hydroxy-C24 and C27 bile acids as well as C27 bile alcohols in both the normal (5β) as well as the (5α) "allo" A/B-ring juncture. The bile salt profile of A. gigas appears to be unique among vertebrates. Copyright © 2016. Published by Elsevier Inc.

  1. Taurine ameliorates cholesterol metabolism by stimulating bile acid production in high-cholesterol-fed rats.

    Science.gov (United States)

    Murakami, Shigeru; Fujita, Michiko; Nakamura, Masakazu; Sakono, Masanobu; Nishizono, Shoko; Sato, Masao; Imaizumi, Katsumi; Mori, Mari; Fukuda, Nobuhiro

    2016-03-01

    This study was designed to investigate the effects of dietary taurine on cholesterol metabolism in high-cholesterol-fed rats. Male Sprague-Dawley rats were randomly divided into two dietary groups (n = 6 in each group): a high-cholesterol diet containing 0.5% cholesterol and 0.15% sodium cholate, and a high-cholesterol diet with 5% (w/w) taurine. The experimental diets were given for 2 weeks. Taurine supplementation reduced the serum and hepatic cholesterol levels by 37% and 32%, respectively. Faecal excretion of bile acids was significantly increased in taurine-treated rats, compared with untreated rats. Biliary bile acid concentrations were also increased by taurine. Taurine supplementation increased taurine-conjugated bile acids by 61% and decreased glycine-conjugated bile acids by 53%, resulting in a significant decrease in the glycine/taurine (G/T) ratio. Among the taurine-conjugated bile acids, cholic acid and deoxycholic acid were significantly increased. In the liver, taurine supplementation increased the mRNA expression and enzymatic activity of hepatic cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting enzyme for bile acid synthesis, by three- and two-fold, respectively. Taurine also decreased the enzymatic activity of acyl-CoA:cholesterol acyltransferase (ACAT) and microsomal triglyceride transfer protein (MTP). These observations suggest that taurine supplementation increases the synthesis and excretion of taurine-conjugated bile acids and stimulates the catabolism of cholesterol to bile acid by elevating the expression and activity of CYP7A1. This may reduce cholesterol esterification and lipoprotein assembly for very low density lipoprotein (VLDL) secretion, leading to reductions in the serum and hepatic cholesterol levels. © 2016 John Wiley & Sons Australia, Ltd.

  2. Hepatobiliary transport kinetics of the conjugated bile acid tracer 11C-CSar quantified in healthy humans and patients by positron emission tomography.

    Science.gov (United States)

    Ørntoft, Nikolaj Worm; Munk, Ole Lajord; Frisch, Kim; Ott, Peter; Keiding, Susanne; Sørensen, Michael

    2017-08-01

    Hepatobiliary secretion of bile acids is an important liver function. Here, we quantified the hepatic transport kinetics of conjugated bile acids using the bile acid tracer [N-methyl- 11 C]cholylsarcosine ( 11 C-CSar) and positron emission tomography (PET). Nine healthy participants and eight patients with varying degrees of cholestasis were examined with 11 C-CSar PET and measurement of arterial and hepatic venous blood concentrations of 11 C-CSar. Results are presented as median (range). The hepatic intrinsic clearance was 1.50 (1.20-1.76) ml blood/min/ml liver tissue in healthy participants and 0.46 (0.13-0.91) in patients. In healthy participants, the rate constant for secretion of 11 C-CSar from hepatocytes to bile was 0.36 (0.30-0.62)min -1 , 20 times higher than the rate constant for backflux from hepatocytes to blood (0.02, 0.005-0.07min -1 ). In the patients, rate constant for transport from hepatocyte to bile was reduced to 0.12 (0.006-0.27)min -1 , 2.3times higher than the rate constant for backflux to blood (0.05, 0.04-0.09). The increased backflux did not fully normalize exposure of the hepatocyte to bile acids as mean hepatocyte residence time of 11 C-CSar was 2.5 (1.6-3.1)min in healthy participants and 6.4 (3.1-23.7)min in patients. The rate constant for transport of 11 C-CSar from intrahepatic to extrahepatic bile was 0.057 (0.023-0.11)min -1 in healthy participants and only slightly reduced in patients 0.039 (0.017-0.066). This first in vivo quantification of individual steps involved in the hepatobiliary secretion of a conjugated bile acid in humans provided new insight into cholestatic disease. Positron emission tomography (PET) using the radiolabelled bile acid ( 11 C-CSar) enabled quantification of the individual steps of the hepatic transport of bile acids from blood to bile in man. Cholestasis reduced uptake and secretion and increased backflux to blood. These findings improve our understanding of cholestatic liver diseases and may support

  3. Synthesis, Spectroscopic and Theoretical Studies of New Quaternary N,N-Dimethyl-3-phthalimidopropylammonium Conjugates of Sterols and Bile Acids

    Directory of Open Access Journals (Sweden)

    Bogumil Brycki

    2014-04-01

    Full Text Available New quaternary 3-phthalimidopropylammonium conjugates of steroids were obtained by reaction of sterols (ergosterol, cholesterol, cholestanol and bile acids (lithocholic, deoxycholic, cholic with bromoacetic acid bromide to give sterol 3β-bromoacetates and bile acid 3α-bromoacetates, respectively. These intermediates were subjected to nuclephilic substitution with N,N-dimethyl-3-phthalimidopropylamine to give the final quaternary ammonium salts. The structures of products were confirmed by spectral (1H-NMR, 13C-NMR, and FT-IR analysis, mass spectrometry (ESI-MS, MALDI as well as PM5 semiempirical methods and B3LYP ab initio methods. Estimation of the pharmacotherapeutic potential has been accomplished for synthesized compounds on the basis of Prediction of Activity Spectra for Substances (PASS.

  4. Interaction of conjugated bile acids and detergents with a radiosorbent assay of vitamin B-12

    International Nuclear Information System (INIS)

    Andersen, K.-J.; Romslo, I.

    1977-01-01

    The effect of conjugated bile acids and detergents on the radiosorbent technique for the determination of vitamin B-12 activity is reported. It is shown that whereas the non-ionic detergent Triton X-100 has no effect on the vitamin B-12-radiosorbent assay, the addition of ionic detergents, e.g. glycocholic acid, taurocholic acid or sodium lauryl sulfate, results in a falsely-elevated vitamin B-12 activity presumably due to the disruption of the binding of vitamin B-12 to the intrinsic factor-Sephadex complex. This effect may be of importance not only to the radiosorbent assaying of vitamin B-12, but to the in vivo intestinal absorption of vitamin B-12 as well

  5. Bile acid metabolism and signaling in cholestasis, inflammation and cancer

    Science.gov (United States)

    Apte, Udayan

    2015-01-01

    Bile acids are synthesized from cholesterol in the liver. Some cytochrome P450 (CYP) enzymes play key roles in bile acid synthesis. Bile acids are physiological detergent molecules, so are highly cytotoxic. They undergo enterohepatic circulation and play important roles in generating bile flow and facilitating biliary secretion of endogenous metabolites and xenobiotics and intestinal absorption of dietary fats and lipid soluble vitamins. Bile acid synthesis, transport and pool size are therefore tightly regulated under physiological conditions. In cholestasis, impaired bile flow leads to accumulation of bile acids in the liver, causing hepatocyte and biliary injury and inflammation. Chronic cholestasis is associated with fibrosis, cirrhosis and eventually liver failure. Chronic cholestasis also increases the risk of developing hepatocellular or cholangiocellular carcinomas. Extensive research in the last two decades has shown that bile acids act as signaling molecules that regulate various cellular processes. The bile acid-activated nuclear receptors are ligand-activated transcriptional factors that play critical roles in the regulation of bile acid, drug and xenobiotic metabolism. In cholestasis, these bile acid-activated receptors regulate a network of genes involved in bile acid synthesis, conjugation, transport and metabolism to alleviate bile acid-induced inflammation and injury. Additionally, bile acids are known to regulate cell growth and proliferation, and altered bile acid levels in diseased conditions have been implicated in liver injury/regeneration and tumorigenesis. We will cover the mechanisms that regulate bile acid homeostasis and detoxification during cholestasis, and the roles of bile acids in the initiation and regulation of hepatic inflammation, regeneration and carcinogenesis. PMID:26233910

  6. Individual bile acids have differential effects on bile acid signaling in mice

    International Nuclear Information System (INIS)

    Song, Peizhen; Rockwell, Cheryl E.; Cui, Julia Yue; Klaassen, Curtis D.

    2015-01-01

    Bile acids (BAs) are known to regulate BA synthesis and transport by the farnesoid X receptor in the liver (FXR-SHP) and intestine (FXR-Fgf15). However, the relative importance of individual BAs in regulating these processes is not known. Therefore, mice were fed various doses of five individual BAs, including cholic acid (CA), chenodeoxycholic acid (CDCA), deoxoycholic acid (DCA), lithocholic acid (LCA), and ursodeoxycholic acid (UDCA) in their diets at various concentrations for one week to increase the concentration of one BA in the enterohepatic circulation. The mRNA of BA synthesis and transporting genes in liver and ileum were quantified. In the liver, the mRNA of SHP, which is the prototypical target gene of FXR, increased in mice fed all concentrations of BAs. In the ileum, the mRNA of the intestinal FXR target gene Fgf15 was increased at lower doses and to a higher extent by CA and DCA than by CDCA and LCA. Cyp7a1, the rate-limiting enzyme in BA synthesis, was decreased more by CA and DCA than CDCA and LCA. Cyp8b1, the enzyme that 12-hydroxylates BAs and is thus responsible for the synthesis of CA, was decreased much more by CA and DCA than CDCA and LCA. Surprisingly, neither a decrease in the conjugated BA uptake transporter (Ntcp) nor increase in BA efflux transporter (Bsep) was observed by FXR activation, but an increase in the cholesterol efflux transporter (Abcg5/Abcg8) was observed with FXR activation. Thus in conclusion, CA and DCA are more potent FXR activators than CDCA and LCA when fed to mice, and thus they are more effective in decreasing the expression of the rate limiting gene in BA synthesis Cyp7a1 and the 12-hydroxylation of BAs Cyp8b1, and are also more effective in increasing the expression of Abcg5/Abcg8, which is responsible for biliary cholesterol excretion. However, feeding BAs do not alter the mRNA or protein levels of Ntcp or Bsep, suggesting that the uptake or efflux of BAs is not regulated by FXR at physiological and

  7. Individual bile acids have differential effects on bile acid signaling in mice

    Energy Technology Data Exchange (ETDEWEB)

    Song, Peizhen, E-mail: songacad@gmail.com; Rockwell, Cheryl E., E-mail: rockwelc@msu.edu; Cui, Julia Yue, E-mail: juliacui@uw.edu; Klaassen, Curtis D., E-mail: curtisklaassenphd@gmail.com

    2015-02-15

    Bile acids (BAs) are known to regulate BA synthesis and transport by the farnesoid X receptor in the liver (FXR-SHP) and intestine (FXR-Fgf15). However, the relative importance of individual BAs in regulating these processes is not known. Therefore, mice were fed various doses of five individual BAs, including cholic acid (CA), chenodeoxycholic acid (CDCA), deoxoycholic acid (DCA), lithocholic acid (LCA), and ursodeoxycholic acid (UDCA) in their diets at various concentrations for one week to increase the concentration of one BA in the enterohepatic circulation. The mRNA of BA synthesis and transporting genes in liver and ileum were quantified. In the liver, the mRNA of SHP, which is the prototypical target gene of FXR, increased in mice fed all concentrations of BAs. In the ileum, the mRNA of the intestinal FXR target gene Fgf15 was increased at lower doses and to a higher extent by CA and DCA than by CDCA and LCA. Cyp7a1, the rate-limiting enzyme in BA synthesis, was decreased more by CA and DCA than CDCA and LCA. Cyp8b1, the enzyme that 12-hydroxylates BAs and is thus responsible for the synthesis of CA, was decreased much more by CA and DCA than CDCA and LCA. Surprisingly, neither a decrease in the conjugated BA uptake transporter (Ntcp) nor increase in BA efflux transporter (Bsep) was observed by FXR activation, but an increase in the cholesterol efflux transporter (Abcg5/Abcg8) was observed with FXR activation. Thus in conclusion, CA and DCA are more potent FXR activators than CDCA and LCA when fed to mice, and thus they are more effective in decreasing the expression of the rate limiting gene in BA synthesis Cyp7a1 and the 12-hydroxylation of BAs Cyp8b1, and are also more effective in increasing the expression of Abcg5/Abcg8, which is responsible for biliary cholesterol excretion. However, feeding BAs do not alter the mRNA or protein levels of Ntcp or Bsep, suggesting that the uptake or efflux of BAs is not regulated by FXR at physiological and

  8. Metabolism of Oxo-Bile Acids and Characterization of Recombinant 12α-Hydroxysteroid Dehydrogenases from Bile Acid 7α-Dehydroxylating Human Gut Bacteria.

    Science.gov (United States)

    Doden, Heidi; Sallam, Lina A; Devendran, Saravanan; Ly, Lindsey; Doden, Greta; Daniel, Steven L; Alves, João M P; Ridlon, Jason M

    2018-05-15

    Bile acids are important cholesterol-derived nutrient signaling hormones, synthesized in the liver, that act as detergents to solubilize dietary lipids. Bile acid 7α-dehydroxylating gut bacteria generate the toxic bile acids deoxycholic acid and lithocholic acid from host bile acids. The ability of these bacteria to remove the 7-hydroxyl group is partially dependent on 7α-hydroxysteroid dehydrogenase (HSDH) activity, which reduces 7-oxo-bile acids generated by other gut bacteria. 3α-HSDH has an important enzymatic activity in the bile acid 7α-dehydroxylation pathway. 12α-HSDH activity has been reported for the low-activity bile acid 7α-dehydroxylating bacterium Clostridium leptum ; however, this activity has not been reported for high-activity bile acid 7α-dehydroxylating bacteria, such as Clostridium scindens , Clostridium hylemonae , and Clostridium hiranonis Here, we demonstrate that these strains express bile acid 12α-HSDH. The recombinant enzymes were characterized from each species and shown to preferentially reduce 12-oxolithocholic acid to deoxycholic acid, with low activity against 12-oxochenodeoxycholic acid and reduced activity when bile acids were conjugated to taurine or glycine. Phylogenetic analysis suggests that 12α-HSDH is widespread among Firmicutes , Actinobacteria in the Coriobacteriaceae family, and human gut Archaea IMPORTANCE 12α-HSDH activity has been established in the medically important bile acid 7α-dehydroxylating bacteria C. scindens , C. hiranonis , and C. hylemonae Experiments with recombinant 12α-HSDHs from these strains are consistent with culture-based experiments that show a robust preference for 12-oxolithocholic acid over 12-oxochenodeoxycholic acid. Phylogenetic analysis identified novel members of the gut microbiome encoding 12α-HSDH. Future reengineering of 12α-HSDH enzymes to preferentially oxidize cholic acid may provide a means to industrially produce the therapeutic bile acid ursodeoxycholic acid. In

  9. Determination of Bile Acids in Piglet Bile by Solid Phase Extraction and Liquid Chromatography-Electrospray Tandem Mass Spectrometry.

    Science.gov (United States)

    Mi, Si; Lim, David W; Turner, Justine M; Wales, Paul W; Curtis, Jonathan M

    2016-03-01

    An LC/MS/MS-based method was developed for the determination of individual bile acids (BA) and their conjugates in porcine bile samples. The C18-based solid-phase extraction (SPE) procedure was optimized so that all 19 target BA and their glycine and taurine conjugates were collected with high recoveries for standards (89.1-100.2%). Following this, all 19 compounds were separated and quantified in a single 12 min chromatographic run. The method was validated in terms of linearity, sensitivity, accuracy, precision, and recovery. An LOD in the low ppb range with measured precisions in the range of 0.5-9.3% was achieved. The recoveries for all of the 19 analytes in bile samples were all >80%. The validated method was successfully applied to the profiling of BA and their conjugates in the bile from piglets treated with exogenous glucagon-like peptide-2 (GLP-2) in a preclinical model of neonatal parenteral nutrition-associated liver disease (PNALD). The method developed is rapid and could be easily implemented for routine analysis of BA and their conjugates in other biofluids or tissues.

  10. Bile acids: regulation of apoptosis by ursodeoxycholic acid.

    Science.gov (United States)

    Amaral, Joana D; Viana, Ricardo J S; Ramalho, Rita M; Steer, Clifford J; Rodrigues, Cecília M P

    2009-09-01

    Bile acids are a group of molecular species of acidic steroids with peculiar physical-chemical and biological characteristics. At high concentrations they become toxic to mammalian cells, and their presence is pertinent in the pathogenesis of several liver diseases and colon cancer. Bile acid cytoxicity has been related to membrane damage, but also to nondetergent effects, such as oxidative stress and apoptosis. Strikingly, hydrophilic ursodeoxycholic acid (UDCA), and its taurine-conjugated form (TUDCA), show profound cytoprotective properties. Indeed, these molecules have been described as potent inhibitors of classic pathways of apoptosis, although their precise mode of action remains to be clarified. UDCA, originally used for cholesterol gallstone dissolution, is currently considered the first choice therapy for several forms of cholestatic syndromes. However, the beneficial effects of both UDCA and TUDCA have been tested in other experimental pathological conditions with deregulated levels of apoptosis, including neurological disorders, such as Alzheimer's, Parkinson's, and Huntington's diseases. Here, we review the role of bile acids in modulating the apoptosis process, emphasizing the anti-apoptotic effects of UDCA and TUDCA, as well as their potential use as novel and alternate therapeutic agents for the treatment of apoptosis-related diseases.

  11. Increased Bile Acid Synthesis and Impaired Bile Acid Transport in Human Obesity

    OpenAIRE

    Haeusler, Rebecca A.; Camastra, Stefania; Nannipieri, Monica; Astiarraga, Brenno; Castro-Perez, Jose; Xie, Dan; Wang, Liangsu; Chakravarthy, Manu; Ferrannini, Ele

    2015-01-01

    We measured plasma bile acids, markers of bile acid synthesis, and expression of bile acid transporters in obese and nonobese subjects. We found that obesity was associated with increased bile acid synthesis and 12-hydroxylation, blunted response of plasma bile acids to insulin infusion or a mixed meal, and decreased expression of liver bile acid transporters.

  12. Heart and bile acids - Clinical consequences of altered bile acid metabolism.

    Science.gov (United States)

    Vasavan, Tharni; Ferraro, Elisa; Ibrahim, Effendi; Dixon, Peter; Gorelik, Julia; Williamson, Catherine

    2018-04-01

    Cardiac dysfunction has an increased prevalence in diseases complicated by liver cirrhosis such as primary biliary cholangitis and primary sclerosing cholangitis. This observation has led to research into the association between abnormalities in bile acid metabolism and cardiac pathology. Approximately 50% of liver cirrhosis cases develop cirrhotic cardiomyopathy. Bile acids are directly implicated in this, causing QT interval prolongation, cardiac hypertrophy, cardiomyocyte apoptosis and abnormal haemodynamics of the heart. Elevated maternal serum bile acids in intrahepatic cholestasis of pregnancy, a disorder which causes an impaired feto-maternal bile acid gradient, have been associated with fatal fetal arrhythmias. The hydrophobicity of individual bile acids in the serum bile acid pool is of relevance, with relatively lipophilic bile acids having a more harmful effect on the heart. Ursodeoxycholic acid can reverse or protect against these detrimental cardiac effects of elevated bile acids. Copyright © 2018 Elsevier B.V. All rights reserved.

  13. Stimulation of apical sodium-dependent bile acid transporter expands the bile acid pool and generates bile acids with positive feedback properties.

    Science.gov (United States)

    Rudling, Mats; Bonde, Ylva

    2015-01-01

    Bile acid synthesis has been considered a prototype for how a physiological process is controlled by end product feedback inhibition. By this feedback inhibition, bile acid concentrations are kept within safe ranges. However, careful examination of published rodent data strongly suggests that bile acid synthesis is also under potent positive feedback control by hydrophilic bile acids. Current concepts on the regulation of bile acid synthesis are derived from mouse models. Recent data have shown that mice have farnesoid X receptor (FXR) antagonistic bile acids capable of quenching responses elicited by FXR agonistic bile acids. This is important to recognize to understand the regulation of bile acid synthesis in the mouse, and in particular to clarify if mouse model findings are valid also in the human situation. In addition to classic end product feedback inhibition, regulation of bile acid synthesis in the mouse largely appears also to be driven by changes in hepatic levels of murine bile acids such as α- and β-muricholic acids. This has not been previously recognized. Stimulated bile acid synthesis or induction of the apical sodium-dependent bile acid transporter in the intestine, increase the availability of chenodeoxycholic acid in the liver, thereby promoting hepatic conversion of this bile acid into muricholic acids. Recognition of these mechanisms is essential for understanding the regulation of bile acid synthesis in the mouse, and for our awareness of important species differences in the regulation of bile acid synthesis in mice and humans. 2015 S. Karger AG, Basel.

  14. Bile acid sequestrants

    DEFF Research Database (Denmark)

    Hansen, Morten; Sonne, David P; Knop, Filip K

    2014-01-01

    Bile acids are synthesized in the liver from cholesterol and have traditionally been recognized for their role in absorption of lipids and in cholesterol homeostasis. In recent years, however, bile acids have emerged as metabolic signaling molecules that are involved in the regulation of lipid...... and glucose metabolism, and possibly energy homeostasis, through activation of the bile acid receptors farnesoid X receptor (FXR) and TGR5. Bile acid sequestrants (BASs) constitute a class of drugs that bind bile acids in the intestine to form a nonabsorbable complex resulting in interruption...... of the enterohepatic circulation. This increases bile acid synthesis and consequently reduces serum low-density lipoprotein cholesterol. Also, BASs improve glycemic control in patients with type 2 diabetes. Despite a growing understanding of the impact of BASs on glucose metabolism, the mechanisms behind their glucose...

  15. Identification of a novel bile acid in swans, tree ducks, and geese: 3alpha,7alpha,15alpha-trihydroxy-5beta-cholan-24-oic acid.

    Science.gov (United States)

    Kakiyama, Genta; Iida, Takashi; Goto, Takaaki; Mano, Nariyasu; Goto, Junichi; Nambara, Toshio; Hagey, Lee R; Schteingart, Claudio D; Hofmann, Alan F

    2006-07-01

    By HPLC, a taurine-conjugated bile acid with a retention time different from that of taurocholate was found to be present in the bile of the black-necked swan, Cygnus melanocoryphus. The bile acid was isolated and its structure, established by (1)H and (13)C NMR and mass spectrometry, was that of the taurine N-acyl amidate of 3alpha,7alpha,15alpha-trihydroxy-5beta-cholan-24-oic acid. The compound was shown to have chromatographic and spectroscopic properties that were identical to those of the taurine conjugate of authentic 3alpha,7alpha,15alpha-trihydroxy-5beta-cholan-24-oic acid, previously synthesized by us from ursodeoxycholic acid. By HPLC, the taurine conjugate of 3alpha,7alpha,15alpha-trihydroxy-5beta-cholan-24-oic acid was found to be present in 6 of 6 species in the subfamily Dendrocygninae (tree ducks) and in 10 of 13 species in the subfamily Anserinae (swans and geese) but not in other subfamilies in the Anatidae family. It was also not present in species from the other two families of the order Anseriformes. 3alpha,7alpha,15alpha-Trihydroxy-5beta-cholan-24-oic acid is a new primary bile acid that is present in the biliary bile acids of swans, tree ducks, and geese and may be termed 15alpha-hydroxy-chenodeoxycholic acid.

  16. The bile acid composition of crane gallbladder bile

    Science.gov (United States)

    Serafin, J.A.

    1983-01-01

    1. The biliary bile acids of the whooping crane (Grus americana) and the Florida sandhill crane (G. canadensis pratensis) have been examined.2. Cholic acid (CA), chenodeoxycholic acid (CDOCA) and lithocholic acid were found in bile from both species of these North American cranes.3. CDOCA and CA were the primary bile acids in both species, together constituting 70% or more of the bile acids by weight.4. The primary bile acids of cranes appear to be the same as those that have been identified in other avian species.

  17. The features of bile acids exchange in rats under the influence of corvitin

    Directory of Open Access Journals (Sweden)

    T. V. Vovkun

    2017-10-01

    Full Text Available Corvitin is a soluble form of quercetin (QUE and its effects are based on the ability to inhibit the activity of 5-lipoxygenase and to block the formation of leukotrienes. Corvitin increases bloodflow in the stomach­, pancreas and liver, but its influence on the excretory liver function has not been studied. We investigated the effect of corvitin (2.5, 5, 10 mg/kg intraportally on bile formation, determined the biliary content of total, free and conjugated bile acids (BAs. Free and conjugated BAs were separated by thin layer chromatography method. It was shown that corvitin increased the content of total BAs in the bile of rats in all tested groups. At a dose of 2.5 mg/kg flavonoid did not сhange free BAs secretion, but while elevated the content of conjugated BAs. Both free and conjugated BAs secretion was increased in rats treated with corvitin at a dose of 5 mg/kg. Increasing of corvitin dose to 10 mg/kg resulted in enhanced secretion of free BAs. Consequently, inhibition of leukotrienes synthesis by corvitin is followed by modulation of total, free and conjugated BAs formation and secretion into the bile.

  18. The composition of bile acids in patients with cholelithiasis according to the data of liquid chromatography with mass spectrometric detection

    Directory of Open Access Journals (Sweden)

    V. M. Klymenko

    2017-12-01

    Full Text Available Bile acids play a leading role in the physical and colloidal properties of bile stabilization. Lack of bile acids consequences result in the formation of cholesterol stones in the gall bladder, diarrhea and steatorrhea, fat-soluble vitamins impaired absorption, and kidney stones formation (oxalates. Investigation of altered bile composition, especially the content of bile acids, in patients with gallstone disease by means of modern analytical analysis methods (liquid chromatography with mass spectrometric detection would complement the modern ideas about mechanisms of lithogenesis and aim efforts at prevention of stone formation in the gall bladder, that was the purpose of our work. Materials and methods. Bile samples were tested for bile acid content using liquid chromatography with mass spectrometry. 14 samples of bile from patients with cholelithiasis were included in the main group, and control group consisted of 7 bile samples from practically healthy persons. Results. In patients with cholelithiasis there is an increase in the content of conjugated forms of bile acids – glycolic acid in 2 times (p = 0.002, taurocholic acid in 1.57 times (p = 0.062 compared with practically healthy persons. In patients with cholelithiasis, the ratio of taurocholic to glycolic acidі content (0.95 vs. 1.27, p = 0.0179, as well as glycogenodeoxycholic to glycodeoxycholic acid (1.11 vs. 1.58, p = 0.027 is significantly less than that in practically healthy persons. In addition, one in two patients with cholelithiasis does not reveal the presence of ursodeoxycholic acid in the bile. Conclusions. The lithogenic properties of bile are primarily caused by conjugated forms of cholic acid with glycine and taurine content violation. The ratio of taurocholic to glycolic acid content in patients with cholelithiasis is significantly lower than the similar index in practically healthy persons (0.95 vs. 1.27, p = 0.0179. The ratio of glycine conjugated bile acids

  19. Bile acid analysis in human disorders of bile acid biosynthesis

    NARCIS (Netherlands)

    Vaz, Frédéric M.; Ferdinandusse, Sacha

    2017-01-01

    Bile acids facilitate the absorption of lipids in the gut, but are also needed to maintain cholesterol homeostasis, induce bile flow, excrete toxic substances and regulate energy metabolism by acting as signaling molecules. Bile acid biosynthesis is a complex process distributed across many cellular

  20. Kinetics for the synthetic bile acid 75-selenohomocholic acid-taurine in humans: comparison with [14C]taurocholate

    International Nuclear Information System (INIS)

    Jazrawi, R.P.; Ferraris, R.; Bridges, C.; Northfield, T.C.

    1988-01-01

    The apparent fractional turnover rate of the gamma-labeled bile acid analogue 75-selenohomocholic acid-taurine (75-SeHCAT) was assessed from decline in radioactivity over the gallbladder area on 4 successive days using a gamma-camera, and was compared in the same subjects with the fractional turnover rate of the corresponding natural bile acid, cholic acid-taurine, labeled with 14C ([14C]CAT) using the classical Lindstedt technique. Very similar results were obtained in 5 healthy individuals (coefficient of variation 4.8%, medians 0.35 and 0.34, respectively). By contrast, the fractional deconjugation rate assessed from zonal scanning of glycine- and taurine-conjugated bile acids on thin-layer chromatography was much less for 75-SeHCAT than for [14C]CAT (0.02 and 0.13, respectively; p less than 0.05). The fractional rate for deconjugation plus dehydroxylation was also determined by zonal scanning, and gave lower values for 75-SeHCAT than for [14C]CAT (0.02 and 0.12, respectively; p less than 0.05). There was a striking similarity between the fractional rate for deconjugation alone and that for deconjugation plus dehydroxylation for both bile acids in individual samples (r = 0.999, p less than 0.001), suggesting that these two processes might occur simultaneously and probably involve the same bacteria. We conclude that our scintiscanning technique provides an accurate, noninvasive method of measuring fractional turnover rate of a bile acid in humans, and that the finding that 75SeHCAT remains conjugated with taurine during enterohepatic recycling means that absorption should be specific for the ileal active transport site, thus rendering it an ideal substance for assessing ileal function

  1. Speed of change in biliary lipids and bile acids with chenodeoxycholic acid--is intermittent therapy feasible?

    Science.gov (United States)

    Iser, J H; Murphy, G M; Dowling, R H

    1977-01-01

    To see whehter intermittent chenodeoxycholic acid (CDCA) therapy is a potential alternative to continous treatment for gallstone dissolution, the speed of change in bile lipid composition was studied after starting and stopping CDCA therapy. In addition, the relationship between bile lipid composition and the proportions of the bile acids was examined. Bile-rich duodenal fluid was collected twice in the first week and then at approximately weekly intervals for four to six weeks, from six gallstone patients starting 13-15 mg CDCA.kg BW-1 day-1 and from another group of six patients whose treatment was stopped after gallstone dissolution. After starting treatment, the mean biliary cholesterol saturation index (based on criteria of Hegardt and Dam, 1971) decreased from 1-49 +/- SEM 0-17 to 0-92 +/- 0-13 at three weeks and 0-88 +/- 0-10 at four weeks, by which time bile lipid composition had become relatively constant. In patients whose treatment was stopped, bile reverted to its supersaturated state within one week, changing from an on-treatment mean saturation index of 0-74 +/- 0-10 to 1-15 +/- 0-15 in six to eight days after withdrawing CDCA. The proportion of conjugated CDCA in the biliary bile acids increased from 27-9 +/- 2-5% to 60-5 +/- 4-2% within four days and to 80-7 +/- 6-2% by four weeks after starting CDCA. When treatment was stopped, the proportion of CDCA reverted to pretreatment levels by two to three weeks. The saturation index was significantly related (P less than 0-001) to the percent of conjugated CDCA present, such that when the proportion of CDCA exceeded 70%, bile was almost invariably unsaturated. Since the mean time taken for bile to become unsaturated was not shorter than the time taken for bile to revert to its supersaturated state, it seems that intermittent treatment would not be adequate to maintain an unsaturated bile and is, therefore, unlikely to be as effective as continuous treatment in dissolving gallstones. PMID:838406

  2. The reversed feto-maternal bile acid gradient in intrahepatic cholestasis of pregnancy is corrected by ursodeoxycholic acid.

    Directory of Open Access Journals (Sweden)

    Victoria Geenes

    Full Text Available Intrahepatic cholestasis of pregnancy (ICP is a pregnancy-specific liver disorder associated with an increased risk of adverse fetal outcomes. It is characterised by raised maternal serum bile acids, which are believed to cause the adverse outcomes. ICP is commonly treated with ursodeoxycholic acid (UDCA. This study aimed to determine the fetal and maternal bile acid profiles in normal and ICP pregnancies, and to examine the effect of UDCA treatment. Matched maternal and umbilical cord serum samples were collected from untreated ICP (n = 18, UDCA-treated ICP (n = 46 and uncomplicated pregnancy (n = 15 cases at the time of delivery. Nineteen individual bile acids were measured using HPLC-MS/MS. Maternal and fetal serum bile acids are significantly raised in ICP compared with normal pregnancy (p = <0.0001 and <0.05, respectively, predominantly due to increased levels of conjugated cholic and chenodeoxycholic acid. There are no differences between the umbilical cord artery and cord vein levels of the major bile acid species. The feto-maternal gradient of bile acids is reversed in ICP. Treatment with UDCA significantly reduces serum bile acids in the maternal compartment (p = <0.0001, thereby reducing the feto-maternal transplacental gradient. UDCA-treatment does not cause a clinically important increase in lithocholic acid (LCA concentrations. ICP is associated with significant quantitative and qualitative changes in the maternal and fetal bile acid pools. Treatment with UDCA reduces the level of bile acids in both compartments and reverses the qualitative changes. We have not found evidence to support the suggestion that UDCA treatment increases fetal LCA concentrations to deleterious levels.

  3. Bile Acid Metabolism in Liver Pathobiology

    Science.gov (United States)

    Chiang, John Y. L.; Ferrell, Jessica M.

    2018-01-01

    Bile acids facilitate intestinal nutrient absorption and biliary cholesterol secretion to maintain bile acid homeostasis, which is essential for protecting liver and other tissues and cells from cholesterol and bile acid toxicity. Bile acid metabolism is tightly regulated by bile acid synthesis in the liver and bile acid biotransformation in the intestine. Bile acids are endogenous ligands that activate a complex network of nuclear receptor farnesoid X receptor and membrane G protein-coupled bile acid receptor-1 to regulate hepatic lipid and glucose metabolic homeostasis and energy metabolism. The gut-to-liver axis plays a critical role in the regulation of enterohepatic circulation of bile acids, bile acid pool size, and bile acid composition. Bile acids control gut bacteria overgrowth, and gut bacteria metabolize bile acids to regulate host metabolism. Alteration of bile acid metabolism by high-fat diets, sleep disruption, alcohol, and drugs reshapes gut microbiome and causes dysbiosis, obesity, and metabolic disorders. Gender differences in bile acid metabolism, FXR signaling, and gut microbiota have been linked to higher prevalence of fatty liver disease and hepatocellular carcinoma in males. Alteration of bile acid homeostasis contributes to cholestatic liver diseases, inflammatory diseases in the digestive system, obesity, and diabetes. Bile acid-activated receptors are potential therapeutic targets for developing drugs to treat metabolic disorders. PMID:29325602

  4. Bile Acid Metabolism and Signaling

    Science.gov (United States)

    Chiang, John Y. L.

    2015-01-01

    Bile acids are important physiological agents for intestinal nutrient absorption and biliary secretion of lipids, toxic metabolites, and xenobiotics. Bile acids also are signaling molecules and metabolic regulators that activate nuclear receptors and G protein-coupled receptor (GPCR) signaling to regulate hepatic lipid, glucose, and energy homeostasis and maintain metabolic homeostasis. Conversion of cholesterol to bile acids is critical for maintaining cholesterol homeostasis and preventing accumulation of cholesterol, triglycerides, and toxic metabolites, and injury in the liver and other organs. Enterohepatic circulation of bile acids from the liver to intestine and back to the liver plays a central role in nutrient absorption and distribution, and metabolic regulation and homeostasis. This physiological process is regulated by a complex membrane transport system in the liver and intestine regulated by nuclear receptors. Toxic bile acids may cause inflammation, apoptosis, and cell death. On the other hand, bile acid-activated nuclear and GPCR signaling protects against inflammation in liver, intestine, and macrophages. Disorders in bile acid metabolism cause cholestatic liver diseases, dyslipidemia, fatty liver diseases, cardiovascular diseases, and diabetes. Bile acids, bile acid derivatives, and bile acid sequestrants are therapeutic agents for treating chronic liver diseases, obesity, and diabetes in humans. PMID:23897684

  5. Endogenous bile acid disposition in rat and human sandwich-cultured hepatocytes

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    Marion, Tracy L., E-mail: tracylmarion@qualyst.com [Curriculum in Toxicology, UNC School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7270 (United States); Perry, Cassandra H., E-mail: cassandraperry@qualyst.com [Qualyst, Inc., Durham, NC 27713 (United States); St Claire, Robert L., E-mail: bobstclaire@qualyst.com [Qualyst, Inc., Durham, NC 27713 (United States); Brouwer, Kim L.R., E-mail: kbrouwer@unc.edu [Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, CB 7569 Kerr Hall, Chapel Hill, NC 27599-7569 (United States)

    2012-05-15

    Sandwich-cultured hepatocytes (SCH) are used commonly to investigate hepatic transport protein-mediated uptake and biliary excretion of substrates. However, little is known about the disposition of endogenous bile acids (BAs) in SCH. In this study, four endogenous conjugated BAs common to rats and humans [taurocholic acid (TCA), glycocholic acid (GCA), taurochenodeoxycholic acid (TCDCA), and glycochenodeoxycholic acid (GCDCA)], as well as two BA species specific to rodents (α- and β-tauromuricholic acid; α/β TMCA), were profiled in primary rat and human SCH. Using B-CLEAR{sup ®} technology, BAs were measured in cells + bile canaliculi, cells, and medium of SCH by LC-MS/MS. Results indicated that, just as in vivo, taurine-conjugated BA species were predominant in rat SCH, while glycine-conjugated BAs were predominant in human SCH. Total intracellular BAs remained relatively constant over days in culture in rat SCH. Total BAs in control (CTL) cells + bile, cells, and medium were approximately 3.4, 2.9, and 8.3-fold greater in human than in rat. The estimated intracellular concentrations of the measured total BAs were 64.3 ± 5.9 μM in CTL rat and 183 ± 56 μM in CTL human SCH, while medium concentrations of the total BAs measured were 1.16 ± 0.21 μM in CTL rat SCH and 9.61 ± 6.36 μM in CTL human SCH. Treatment of cells for 24 h with 10 μM troglitazone (TRO), an inhibitor of the bile salt export pump (BSEP) and the Na{sup +}-taurocholate cotransporting polypeptide (NTCP), had no significant effect on endogenous BAs measured at the end of the 24-h culture period, potentially due to compensatory mechanisms that maintain BA homeostasis. These data demonstrate that BAs in SCH are similar to in vivo, and that SCH may be a useful in vitro model to study alterations in BA disposition if species differences are taken into account. -- Highlights: ► Bile acids (BAs) were measured in rat and human sandwich-cultured hepatocytes (SCH). ► Cell and medium BA

  6. Endogenous bile acid disposition in rat and human sandwich-cultured hepatocytes

    International Nuclear Information System (INIS)

    Marion, Tracy L.; Perry, Cassandra H.; St Claire, Robert L.; Brouwer, Kim L.R.

    2012-01-01

    Sandwich-cultured hepatocytes (SCH) are used commonly to investigate hepatic transport protein-mediated uptake and biliary excretion of substrates. However, little is known about the disposition of endogenous bile acids (BAs) in SCH. In this study, four endogenous conjugated BAs common to rats and humans [taurocholic acid (TCA), glycocholic acid (GCA), taurochenodeoxycholic acid (TCDCA), and glycochenodeoxycholic acid (GCDCA)], as well as two BA species specific to rodents (α- and β-tauromuricholic acid; α/β TMCA), were profiled in primary rat and human SCH. Using B-CLEAR ® technology, BAs were measured in cells + bile canaliculi, cells, and medium of SCH by LC-MS/MS. Results indicated that, just as in vivo, taurine-conjugated BA species were predominant in rat SCH, while glycine-conjugated BAs were predominant in human SCH. Total intracellular BAs remained relatively constant over days in culture in rat SCH. Total BAs in control (CTL) cells + bile, cells, and medium were approximately 3.4, 2.9, and 8.3-fold greater in human than in rat. The estimated intracellular concentrations of the measured total BAs were 64.3 ± 5.9 μM in CTL rat and 183 ± 56 μM in CTL human SCH, while medium concentrations of the total BAs measured were 1.16 ± 0.21 μM in CTL rat SCH and 9.61 ± 6.36 μM in CTL human SCH. Treatment of cells for 24 h with 10 μM troglitazone (TRO), an inhibitor of the bile salt export pump (BSEP) and the Na + -taurocholate cotransporting polypeptide (NTCP), had no significant effect on endogenous BAs measured at the end of the 24-h culture period, potentially due to compensatory mechanisms that maintain BA homeostasis. These data demonstrate that BAs in SCH are similar to in vivo, and that SCH may be a useful in vitro model to study alterations in BA disposition if species differences are taken into account. -- Highlights: ► Bile acids (BAs) were measured in rat and human sandwich-cultured hepatocytes (SCH). ► Cell and medium BA concentrations

  7. Protective effect of bile acid derivatives in phalloidin-induced rat liver toxicity

    International Nuclear Information System (INIS)

    Herraez, Elisa; Macias, Rocio I.R.; Vazquez-Tato, Jose; Hierro, Carlos; Monte, Maria J.; Marin, Jose J.G.

    2009-01-01

    Phalloidin causes severe liver damage characterized by marked cholestasis, which is due in part to irreversible polymerization of actin filaments. Liver uptake of this toxin through the transporter OATP1B1 is inhibited by the bile acid derivative BALU-1, which does not inhibit the sodium-dependent bile acid transporter NTCP. The aim of the present study was to investigate whether BALU-1 prevents liver uptake of phalloidin without impairing endogenous bile acid handling and hence may have protective effects against the hepatotoxicity induced by this toxin. In anaesthetized rats, i.v. administration of BALU-1 increased bile flow more than taurocholic acid (TCA). Phalloidin administration decreased basal (- 60%) and TCA-stimulated bile flow (- 55%) without impairing bile acid output. Phalloidin-induced cholestasis was accompanied by liver necrosis, nephrotoxicity and haematuria. In BALU-1-treated animals, phalloidin-induced cholestasis was partially prevented. Moreover haematuria was not observed, which was consistent with histological evidences of BALU-1-prevented injury of liver and kidney tissue. HPLC-MS/MS analysis revealed that BALU-1 was secreted in bile mainly in non-conjugated form, although a small proportion ( TCA > DHCA > UDCA. In conclusion, BALU-1 is able to protect against phalloidin-induced hepatotoxicity, probably due to an inhibition of the liver uptake and an enhanced biliary secretion of this toxin.

  8. Role of the Intestinal Bile Acid Transporters in Bile Acid and Drug Disposition

    Science.gov (United States)

    Dawson, Paul A.

    2011-01-01

    Membrane transporters expressed by the hepatocyte and enterocyte play critical roles in maintaining the enterohepatic circulation of bile acids, an effective recycling and conservation mechanism that largely restricts these potentially cytotoxic detergents to the intestinal and hepatobiliary compartments. In doing so, the hepatic and enterocyte transport systems ensure a continuous supply of bile acids to be used repeatedly during the digestion of multiple meals throughout the day. Absorption of bile acids from the intestinal lumen and export into the portal circulation is mediated by a series of transporters expressed on the enterocyte apical and basolateral membranes. The ileal apical sodium-dependent bile acid cotransporter (abbreviated ASBT; gene symbol, SLC10A2) is responsible for the initial uptake of bile acids across the enterocyte brush border membrane. The bile acids are then efficiently shuttled across the cell and exported across the basolateral membrane by the heteromeric Organic Solute Transporter, OSTα-OSTβ. This chapter briefly reviews the tissue expression, physiology, genetics, pathophysiology, and transport properties of the ASBT and OSTα-OSTα. In addition, the chapter discusses the relationship between the intestinal bile acid transporters and drug metabolism, including development of ASBT inhibitors as novel hypocholesterolemic or hepatoprotective agents, prodrug targeting of the ASBT to increase oral bioavailability, and involvement of the intestinal bile acid transporters in drug absorption and drug-drug interactions. PMID:21103970

  9. Bile acid-induced necrosis in primary human hepatocytes and in patients with obstructive cholestasis

    Energy Technology Data Exchange (ETDEWEB)

    Woolbright, Benjamin L.; Dorko, Kenneth [Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Antoine, Daniel J.; Clarke, Joanna I. [MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool (United Kingdom); Gholami, Parviz [Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS (United States); Li, Feng [Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Kumer, Sean C.; Schmitt, Timothy M.; Forster, Jameson [Department of Surgery, University of Kansas Medical Center, Kansas City, KS (United States); Fan, Fang [Department of Pathology, University of Kansas Medical Center, Kansas City, KS (United States); Jenkins, Rosalind E.; Park, B. Kevin [MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool (United Kingdom); Hagenbuch, Bruno [Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Olyaee, Mojtaba [Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS (United States); Jaeschke, Hartmut, E-mail: hjaeschke@kumc.edu [Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States)

    2015-03-15

    Accumulation of bile acids is a major mediator of cholestatic liver injury. Recent studies indicate bile acid composition between humans and rodents is dramatically different, as humans have a higher percent of glycine conjugated bile acids and increased chenodeoxycholate content, which increases the hydrophobicity index of bile acids. This increase may lead to direct toxicity that kills hepatocytes, and promotes inflammation. To address this issue, this study assessed how pathophysiological concentrations of bile acids measured in cholestatic patients affected primary human hepatocytes. Individual bile acid levels were determined in serum and bile by UPLC/QTOFMS in patients with extrahepatic cholestasis with, or without, concurrent increases in serum transaminases. Bile acid levels increased in serum of patients with liver injury, while biliary levels decreased, implicating infarction of the biliary tracts. To assess bile acid-induced toxicity in man, primary human hepatocytes were treated with relevant concentrations, derived from patient data, of the model bile acid glycochenodeoxycholic acid (GCDC). Treatment with GCDC resulted in necrosis with no increase in apoptotic parameters. This was recapitulated by treatment with biliary bile acid concentrations, but not serum concentrations. Marked elevations in serum full-length cytokeratin-18, high mobility group box 1 protein (HMGB1), and acetylated HMGB1 confirmed inflammatory necrosis in injured patients; only modest elevations in caspase-cleaved cytokeratin-18 were observed. These data suggest human hepatocytes are more resistant to human-relevant bile acids than rodent hepatocytes, and die through necrosis when exposed to bile acids. These mechanisms of cholestasis in humans are fundamentally different to mechanisms observed in rodent models. - Highlights: • Cholestatic liver injury is due to cytoplasmic bile acid accumulation in hepatocytes. • Primary human hepatocytes are resistant to BA-induced injury

  10. Comparison of commercially available radioimmunoassays for the determination of bile acids in serum

    Energy Technology Data Exchange (ETDEWEB)

    Wildgrube, H.J.; Schiller, W.; Winkler, M.; Weber, J.; Campana, H.; Mauritz, G.

    1982-05-01

    Three commercially available radioimmunoassays for the determination of bile acids in serum were evaluated with respect to specificity and precision. The SLCG-radioimmunoassay (Abbott) measures only sulphated glycolithocholic acid, the CG-radioimmunoassay (Abbott) measures chiefly cholic acid conjugates, and the CBA-radioimmunoassay (Becton-Dickinson) measures all conjugated bile acids, with an over-response to taurine metabolites. With respect to cross reactions, the performances of the CG-and the CBA-radioimmunoassays differed significantly from those stated by the manufacturers, the former showing a 32% response to taurocholic acid, the latter responding only 118% to taurochenodeoxycholic acid. At physiological concentrations of albumin + globulin, the recovery of defined cholanic acids was 85-101%. Good reproducibility was shown by the CG-radioimmunoassay in the range 0.5-10.9 ..mu..mol/l, by the CBA-radioimmunoassay in the range 1.0-25.0 ..mu..mol/l, and by the SLCG-radioimmunoassay in the range 0.5-3.0 ..mu..mol/l. There were no important differences in the inter- and intra-assay precision of the three methods.

  11. Rapid analysis of bile acids in different biological matrices using LC-ESI-MS/MS for the investigation of bile acid transformation by mammalian gut bacteria.

    Science.gov (United States)

    Wegner, Katrin; Just, Sarah; Gau, Laura; Mueller, Henrike; Gérard, Philippe; Lepage, Patricia; Clavel, Thomas; Rohn, Sascha

    2017-02-01

    Bile acids are important signaling molecules that regulate cholesterol, glucose, and energy homoeostasis and have thus been implicated in the development of metabolic disorders. Their bioavailability is strongly modulated by the gut microbiota, which contributes to generation of complex individual-specific bile acid profiles. Hence, it is important to have accurate methods at hand for precise measurement of these important metabolites. Here, a rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous identification and quantitation of primary and secondary bile acids as well as their taurine and glycine conjugates was developed and validated. Applicability of the method was demonstrated for mammalian tissues, biofluids, and cell culture media. The analytical approach mainly consists of a simple and rapid liquid-liquid extraction procedure in presence of deuterium-labeled internal standards. Baseline separation of all isobaric bile acid species was achieved and a linear correlation over a broad concentration range was observed. The method showed acceptable accuracy and precision on intra-day (1.42-11.07 %) and inter-day (2.11-12.71 %) analyses and achieved good recovery rates for representative analytes (83.7-107.1 %). As a proof of concept, the analytical method was applied to mouse tissues and biofluids, but especially to samples from in vitro fermentations with gut bacteria of the family Coriobacteriaceae. The developed method revealed that the species Eggerthella lenta and Collinsella aerofaciens possess bile salt hydrolase activity, and for the first time that the species Enterorhabdus mucosicola is able to deconjugate and dehydrogenate primary bile acids in vitro.

  12. Comparison of Bile Acids and Acetaminophen Protein Adducts in Children and Adolescents with Acetaminophen Toxicity.

    Directory of Open Access Journals (Sweden)

    Laura James

    Full Text Available Metabolomics approaches have enabled the study of new mechanisms of liver injury in experimental models of drug toxicity. Disruption of bile acid homeostasis is a known mechanism of drug induced liver injury. The relationship of individual bile acids to indicators of oxidative drug metabolism (acetaminophen protein adducts and liver injury was examined in children with acetaminophen overdose, hospitalized children with low dose exposure to acetaminophen, and children with no recent exposure to acetaminophen. Nine bile acids were quantified through targeted metabolomic analysis in the serum samples of the three groups. Bile acids were compared to serum levels of acetaminophen protein adducts and alanine aminotransferase. Glycodeoxycholic acid, taurodeoxycholic acid, and glycochenodeoxycholic acid were significantly increased in children with acetaminophen overdose compared to healthy controls. Among patients with acetaminophen overdose, bile acids were higher in subjects with acetaminophen protein adduct values > 1.0 nmol/mL and modest correlations were noted for three bile acids and acetaminophen protein adducts as follows: taurodeoxycholic acid (R=0.604; p<0.001, glycodeoxycholic acid (R=0.581; p<0.001, and glycochenodeoxycholic acid (R=0.571; p<0.001. Variability in bile acids was greater among hospitalized children receiving low doses of acetaminophen than in healthy children with no recent acetaminophen exposure. Compared to bile acids, acetaminophen protein adducts more accurately discriminated among children with acetaminophen overdose, children with low dose exposure to acetaminophen, and healthy control subjects. In children with acetaminophen overdose, elevations of conjugated bile acids were associated with specific indicators of acetaminophen metabolism and non-specific indicators of liver injury.

  13. Key discoveries in bile acid chemistry and biology and their clinical applications: history of the last eight decades

    Science.gov (United States)

    Hofmann, Alan F.; Hagey, Lee R.

    2014-01-01

    During the last 80 years there have been extraordinary advances in our knowledge of the chemistry and biology of bile acids. We present here a brief history of the major achievements as we perceive them. Bernal, a physicist, determined the X-ray structure of cholesterol crystals, and his data together with the vast chemical studies of Wieland and Windaus enabled the correct structure of the steroid nucleus to be deduced. Today, C24 and C27 bile acids together with C27 bile alcohols constitute most of the bile acid “family”. Patterns of bile acid hydroxylation and conjugation are summarized. Bile acid measurement encompasses the techniques of GC, HPLC, and MS, as well as enzymatic, bioluminescent, and competitive binding methods. The enterohepatic circulation of bile acids results from vectorial transport of bile acids by the ileal enterocyte and hepatocyte; the key transporters have been cloned. Bile acids are amphipathic, self-associate in solution, and form mixed micelles with polar lipids, phosphatidylcholine in bile, and fatty acids in intestinal content during triglyceride digestion. The rise and decline of dissolution of cholesterol gallstones by the ingestion of 3,7-dihydroxy bile acids is chronicled. Scientists from throughout the world have contributed to these achievements. PMID:24838141

  14. Key discoveries in bile acid chemistry and biology and their clinical applications: history of the last eight decades.

    Science.gov (United States)

    Hofmann, Alan F; Hagey, Lee R

    2014-08-01

    During the last 80 years there have been extraordinary advances in our knowledge of the chemistry and biology of bile acids. We present here a brief history of the major achievements as we perceive them. Bernal, a physicist, determined the X-ray structure of cholesterol crystals, and his data together with the vast chemical studies of Wieland and Windaus enabled the correct structure of the steroid nucleus to be deduced. Today, C24 and C27 bile acids together with C27 bile alcohols constitute most of the bile acid "family". Patterns of bile acid hydroxylation and conjugation are summarized. Bile acid measurement encompasses the techniques of GC, HPLC, and MS, as well as enzymatic, bioluminescent, and competitive binding methods. The enterohepatic circulation of bile acids results from vectorial transport of bile acids by the ileal enterocyte and hepatocyte; the key transporters have been cloned. Bile acids are amphipathic, self-associate in solution, and form mixed micelles with polar lipids, phosphatidylcholine in bile, and fatty acids in intestinal content during triglyceride digestion. The rise and decline of dissolution of cholesterol gallstones by the ingestion of 3,7-dihydroxy bile acids is chronicled. Scientists from throughout the world have contributed to these achievements. Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.

  15. Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD.

    Science.gov (United States)

    Jiao, Na; Baker, Susan S; Chapa-Rodriguez, Adrian; Liu, Wensheng; Nugent, Colleen A; Tsompana, Maria; Mastrandrea, Lucy; Buck, Michael J; Baker, Robert D; Genco, Robert J; Zhu, Ruixin; Zhu, Lixin

    2017-08-03

    Bile acids are regulators of lipid and glucose metabolism, and modulate inflammation in the liver and other tissues. Primary bile acids such as cholic acid and chenodeoxycholic acid (CDCA) are produced in the liver, and converted into secondary bile acids such as deoxycholic acid (DCA) and lithocholic acid by gut microbiota. Here we investigated the possible roles of bile acids in non-alcoholic fatty liver disease (NAFLD) pathogenesis and the impact of the gut microbiome on bile acid signalling in NAFLD. Serum bile acid levels and fibroblast growth factor 19 (FGF19), liver gene expression profiles and gut microbiome compositions were determined in patients with NAFLD, high-fat diet-fed rats and their controls. Serum concentrations of primary and secondary bile acids were increased in patients with NAFLD. In per cent, the farnesoid X receptor (FXR) antagonistic DCA was increased, while the agonistic CDCA was decreased in NAFLD. Increased mRNA expression for cytochrome P450 7A1, Na + -taurocholate cotransporting polypeptide and paraoxonase 1, no change in mRNA expression for small heterodimer partner and bile salt export pump, and reduced serum FGF19 were evidence of impaired FXR and fibroblast growth factor receptor 4 (FGFR4)-mediated signalling in NAFLD. Taurine and glycine metabolising bacteria were increased in the gut of patients with NAFLD, reflecting increased secondary bile acid production. Similar changes in liver gene expression and the gut microbiome were observed in high-fat diet-fed rats. The serum bile acid profile, the hepatic gene expression pattern and the gut microbiome composition consistently support an elevated bile acid production in NAFLD. The increased proportion of FXR antagonistic bile acid explains, at least in part, the suppression of hepatic FXR-mediated and FGFR4-mediated signalling. Our study suggests that future NAFLD intervention may target the components of FXR signalling, including the bile acid converting gut microbiome. © Article

  16. Determination of total bile acids in serum. A comparison of a radioimmunoassay with an enzymatic-fluorimetric method

    International Nuclear Information System (INIS)

    Starkey, B.J.; Marks, V.

    1982-01-01

    A solid phase radioimmunoassay kit method for total conjugated bile acids has been compared to an enzymatic fluorimetric method for total serum bile acids. The methods were compared with respect to: precision, cross-reactivity (molar equivalence) of different bile salts, recovery of different bile salts from serum, the reference range for a healthy population, linearity, coefficient of correlation, diagnostic effectiveness, cost and ease of assay. Both assays seemed equally capable of predicting the presence or absence of liver disease. Radioimmunoassay had little advantage over the enzymatic-fluorimetric method. Its relative ease was far outweighed by its greater cost and poorer analytical performance. (Auth.)

  17. SeHCAT. A new radiopharmaceutical for evaluating ileal function and the enterohepatic circulation of bile acids

    International Nuclear Information System (INIS)

    Merrick, M.V.; Boyd, G.S.; Eastwood, M.A.; Monks, R.

    1982-01-01

    SeHCAT( 75 Se-23-selena-25-homotaurocholate) is the taurine conjugate of a synthetic trihydroxy-bile acid, containing the gamma-ray emitting radionuclide 75 Se. Studies in the laboratory, and initial clinical experience, indicate that SeHCAT is a potentially useful clinical tool. Work to date has concentrated on its ability to detect malfunction of the terminal ileum. It is however the first radiopharmaceutical which facilitates study of the complete cycle of the enterohepatic circulation of bile acids

  18. Comparative potency of obeticholic acid and natural bile acids on FXR in hepatic and intestinal in vitro cell models.

    Science.gov (United States)

    Zhang, Yuanyuan; LaCerte, Carl; Kansra, Sanjay; Jackson, Jonathan P; Brouwer, Kenneth R; Edwards, Jeffrey E

    2017-12-01

    Obeticholic acid (OCA) is a semisynthetic farnesoid X receptor (FXR) agonist, an analogue of chenodeoxycholic acid (CDCA) which is indicated for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA). OCA efficiently inhibits bile acid synthesis and promotes bile acid efflux via activating FXR-mediated mechanisms in a physiologically relevant in vitro cell system, Sandwich-cultured Transporter Certified ™ human primary hepatocytes (SCHH). The study herein evaluated the effects of UDCA alone or in combination with OCA in SCHH. UDCA (≤100 μmol/L) alone did not inhibit CYP7A1 mRNA, and thus, no reduction in the endogenous bile acid pool observed. UDCA ≤100 μmol/L concomitantly administered with 0.1 μmol/L OCA had no effect on bile acid synthesis beyond what was observed with OCA alone. Furthermore, this study evaluated human Caco-2 cells (clone C2BBe1) as in vitro intestinal models. Glycine conjugate of OCA increased mRNA levels of FXR target genes in Caco-2 cells, FGF-19, SHP, OSTα/β, and IBABP, but not ASBT, in a concentration-dependent manner, while glycine conjugate of UDCA had no effect on the expression of these genes. The results suggested that UDCA ≤100 μmol/L did not activate FXR in human primary hepatocytes or intestinal cell line Caco-2. Thus, co-administration of UDCA with OCA did not affect OCA-dependent pharmacological effects. © 2017 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.

  19. Physiological and molecular biochemical mechanisms of bile formation

    Science.gov (United States)

    Reshetnyak, Vasiliy Ivanovich

    2013-01-01

    This review considers the physiological and molecular biochemical mechanisms of bile formation. The composition of bile and structure of a bile canaliculus, biosynthesis and conjugation of bile acids, bile phospholipids, formation of bile micellar structures, and enterohepatic circulation of bile acids are described. In general, the review focuses on the molecular physiology of the transporting systems of the hepatocyte sinusoidal and apical membranes. Knowledge of physiological and biochemical basis of bile formation has implications for understanding the mechanisms of development of pathological processes, associated with diseases of the liver and biliary tract. PMID:24259965

  20. Serum Bile Acids in Repaired Tetralogy of Fallot: A Marker for Liver and Heart?

    Science.gov (United States)

    Grangl, Gernot; Zöhrer, Evelyn; Köstenberger, Martin; Jud, Alexandra; Fauler, Günter; Scharnagl, Hubert; Stojakovic, Tatjana; Marterer, Robert; Gamillscheg, Andreas; Jahnel, Jörg

    2015-01-01

    Patients with repaired tetralogy of Fallot may develop chronic right ventricular dysfunction and hepatic congestion over time. We hypothesized that bile acid metabolism is altered in repaired tetralogy of Fallot patients and therefore sought to correlate right ventricular indices with serum bile acid levels. Indexed right ventricular end diastolic volume, as assessed by cardiac magnetic-resonance imaging, was classified as 150ml/m2 (Group 3, n = 6) in 29 patients with repaired tetralogy of Fallot. Pulmonary regurgitation fraction and right ventricular ejection fraction were calculated. The serum bile acid profile, including 15 species, in these patients was determined by liquid chromatography coupled with mass spectrometry. Serum bile acid levels increased from Group 1 to Group 3 (2.5 ± 0.7; 4.1 ± 2.5; 6.0 ± 2.8 μmol/l, respectively) with significantly increased bile acid values in Group 3 compared to Group 1 (p≤0.05). In Group 3, but not in Group 1 and 2, a significant increase in glycine-conjugated bile acids was observed. Pulmonary regurgitation fraction increased (12 ± 1; 28 ± 16; 43 ± 3%, Groups 1-3, respectively) and right ventricular ejection fraction decreased (48.4 ± 6.4; 48.5 ± 6.5; 42.1 ± 5.3%, Groups 1-3, respectively) with rising indexed right ventricular end diastolic volume. These preliminary results suggest that serum bile acid levels are positively correlated with indexed right ventricular end-diastolic volume in patients with repaired tetralogy of Fallot; however, this needs to be confirmed in a larger patient cohort.

  1. Decreased hepatotoxic bile acid composition and altered synthesis in progressive human nonalcoholic fatty liver disease

    International Nuclear Information System (INIS)

    Lake, April D.; Novak, Petr; Shipkova, Petia; Aranibar, Nelly; Robertson, Donald; Reily, Michael D.; Lu, Zhenqiang; Lehman-McKeeman, Lois D.; Cherrington, Nathan J.

    2013-01-01

    Bile acids (BAs) have many physiological roles and exhibit both toxic and protective influences within the liver. Alterations in the BA profile may be the result of disease induced liver injury. Nonalcoholic fatty liver disease (NAFLD) is a prevalent form of chronic liver disease characterized by the pathophysiological progression from simple steatosis to nonalcoholic steatohepatitis (NASH). The hypothesis of this study is that the ‘classical’ (neutral) and ‘alternative’ (acidic) BA synthesis pathways are altered together with hepatic BA composition during progression of human NAFLD. This study employed the use of transcriptomic and metabolomic assays to study the hepatic toxicologic BA profile in progressive human NAFLD. Individual human liver samples diagnosed as normal, steatosis, and NASH were utilized in the assays. The transcriptomic analysis of 70 BA genes revealed an enrichment of downregulated BA metabolism and transcription factor/receptor genes in livers diagnosed as NASH. Increased mRNA expression of BAAT and CYP7B1 was observed in contrast to decreased CYP8B1 expression in NASH samples. The BA metabolomic profile of NASH livers exhibited an increase in taurine together with elevated levels of conjugated BA species, taurocholic acid (TCA) and taurodeoxycholic acid (TDCA). Conversely, cholic acid (CA) and glycodeoxycholic acid (GDCA) were decreased in NASH liver. These findings reveal a potential shift toward the alternative pathway of BA synthesis during NASH, mediated by increased mRNA and protein expression of CYP7B1. Overall, the transcriptomic changes of BA synthesis pathway enzymes together with altered hepatic BA composition signify an attempt by the liver to reduce hepatotoxicity during disease progression to NASH. - Highlights: ► Altered hepatic bile acid composition is observed in progressive NAFLD. ► Bile acid synthesis enzymes are transcriptionally altered in NASH livers. ► Increased levels of taurine and conjugated bile acids

  2. Decreased hepatotoxic bile acid composition and altered synthesis in progressive human nonalcoholic fatty liver disease

    Energy Technology Data Exchange (ETDEWEB)

    Lake, April D. [University of Arizona, Department of Pharmacology and Toxicology, Tucson, AZ 85721 (United States); Novak, Petr [Biology Centre ASCR, Institute of Plant Molecular Biology, Ceske Budejovice 37001 (Czech Republic); Shipkova, Petia; Aranibar, Nelly; Robertson, Donald; Reily, Michael D. [Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Co., Princeton, NJ 08543 (United States); Lu, Zhenqiang [The Arizona Statistical Consulting Laboratory, University of Arizona, Tucson, AZ 85721 (United States); Lehman-McKeeman, Lois D. [Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Co., Princeton, NJ 08543 (United States); Cherrington, Nathan J., E-mail: cherrington@pharmacy.arizona.edu [University of Arizona, Department of Pharmacology and Toxicology, Tucson, AZ 85721 (United States)

    2013-04-15

    Bile acids (BAs) have many physiological roles and exhibit both toxic and protective influences within the liver. Alterations in the BA profile may be the result of disease induced liver injury. Nonalcoholic fatty liver disease (NAFLD) is a prevalent form of chronic liver disease characterized by the pathophysiological progression from simple steatosis to nonalcoholic steatohepatitis (NASH). The hypothesis of this study is that the ‘classical’ (neutral) and ‘alternative’ (acidic) BA synthesis pathways are altered together with hepatic BA composition during progression of human NAFLD. This study employed the use of transcriptomic and metabolomic assays to study the hepatic toxicologic BA profile in progressive human NAFLD. Individual human liver samples diagnosed as normal, steatosis, and NASH were utilized in the assays. The transcriptomic analysis of 70 BA genes revealed an enrichment of downregulated BA metabolism and transcription factor/receptor genes in livers diagnosed as NASH. Increased mRNA expression of BAAT and CYP7B1 was observed in contrast to decreased CYP8B1 expression in NASH samples. The BA metabolomic profile of NASH livers exhibited an increase in taurine together with elevated levels of conjugated BA species, taurocholic acid (TCA) and taurodeoxycholic acid (TDCA). Conversely, cholic acid (CA) and glycodeoxycholic acid (GDCA) were decreased in NASH liver. These findings reveal a potential shift toward the alternative pathway of BA synthesis during NASH, mediated by increased mRNA and protein expression of CYP7B1. Overall, the transcriptomic changes of BA synthesis pathway enzymes together with altered hepatic BA composition signify an attempt by the liver to reduce hepatotoxicity during disease progression to NASH. - Highlights: ► Altered hepatic bile acid composition is observed in progressive NAFLD. ► Bile acid synthesis enzymes are transcriptionally altered in NASH livers. ► Increased levels of taurine and conjugated bile acids

  3. The features of bile acids exchange in rats under the influence of corvitin

    OpenAIRE

    T. V. Vovkun; P. I. Yanchuk; L. Ya. Shtanova; S. P. Veselskiy; N. B. Filimonova; A. S. Shalamay; V. G. Vedmid

    2017-01-01

    Corvitin is a soluble form of quercetin (QUE) and its effects are based on the ability to inhibit the activity of 5-lipoxygenase and to block the formation of leukotrienes. Corvitin increases bloodflow in the stomach­, pancreas and liver, but its influence on the excretory liver function has not been studied. We investigated the effect of corvitin (2.5, 5, 10 mg/kg intraportally) on bile formation, determined the biliary content of total, free and conjugated bile acids (BAs). Free and conjuga...

  4. Hormesis in Cholestatic Liver Disease; Preconditioning with Low Bile Acid Concentrations Protects against Bile Acid-Induced Toxicity.

    Directory of Open Access Journals (Sweden)

    Esther M Verhaag

    Full Text Available Cholestasis is characterized by accumulation of bile acids and inflammation, causing hepatocellular damage. Still, liver damage markers are highest in acute cholestasis and drop when this condition becomes chronic, indicating that hepatocytes adapt towards the hostile environment. This may be explained by a hormetic response in hepatocytes that limits cell death during cholestasis.To investigate the mechanisms that underlie the hormetic response that protect hepatocytes against experimental cholestatic conditions.HepG2.rNtcp cells were preconditioned (24 h with sub-apoptotic concentrations (0.1-50 μM of various bile acids, the superoxide donor menadione, TNF-α or the Farsenoid X Receptor agonist GW4064, followed by a challenge with the apoptosis-inducing bile acid glycochenodeoxycholic acid (GCDCA; 200 μM for 4 h, menadione (50 μM, 6 h or cytokine mixture (CM; 6 h. Levels of apoptotic and necrotic cell death, mRNA expression of the bile salt export pump (ABCB11 and bile acid sensors, as well as intracellular GCDCA levels were analyzed.Preconditioning with the pro-apoptotic bile acids GCDCA, taurocholic acid, or the protective bile acids (tauroursodeoxycholic acid reduced GCDCA-induced caspase-3/7 activity in HepG2.rNtcp cells. Bile acid preconditioning did not induce significant levels of necrosis in GCDCA-challenged HepG2.rNtcp cells. In contrast, preconditioning with cholic acid, menadione or TNF-α potentiated GCDCA-induced apoptosis. GCDCA preconditioning specifically reduced GCDCA-induced cell death and not CM- or menadione-induced apoptosis. The hormetic effect of GCDCA preconditioning was concentration- and time-dependent. GCDCA-, CDCA- and GW4064- preconditioning enhanced ABCB11 mRNA levels, but in contrast to the bile acids, GW4064 did not significantly reduce GCDCA-induced caspase-3/7 activity. The GCDCA challenge strongly increased intracellular levels of this bile acid, which was not lowered by GCDCA

  5. Bile Acids Trigger GLP-1 Release Predominantly by Accessing Basolaterally Located G Protein-Coupled Bile Acid Receptors

    DEFF Research Database (Denmark)

    Brighton, Cheryl A.; Rievaj, Juraj; Kuhre, Rune E.

    2015-01-01

    Bile acids are well-recognized stimuli of glucagon-like peptide-1 (GLP-1) secretion. This action has been attributed to activation of the G protein-coupled bile acid receptor GPBAR1 (TGR5), although other potential bile acid sensors include the nuclear farnesoid receptor and the apical sodium......-coupled bile acid transporter ASBT. The aim of this study was to identify pathways important for GLP-1 release and to determine whether bile acids target their receptors on GLP-1-secreting L-cells from the apical or basolateral compartment. Using transgenic mice expressing fluorescent sensors specifically in L...... to either TLCA or TDCA. We conclude that the action of bile acids on GLP-1 secretion is predominantly mediated by GPBAR1 located on the basolateral L-cell membrane, suggesting that stimulation of gut hormone secretion may include postabsorptive mechanisms....

  6. 125I Radioimmunoassay of serum ursodeoxycholyl conjugates

    International Nuclear Information System (INIS)

    Hill, A.; Ross, P.E.; Bouchier, I.A.D.

    1983-01-01

    A radioimmunoassay for serum ursodeoxycholic conjugates using an iodine-125 ligand has been developed. The bile acid was present in normal fasting serum (0.19 +- SD 0.19 μmol/l, n=24) and 2-hour post-prandial serum (0.8 +- SD 0.8 μmol/l, n=16). Gallstone patients undergoing oral ursodeoxycholic acid therapy had significantly higher post-prandial serum levels (21.5 +- SD 14.0 μmol/l, n=15) by radioimmunoassay. Gas liquid chromatography analysis indicated that in normal serum ursodeoxycholic acid was totally conjugated, whereas sera from gallstone patients contained a proportion as the free bile acid (10.2 +- SD 8.1 μmol/l, n=15). Following an oral dose of ursodeoxycholic acid, both unconjugated and conjugated forms of the bile acid appeared in the serum of healthy individuals. (Auth.)

  7. /sup 125/I Radioimmunoassay of serum ursodeoxycholyl conjugates

    Energy Technology Data Exchange (ETDEWEB)

    Hill, A.; Ross, P.E.; Bouchier, I.A.D. (Ninewells Hospital and Medical School, Dundee (UK))

    1983-02-07

    A radioimmunoassay for serum ursodeoxycholic conjugates using an iodine-125 ligand has been developed. The bile acid was present in normal fasting serum (0.19 +- SD 0.19 ..mu..mol/l, n=24) and 2-hour post-prandial serum (0.8 +- SD 0.8 ..mu..mol/l, n=16). Gallstone patients undergoing oral ursodeoxycholic acid therapy had significantly higher post-prandial serum levels (21.5 +- SD 14.0 ..mu..mol/l, n=15) by radioimmunoassay. Gas liquid chromatography analysis indicated that in normal serum ursodeoxycholic acid was totally conjugated, whereas sera from gallstone patients contained a proportion as the free bile acid (10.2 +- SD 8.1 ..mu..mol/l, n=15). Following an oral dose of ursodeoxycholic acid, both unconjugated and conjugated forms of the bile acid appeared in the serum of healthy individuals.

  8. Classical bile acids in animals, beta-phocaecholic acid in ducks.

    Science.gov (United States)

    Jirsa, M; Klinot, J; Klinotová, E; Ubik, K; Kucera, K

    1989-01-01

    1. Bile samples of different animals were analysed and the percentage content of classical bile acids was determined. 2. Herbivorous birds mostly excreted a large proportion of chenodeoxycholic acid. 3. The anteater (Myrmecophaga tridactyla) excreted deoxycholic acid most probably as a primary bile acid. 4. In the bile of ducks (Anas platyrhynchos) a large amount of (23R)3 alpha, 7 alpha, 23-trihydroxy-5 beta-cholan-24-oic acid (beta-phocaecholic acid) was found.

  9. Evaluating Hepatobiliary Transport with 18F-Labeled Bile Acids: The Effect of Radiolabel Position and Bile Acid Structure on Radiosynthesis and In Vitro and In Vivo Performance

    Directory of Open Access Journals (Sweden)

    Stef De Lombaerde

    2018-01-01

    Full Text Available Introduction. An in vivo determination of bile acid hepatobiliary transport efficiency can be of use in liver disease and preclinical drug development. Given the increased interest in bile acid Positron Emission Tomography- (PET- imaging, a further understanding of the impact of 18-fluorine substitution on bile acid handling in vitro and in vivo can be of significance. Methods. A number of bile acid analogues were conceived for nucleophilic substitution with [18F]fluoride: cholic acid analogues of which the 3-, 7-, or 12-OH function is substituted with a fluorine atom (3α-[18F]FCA; 7β-[18F]FCA; 12β-[18F]FCA; a glycocholic and chenodeoxycholic acid analogue, substituted on the 3-position (3β-[18F]FGCA and 3β-[18F]FCDCA, resp.. Uptake by the bile acid transporters NTCP and OATP1B1 was evaluated with competition assays in transfected CHO and HEK cell lines and efflux by BSEP in membrane vesicles. PET-scans with the tracers were performed in wild-type mice (n=3 per group: hepatobiliary transport was monitored and compared to a reference tracer, namely, 3β-[18F]FCA. Results. Compounds 3α-[18F]FCA, 3β-[18F]FGCA, and 3β-[18F]FCDCA were synthesized in moderate radiochemical yields (4–10% n.d.c. and high radiochemical purity (>99%; 7β-[18F]FCA and 12β-[18F]FCA could not be synthesized and included further in this study. In vitro evaluation showed that 3α-FCA, 3β-FGCA, and 3β-FCDCA all had a low micromolar Ki-value for NTCP, OATP1B1, and BSEP. In vivo, 3α-[18F]FCA, 3β-[18F]FGCA, and 3β-[18F]FCDCA displayed hepatobiliary transport with varying efficiency. A slight yet significant difference in uptake and efflux rate was noticed between the 3α-[18F]FCA and 3β-[18F]FCA epimers. Conjugation of 3β-[18F]FCA with glycine had no significant effect in vivo. Compound 3β-[18F]FCDCA showed a significantly slower hepatic uptake and efflux towards gallbladder and intestines. Conclusion. A set of 18F labeled bile acids was synthesized that are

  10. Changes in the absorption of bile acids after total colectomy in patients with an ileostomy or pouch-anal anastomosis

    International Nuclear Information System (INIS)

    Nasmyth, D.G.; Johnston, D.; Williams, N.S.; King, R.F.; Burkinshaw, L.; Brooks, K.

    1989-01-01

    Bile acid absorption was investigated using 75 Se Taurohomocholate (SeHCAT) in controls and patients who had undergone total colectomy with either conventional ileostomy or pouch-anal anastomosis for ulcerative colitis or adenomatous polyposis. Whole-body retention of SeHCAT after 168 hours was greater in the controls than the patients who had undergone colectomy (P less than .05). Retention of SeHCAT did not differ significantly between patients with an ileostomy and patients with pouch-anal anastomosis, but patients with an ileostomy and ileal resection of more than 20 cm retained less SeHCAT than patients with a pouch-anal anastomosis (P less than .01). Analysis of fecal bile acids from ileostomies and pouches showed that bacterial metabolism of primary conjugated bile acids was greater in patients with a pouch. It was concluded that bile acid absorption was not significantly impaired by construction of a pouch compared with conventional ileostomy, but bacterial metabolism of bile acids was greater in the pouches

  11. Changes in the absorption of bile acids after total colectomy in patients with an ileostomy or pouch-anal anastomosis

    Energy Technology Data Exchange (ETDEWEB)

    Nasmyth, D.G.; Johnston, D.; Williams, N.S.; King, R.F.; Burkinshaw, L.; Brooks, K.

    1989-03-01

    Bile acid absorption was investigated using /sup 75/Se Taurohomocholate (SeHCAT) in controls and patients who had undergone total colectomy with either conventional ileostomy or pouch-anal anastomosis for ulcerative colitis or adenomatous polyposis. Whole-body retention of SeHCAT after 168 hours was greater in the controls than the patients who had undergone colectomy (P less than .05). Retention of SeHCAT did not differ significantly between patients with an ileostomy and patients with pouch-anal anastomosis, but patients with an ileostomy and ileal resection of more than 20 cm retained less SeHCAT than patients with a pouch-anal anastomosis (P less than .01). Analysis of fecal bile acids from ileostomies and pouches showed that bacterial metabolism of primary conjugated bile acids was greater in patients with a pouch. It was concluded that bile acid absorption was not significantly impaired by construction of a pouch compared with conventional ileostomy, but bacterial metabolism of bile acids was greater in the pouches.

  12. Preparation of [3beta-3H] labeled bile acids and bile alcohols

    International Nuclear Information System (INIS)

    Dayal, B.; Baga, E.; Tint, G.S.; Shefer, S.; Salen, G.

    1979-01-01

    [3beta-3H]-bile acids and bile alcohols may be useful for metabolic studies in man and animals because the 3-position is invulnerable to bacterial attack. A number of tritium labeled bile acids and bile alcohols were prepared by selective oxidation of the hydroxyl group at carbon-3 followed by reduction with NaBT4. In each case, the bile acids and bile alcohols epimeric at carbon-3 were resolved by analytical and preparative thin-layer chromatography and characterized by gas liquid chromatography. The average yield was 60 to 65% and specific activities of the final products were in the range of 7.4 x 10 7 dpm/mg

  13. Bile acids in treatment of ocular disease

    OpenAIRE

    Boatright, Jeffrey H.; Nickerson, John M.; Moring, Anisha G.; Pardue, Machelle T.

    2009-01-01

    Bear bile has been included in Asian pharmacopeias for thousands of years in treatment of several diseases, ranging from sore throat to hemorrhoids. The hydrophilic bile acids tauroursodeoxycholic acid (TUDCA) and ursodeoxycholic acid (UDCA) are the major bile acids of bear bile. Both of these are available as synthetic formulations and are approved by the health administrations of several countries for treatment of cirrhosis and gallstones. This review briefly covers the use of bear bile in ...

  14. Bile Acid Signaling in Liver Metabolism and Diseases

    Directory of Open Access Journals (Sweden)

    Tiangang Li

    2012-01-01

    Full Text Available Obesity, diabetes, and metabolic syndromes are increasingly recognized as health concerns worldwide. Overnutrition and insulin resistance are the major causes of diabetic hyperglycemia and hyperlipidemia in humans. Studies in the past decade provide evidence that bile acids are not just biological detergents facilitating gut nutrient absorption, but also important metabolic regulators of glucose and lipid homeostasis. Pharmacological alteration of bile acid metabolism or bile acid signaling pathways such as using bile acid receptor agonists or bile acid binding resins may be a promising therapeutic strategy for the treatment of obesity and diabetes. On the other hand, bile acid signaling is complex, and the molecular mechanisms mediating the bile acid effects are still not completely understood. This paper will summarize recent advances in our understanding of bile acid signaling in regulation of glucose and lipid metabolism, and the potentials of developing novel therapeutic strategies that target bile acid metabolism for the treatment of metabolic disorders.

  15. Bile acids in radiation-induced diarrhea

    International Nuclear Information System (INIS)

    Arlow, F.L.; Dekovich, A.A.; Priest, R.J.; Beher, W.T.

    1987-01-01

    Radiation-induced bowel disease manifested by debilitating diarrhea is an unfortunate consequence of therapeutic irradiation for pelvic malignancies. Although the mechanism for this diarrhea is not well understood, many believe it is the result of damage to small bowel mucosa and subsequent bile acid malabsorption. Excess amounts of bile acids, especially the dihydroxy components, are known to induce water and electrolyte secretion and increase bowel motility. We have directly measured individual and total bile acids in the stool samples of 11 patients with radiation-induced diarrhea and have found bile acids elevated two to six times normal in eight of them. Our patients with diarrhea and increased bile acids in their stools had prompt improvement when given cholestyramine. They had fewer stools and returned to a more normal life-style

  16. Modulation of hepatic biotransformation and biliary excretion of bile acid by age and sinusoidal bile acid load

    International Nuclear Information System (INIS)

    Baumgartner, U.; Miyai, K.; Hardison, W.G.M.

    1987-01-01

    Pericentral hepatocytes excrete bile acids more slowly and biotransform them more than periportal cells. This may reflect adaptation to low pericentral bile acid concentration or may be intrinsic. The authors studied two models in which pericentral bile acid concentrations are high: the 72-h choledocho-caval shunt (CCS) rat and the 3- to 4-wk-old rat. Livers were perfused forward or backward to assess periportal or pericentral hepatocyte function. Taurodeoxycholate (TDC) was infused at 32 nmol x min -1 x g liver -1 , and a bolus of [ 3 H]TDC was given to assess metabolism and excretion of bile acids. In CCS livers perfused backward, pericentral cells resembled periportal cells of controls in that time to excrete 50% of administered [ 3 H]-TDC (t 50 ) was reduced by two-thirds and [ 3 H]TDC biotransformation was reduced by about half. In young livers t 50 was half that of adult livers when perfused backward. Biotransformation, however, was not reduced. Young livers biotransformed more than adult controls for any given residence time of bile acid in the liver. They conclude that the difference between pericentral and perioportal cells as regards bile acid processing is adaptive. Livers from young rats biotransform more bile acid than those from controls under similar conditions

  17. Bile Acid-Mediated Sphingosine-1-Phosphate Receptor 2 Signaling Promotes Neuroinflammation during Hepatic Encephalopathy in Mice

    Directory of Open Access Journals (Sweden)

    Matthew McMillin

    2017-07-01

    Full Text Available Hepatic encephalopathy (HE is a neuropsychiatric complication that occurs due to deteriorating hepatic function and this syndrome influences patient quality of life, clinical management strategies and survival. During acute liver failure, circulating bile acids increase due to a disruption of the enterohepatic circulation. We previously identified that bile acid-mediated signaling occurs in the brain during HE and contributes to cognitive impairment. However, the influences of bile acids and their downstream signaling pathways on HE-induced neuroinflammation have not been assessed. Conjugated bile acids, such as taurocholic acid (TCA, can activate sphingosine-1-phosphate receptor 2 (S1PR2, which has been shown to promote immune cell infiltration and inflammation in other models. The current study aimed to assess the role of bile-acid mediated S1PR2 signaling in neuroinflammation and disease progression during azoxymethane (AOM-induced HE in mice. Our findings demonstrate a temporal increase of bile acids in the cortex during AOM-induced HE and identified that cortical bile acids were elevated as an early event in this model. In order to classify the specific bile acids that were elevated during HE, a metabolic screen was performed and this assay identified that TCA was increased in the serum and cortex during AOM-induced HE. To reduce bile acid concentrations in the brain, mice were fed a diet supplemented with cholestyramine, which alleviated neuroinflammation by reducing proinflammatory cytokine expression in the cortex compared to the control diet-fed AOM-treated mice. S1PR2 was expressed primarily in neurons and TCA treatment increased chemokine ligand 2 mRNA expression in these cells. The infusion of JTE-013, a S1PR2 antagonist, into the lateral ventricle prior to AOM injection protected against neurological decline and reduced neuroinflammation compared to DMSO-infused AOM-treated mice. Together, this identifies that reducing bile acid

  18. Bile acids for viral hepatitis

    DEFF Research Database (Denmark)

    Chen, Weikeng; Liu, J; Gluud, C

    2007-01-01

    Trials have assessed bile acids for patients with viral hepatitis, but no consensus has been reached regarding their usefulness.......Trials have assessed bile acids for patients with viral hepatitis, but no consensus has been reached regarding their usefulness....

  19. Oleanolic acid alters bile acid metabolism and produces cholestatic liver injury in mice

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Jie, E-mail: JLiu@kumc.edu [University of Kansas Medical Center, Kansas City, KS 66160 (United States); Zunyi Medical College, Zunyi 563003 (China); Lu, Yuan-Fu [University of Kansas Medical Center, Kansas City, KS 66160 (United States); Zunyi Medical College, Zunyi 563003 (China); Zhang, Youcai; Wu, Kai Connie [University of Kansas Medical Center, Kansas City, KS 66160 (United States); Fan, Fang [Cytopathology, University of Kansas Medical Center, Kansas City, KS 66160 (United States); Klaassen, Curtis D. [University of Kansas Medical Center, Kansas City, KS 66160 (United States)

    2013-11-01

    Oleanolic acid (OA) is a triterpenoids that exists widely in plants. OA is effective in protecting against hepatotoxicants. Whereas a low dose of OA is hepatoprotective, higher doses and longer-term use of OA produce liver injury. This study characterized OA-induced liver injury in mice. Adult C57BL/6 mice were given OA at doses of 0, 22.5, 45, 90, and 135 mg/kg, s.c., daily for 5 days, and liver injury was observed at doses of 90 mg/kg and above, as evidenced by increases in serum activities of alanine aminotransferase and alkaline phosphatase, increases in serum total bilirubin, as well as by liver histopathology. OA-induced cholestatic liver injury was further evidenced by marked increases of both unconjugated and conjugated bile acids (BAs) in serum. Gene and protein expression analysis suggested that livers of OA-treated mice had adaptive responses to prevent BA accumulation by suppressing BA biosynthetic enzyme genes (Cyp7a1, 8b1, 27a1, and 7b1); lowering BA uptake transporters (Ntcp and Oatp1b2); and increasing a BA efflux transporter (Ostβ). OA increased the expression of Nrf2 and its target gene, Nqo1, but decreased the expression of AhR, CAR and PPARα along with their target genes, Cyp1a2, Cyp2b10 and Cyp4a10. OA had minimal effects on PXR and Cyp3a11. Taken together, the present study characterized OA-induced liver injury, which is associated with altered BA homeostasis, and alerts its toxicity potential. - Highlights: • Oleanolic acid at higher doses and long-term use may produce liver injury. • Oleanolic acid increased serum ALT, ALP, bilirubin and bile acid concentrations. • OA produced feathery degeneration, inflammation and cell death in the liver. • OA altered bile acid homeostasis, affecting bile acid synthesis and transport.

  20. Bile acids in regulation of intestinal physiology.

    LENUS (Irish Health Repository)

    Keating, Niamh

    2009-10-01

    In addition to their roles in facilitating lipid digestion and absorption, bile acids are recognized as important regulators of intestinal function. Exposure to bile acids can dramatically influence intestinal transport and barrier properties; in recent years, they have also become appreciated as important factors in regulating cell growth and survival. Indeed, few cells reside within the intestinal mucosa that are not altered to some degree by exposure to bile acids. The past decade saw great advances in the knowledge of how bile acids exert their actions at the cellular and molecular levels. In this review, we summarize the current understanding of the role of bile acids in regulation of intestinal physiology.

  1. [Analysis on replacement of traditional Chinese medicine bear bile with bile acids based on drug properties].

    Science.gov (United States)

    Yuan, Bin; Ren, Ying-Long; Ma, Li; Gu, Hao; Wang, Yun; Qiao, Yan-Jiang

    2014-02-01

    To discuss the rationality of the clinical replacement of traditional Chinese medicine (TCM) bear bile with bile acid constituents, and analyze the difference between these constituents and bear bile in drug properties. Summarizing the drug properties of bear bile by reference to medical literatures for drug properties of TCM bear bile and Science of Traditional Chinese Medicine (China Press of Traditional Chinese Medicine, 2007). Analyzing and summarizing the pharmacological effects of main bile acid constituents according to relevant literatures for studies on pharmacological effects of main bile acid constituents in CNKI database. Predicating the drug properties of these bile acid constituents by using the drug property predication model established by the study group according the pharmacological effects of main bile acid constituents in the paper, and compare the prediction results with the drug properties of bear bile. Bile acid constituents in bear bile were mostly cold in property, bitter in taste, and the combination of their drug properties could reflect the combined drug properties of bear bile. All of these bile acid constituents in bear bile could show part of effects of bear bile. Attention shall be given to regulate the medication scheme in clinical application according to actual conditions.

  2. Intestinal transport and metabolism of bile acids

    Science.gov (United States)

    Dawson, Paul A.; Karpen, Saul J.

    2015-01-01

    In addition to their classical roles as detergents to aid in the process of digestion, bile acids have been identified as important signaling molecules that function through various nuclear and G protein-coupled receptors to regulate a myriad of cellular and molecular functions across both metabolic and nonmetabolic pathways. Signaling via these pathways will vary depending on the tissue and the concentration and chemical structure of the bile acid species. Important determinants of the size and composition of the bile acid pool are their efficient enterohepatic recirculation, their host and microbial metabolism, and the homeostatic feedback mechanisms connecting hepatocytes, enterocytes, and the luminal microbiota. This review focuses on the mammalian intestine, discussing the physiology of bile acid transport, the metabolism of bile acids in the gut, and new developments in our understanding of how intestinal metabolism, particularly by the gut microbiota, affects bile acid signaling. PMID:25210150

  3. The influence of bile acids homeostasis by cryptotanshinone ...

    African Journals Online (AJOL)

    The homeostasis of bile acids can be tightly regulated through feed-back and feed-forward regula- tion pathways. Bile acids exert their toxicity towards cells at high concentrations, and the accumulation of bile acids can induce the severe damage towards liver cells 2. Bile acids have been reported to induce cell injury.

  4. Increased serum bile acid concentration following low-dose chronic administration of thioacetamide in rats, as evidenced by metabolomic analysis

    Energy Technology Data Exchange (ETDEWEB)

    Jeong, Eun Sook; Kim, Gabin; Shin, Ho Jung [Department of Pharmacology and Pharmacogenomics Research Center, Inje University, College of Medicine, Bokjiro 75, Busanjin-Gu, Busan 614-735 (Korea, Republic of); Park, Se-Myo; Oh, Jung-Hwa; Kim, Yong-Bum; Moon, Kyoung-Sik [Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon 305-343 (Korea, Republic of); Choi, Hyung-Kyoon [College of Pharmacy, Chung-Ang University, Seoul (Korea, Republic of); Jeong, Jayoung [Ministry of Food and Drug Safety, Osong-eup, Heungdeok-gu, Cheongju-si, Chungcheongbuk-do 361-951 (Korea, Republic of); Shin, Jae-Gook [Department of Pharmacology and Pharmacogenomics Research Center, Inje University, College of Medicine, Bokjiro 75, Busanjin-Gu, Busan 614-735 (Korea, Republic of); Kim, Dong Hyun, E-mail: dhkim@inje.ac.kr [Department of Pharmacology and Pharmacogenomics Research Center, Inje University, College of Medicine, Bokjiro 75, Busanjin-Gu, Busan 614-735 (Korea, Republic of)

    2015-10-15

    A liquid chromatography/time-of-flight mass spectrometry (LC/TOF-MS)-based metabolomics approach was employed to identify endogenous metabolites as potential biomarkers for thioacetamide (TAA)-induced liver injury. TAA (10 and 30 mg/kg), a well-known hepatotoxic agent, was administered daily to male Sprague–Dawley (SD) rats for 28 days. We then conducted untargeted analyses of endogenous serum and liver metabolites. Partial least squares discriminant analysis (PLS-DA) was performed on serum and liver samples to evaluate metabolites associated with TAA-induced perturbation. TAA administration resulted in altered levels of bile acids, acyl carnitines, and phospholipids in serum and in the liver. We subsequently demonstrated and confirmed the occurrence of compromised bile acid homeostasis. TAA treatment significantly increased serum levels of conjugated bile acids in a dose-dependent manner, which correlated well with toxicity. However, hepatic levels of these metabolites were not substantially changed. Gene expression profiling showed that the hepatic mRNA levels of Ntcp, Bsep, and Oatp1b2 were significantly suppressed, whereas those of basolateral Mrp3 and Mrp4 were increased. Decreased levels of Ntcp, Oatp1b2, and Ostα proteins in the liver were confirmed by western blot analysis. These results suggest that serum bile acids might be increased due to the inhibition of bile acid enterohepatic circulation rather than increased endogenous bile acid synthesis. Moreover, serum bile acids are a good indicator of TAA-induced hepatotoxicity. - Highlights: • Endogenous metabolic profiles were assessed in rat after treatment of thioacetamide. • It significantly increased the levels of bile acids in serum but not in the liver. • Expression of the genes related to bile acid secretion and reuptake was decreased. • Increased serum bile acids result from block of enterohepatic circulation of bile acids.

  5. Increased serum bile acid concentration following low-dose chronic administration of thioacetamide in rats, as evidenced by metabolomic analysis

    International Nuclear Information System (INIS)

    Jeong, Eun Sook; Kim, Gabin; Shin, Ho Jung; Park, Se-Myo; Oh, Jung-Hwa; Kim, Yong-Bum; Moon, Kyoung-Sik; Choi, Hyung-Kyoon; Jeong, Jayoung; Shin, Jae-Gook; Kim, Dong Hyun

    2015-01-01

    A liquid chromatography/time-of-flight mass spectrometry (LC/TOF-MS)-based metabolomics approach was employed to identify endogenous metabolites as potential biomarkers for thioacetamide (TAA)-induced liver injury. TAA (10 and 30 mg/kg), a well-known hepatotoxic agent, was administered daily to male Sprague–Dawley (SD) rats for 28 days. We then conducted untargeted analyses of endogenous serum and liver metabolites. Partial least squares discriminant analysis (PLS-DA) was performed on serum and liver samples to evaluate metabolites associated with TAA-induced perturbation. TAA administration resulted in altered levels of bile acids, acyl carnitines, and phospholipids in serum and in the liver. We subsequently demonstrated and confirmed the occurrence of compromised bile acid homeostasis. TAA treatment significantly increased serum levels of conjugated bile acids in a dose-dependent manner, which correlated well with toxicity. However, hepatic levels of these metabolites were not substantially changed. Gene expression profiling showed that the hepatic mRNA levels of Ntcp, Bsep, and Oatp1b2 were significantly suppressed, whereas those of basolateral Mrp3 and Mrp4 were increased. Decreased levels of Ntcp, Oatp1b2, and Ostα proteins in the liver were confirmed by western blot analysis. These results suggest that serum bile acids might be increased due to the inhibition of bile acid enterohepatic circulation rather than increased endogenous bile acid synthesis. Moreover, serum bile acids are a good indicator of TAA-induced hepatotoxicity. - Highlights: • Endogenous metabolic profiles were assessed in rat after treatment of thioacetamide. • It significantly increased the levels of bile acids in serum but not in the liver. • Expression of the genes related to bile acid secretion and reuptake was decreased. • Increased serum bile acids result from block of enterohepatic circulation of bile acids.

  6. Bile acids in health and disease

    DEFF Research Database (Denmark)

    Krag, E; Thaysen, E H

    1996-01-01

    Over the last quarter of a century Danish research on bile acids has comprised studies of their physical and chemical properties, their physiology, pathophysiology, metabolism, and kinetics, and their clinical applicability. In the beginning of the period a major contribution was made to the unde......Over the last quarter of a century Danish research on bile acids has comprised studies of their physical and chemical properties, their physiology, pathophysiology, metabolism, and kinetics, and their clinical applicability. In the beginning of the period a major contribution was made...... to the understanding of the factors involved in the solubility of cholesterol in bile. The growing international understanding of the potential importance of the bile acids in health and disease gave raise to a substantial Danish contribution in the 1970s and 1980s in parallel with international achievements. Emphasis...... was on the possible clinical implications of bile acids. Studies on physiology and pathophysiology were in focus. Patients who have had an intestinal bypass operation for obesity served as a model for obtaining new knowledge on various aspects of the properties of the bile acids. Also the analytical methods were...

  7. Reduction of 3 alpha-hydroxy-5 beta-chol-6-en-24-oic acid to lithocholic acid in rats

    International Nuclear Information System (INIS)

    Kimura, K.; Ogura, M.

    1988-01-01

    After [24- 14 C]delta 6-lithocholic acid was injected into the cecum of rats, [ 14 C]lithocholic acid was identified as a metabolite in feces. When the labeled delta 6-bile acid was injected intraperitoneally into bile-fistula rats, radioactivity excreted in bile was contained most abundantly in the taurine-conjugated fraction of bile acids. In the fraction, taurine conjugate of [ 14 C]delta 6-lithocholic acid but of neither [ 14 C]lithocholic acid nor other bile acids was found. The results showed that [24- 14 C]delta 6-lithocholic acid was reduced to [ 14 C]lithocholic acid by the intestinal flora but not by the liver, which, however, was capable of conjugating delta 6-lithocholic acid with taurine

  8. Use of D(acid)-, D(bile)-, z(acid)-, and z(bile)-values in evaluating Bifidobacteria with regard to stomach pH and bile salt sensitivity.

    Science.gov (United States)

    Jia, Li; Shigwedha, Nditange; Mwandemele, Osmund D

    2010-01-01

    The survival of bifidobacteria in simulated conditions of the gastrointestinal (GI) tract was studied based on the D- and z-value concept. Some Bifidobacterium spp. are probiotics that improve microbial balance in the human GI tract. Because they are sensitive to low pH and bile salt concentrations, their viability in the GI tract is limited. The D- and z-value approach was therefore adopted as a result of observing constant log-cell reduction (90%) when Bifidobacterium spp. were exposed to these 2 different stressing factors. Survivals of one strain each or 4 species of Bifidobacterium was studied at pH between 3.0 and 4.5 and in ox-bile between 0.15% and 0.60% for times up to 41 h. From the D(acid)- and D(bile)-values, the order of resistance to acid and bile was B. bifidum > B. infantis > B. longum > B. adolescentis. While the former 3 strains retained high cell viability at pH 3.5 (>5.5 log CFU/mL after 5 h) and at elevated bile salt concentration of 0.6% (>4.5 log CFU/mL after 3 h), B. adolescentis was less resistant (pH units and 0.40% to 0.49%, respectively. The results suggest that the D(acid)-, D(bile)-, z(acid)-, and z(bile)-value approach could be more appropriate than the screening and selection method in evaluating survival of probiotic bacteria, and in measuring their tolerance or resistance to gastric acidity and the associated bile salt concentration in the small intestine. The evaluation of the tolerance of bifidobacteria to bile salts and low pH has been made possible by use of D- and z-value concept. The calculated z(acid)- and z(bile)-values were all fairly similar for the strains used and suggest the effect of increasing the bile salt concentration or decreasing the pH on the D(acid)- and D(bile)-values. This approach would be useful for predicting the suitability of bifidobacteria and other lactic acid bacteria (LAB) as probiotics for use in real-life situations.

  9. Role of glucuronidation for hepatic detoxification and urinary elimination of toxic bile acids during biliary obstruction.

    Directory of Open Access Journals (Sweden)

    Martin Perreault

    Full Text Available Biliary obstruction, a severe cholestatic condition, results in a huge accumulation of toxic bile acids (BA in the liver. Glucuronidation, a conjugation reaction, is thought to protect the liver by both reducing hepatic BA toxicity and increasing their urinary elimination. The present study evaluates the contribution of each process in the overall BA detoxification by glucuronidation. Glucuronide (G, glycine, taurine conjugates, and unconjugated BAs were quantified in pre- and post-biliary stenting urine samples from 12 patients with biliary obstruction, using liquid chromatography-tandem mass spectrometry (LC-MS/MS. The same LC-MS/MS procedure was used to quantify intra- and extracellular BA-G in Hepatoma HepG2 cells. Bile acid-induced toxicity in HepG2 cells was evaluated using MTS reduction, caspase-3 and flow cytometry assays. When compared to post-treatment samples, pre-stenting urines were enriched in glucuronide-, taurine- and glycine-conjugated BAs. Biliary stenting increased the relative BA-G abundance in the urinary BA pool, and reduced the proportion of taurine- and glycine-conjugates. Lithocholic, deoxycholic and chenodeoxycholic acids were the most cytotoxic and pro-apoptotic/necrotic BAs for HepG2 cells. Other species, such as the cholic, hyocholic and hyodeoxycholic acids were nontoxic. All BA-G assayed were less toxic and displayed lower pro-apoptotic/necrotic effects than their unconjugated precursors, even if they were able to penetrate into HepG2 cells. Under severe cholestatic conditions, urinary excretion favors the elimination of amidated BAs, while glucuronidation allows the conversion of cytotoxic BAs into nontoxic derivatives.

  10. Bile Acid Signaling in Metabolic Disease and Drug Therapy

    Science.gov (United States)

    Li, Tiangang

    2014-01-01

    Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates hepatobiliary secretion of lipids, lipophilic metabolites, and xenobiotics. In the intestine, bile acids are essential for the absorption, transport, and metabolism of dietary fats and lipid-soluble vitamins. Extensive research in the last 2 decades has unveiled new functions of bile acids as signaling molecules and metabolic integrators. The bile acid–activated nuclear receptors farnesoid X receptor, pregnane X receptor, constitutive androstane receptor, vitamin D receptor, and G protein–coupled bile acid receptor play critical roles in the regulation of lipid, glucose, and energy metabolism, inflammation, and drug metabolism and detoxification. Bile acid synthesis exhibits a strong diurnal rhythm, which is entrained by fasting and refeeding as well as nutrient status and plays an important role for maintaining metabolic homeostasis. Recent research revealed an interaction of liver bile acids and gut microbiota in the regulation of liver metabolism. Circadian disturbance and altered gut microbiota contribute to the pathogenesis of liver diseases, inflammatory bowel diseases, nonalcoholic fatty liver disease, diabetes, and obesity. Bile acids and their derivatives are potential therapeutic agents for treating metabolic diseases of the liver. PMID:25073467

  11. Bile acids for primary sclerosing cholangitis

    DEFF Research Database (Denmark)

    Chen, Weikeng; Gluud, C

    2003-01-01

    Bile acids have been used for treating primary sclerosing cholangitis, but their beneficial and harmful effects remain unclear.......Bile acids have been used for treating primary sclerosing cholangitis, but their beneficial and harmful effects remain unclear....

  12. A novel varanic acid epimer--(24R,25S)-3α,7α,12α,24-tetrahydroxy-5β-cholestan-27-oic acid--is a major biliary bile acid in two varanid lizards and the Gila monster.

    Science.gov (United States)

    Hagey, Lee R; Ogawa, Shoujiro; Kato, Narimi; Satoh née Okihara, Rika; Une, Mizuho; Mitamura, Kuniko; Ikegawa, Shigeo; Hofmann, Alan F; Iida, Takashi

    2012-11-01

    A key intermediate in the biosynthetic pathway by which C(24) bile acids are formed from cholesterol has long been considered to be varanic acid, (24ξ,25ξ)-3α,7α,12α-24-tetrahydroxy-5β-cholestan-27-oic acid. The (24R,25R)-epimer of this tetrahydroxy bile acid, in the form of its taurine N-acyl amidate, was thought to be the major biliary bile acid in lizards of the family Varanidae. We report here that a major biliary bile acid of three lizard species - the Komodo dragon (Varanus komodoensis), Gray's monitor (Varanus olivaceus), and the Gila monster (Heloderma suspectum) - is a novel epimer of varanic acid. The epimer was shown to be (24R,25S)-3α,7α,12α,24-tetrahydroxy-5β-cholestan-27-oic acid (present in bile as its taurine conjugate). The structure was established by mass spectroscopy and by (1)H and (13)C nuclear magnetic spectroscopy, as well as by synthesis of the compound. Copyright © 2012 Elsevier Inc. All rights reserved.

  13. Bile acids for viral hepatitis

    DEFF Research Database (Denmark)

    Chen, Weikeng; Liu, J; Gluud, C

    2003-01-01

    The viral hepatitides are common causes of liver diseases globally. Trials have assessed bile acids for patients with viral hepatitis, but no consensus was reached regarding their usefulness.......The viral hepatitides are common causes of liver diseases globally. Trials have assessed bile acids for patients with viral hepatitis, but no consensus was reached regarding their usefulness....

  14. Association of canalicular membrane enzymes with bile acid micelles and lipid aggregates in human and rat bile.

    Science.gov (United States)

    Accatino, L; Pizarro, M; Solís, N; Koenig, C S

    1995-01-18

    This study was undertaken to gain insights into the characteristics of the polymolecular association between canalicular membrane enzymes, bile acids, cholesterol and phospholipids in bile and into the celular mechanisms whereby the enzymes are secreted into bile. With this purpose, we studied the distribution of bile acids, cholesterol, phospholipids, proteins and representative canalicular membrane enzymes (alkaline phosphatase, 5'-nucleotidase and gamma-glutamyl transpeptidase), which can be considered specific marker constituents, in bile fractions enriched in phospholipid-cholesterol lamellar structures (multilamellar and unilamellar vesicles) and bile acid-mixed micelles. These fractions were isolated by ultracentrifugation from human hepatic bile, normal rat bile and bile of rats treated with diosgenin, a steroid that induces a marked increase in biliary cholesterol secretion, and were characterized by density, lipid composition and transmission electron microscopy. These studies demonstrate that alkaline phosphatase, 5'-nucleotidase and gamma-glutamyl transpeptidase are secreted into both human and rat bile where they are preferentially associated with bile acid-mixed micelles, suggesting a role for bile acids in both release of these enzymes and lipids from the canalicular membrane and solubilization in bile. In addition, heterogeneous association of these enzymes with nonmicellar, lamellar structures in human and rat bile is consistent with the hypothesis that processes independent of the detergent effects of bile acids might also result in the release of specific intrinsic membrane proteins into bile.

  15. Isotope derivative assay of human serum bile acids

    International Nuclear Information System (INIS)

    Pageaux, J.F.; Duperray, B.; Dubois, M.; Pacheco, H.

    1981-01-01

    A new method for the selective determination of the main serum bile acids has been developed. Serum samples with added 14 C-labeled bile acid were submitted to deproteinization, alkaline hydrolysis, methylation, and were then chromatographed on alumina before acetylation with 2 microliters of [ 3 H]acetic anhydride. Excess reagent was eliminated by evaporation; elimination of residual tritiated contaminants and separation of the doubly labeled bile acid derivatives were obtained by thin-layer chromatography, column chromatography on Lipidex 5000, and crystallization. The sensitivity of the method is about 10 pmol of each bile acid. Analyses of seven sera with normal or elevated concentration of bile acids by the proposed method and gas-liquid chromatography showed a close correlation

  16. Nocturnal weakly acidic reflux promotes aspiration of bile acids in lung transplant recipients.

    Science.gov (United States)

    Blondeau, Kathleen; Mertens, Veerle; Vanaudenaerde, Bart A; Verleden, Geert M; Van Raemdonck, Dirk E; Sifrim, Daniel; Dupont, Lieven J

    2009-02-01

    Gastroesophageal reflux (GER) and aspiration of bile acids have been implicated as non-alloimmune risk factors for the development of bronchiolitis obliterans syndrome (BOS) after lung transplantation. The aim of our study was to investigate the association between GER and gastric aspiration of bile acids and to establish which reflux characteristics may promote aspiration of bile acids into the lungs and may feature as a potential diagnostic tool in identifying lung transplantation (LTx) patients at risk for aspiration. Twenty-four stable LTx recipients were studied 1 year after transplantation. All patients underwent 24-hour ambulatory impedance-pH recording for the detection of acid (pH acidic (pH 4 to 7) reflux. On the same day, bronchoalveolar lavage fluid (BALF) was collected and then analyzed for the presence of bile acids (Bioquant enzymatic assay). Increased GER was detected in 13 patients, of whom 9 had increased acid reflux and 4 had exclusively increased weakly acidic reflux. Sixteen patients had detectable bile acids in the BALF (0.6 [0.4 to 1.5] micromol/liter). The 24-hour esophageal volume exposure was significantly increased in patients with bile acids compared to patients without bile acids in the BALF. Acid exposure and the number of reflux events (total, acid and weakly acidic) were unrelated to the presence of bile acids in the BALF. However, both nocturnal volume exposure and the number of nocturnal weakly acidic reflux events were significantly higher in patients with bile acids in the BALF. Weakly acidic reflux events, especially during the night, are associated with the aspiration of bile acids in LTx recipients and may therefore feature as a potential risk factor for the development of BOS.

  17. Mechanisms of bile acid mediated inflammation in the liver.

    Science.gov (United States)

    Li, Man; Cai, Shi-Ying; Boyer, James L

    2017-08-01

    Bile acids are synthesized in the liver and are the major component in bile. Impaired bile flow leads to cholestasis that is characterized by elevated levels of bile acid in the liver and serum, followed by hepatocyte and biliary injury. Although the causes of cholestasis have been extensively studied, the molecular mechanisms as to how bile acids initiate liver injury remain controversial. In this chapter, we summarize recent advances in the pathogenesis of bile acid induced liver injury. These include bile acid signaling pathways in hepatocytes as well as the response of cholangiocytes and innate immune cells in the liver in both patients with cholestasis and cholestatic animal models. We focus on how bile acids trigger the production of molecular mediators of neutrophil recruitment and the role of the inflammatory response in this pathological process. These advances point to a number of novel targets where drugs might be judged to be effective therapies for cholestatic liver injury. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Biomaterials made of bile acids

    Institute of Scientific and Technical Information of China (English)

    ZHANG JiaWei; ZHU XiaoXia

    2009-01-01

    The use of natural compounds in the preparation of new materials can improve the biocompatibility of the materials and avoid any potential toxicity of the degradation products when used for biomedical applications.Bile acids are amphiphilic molecules biosynthesized in the liver.They are used to prepare various polymers and oligomers.These polymers made of bile acids are promising materials in both biomedical and pharmaceutical fields.

  19. Biomaterials made of bile acids

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    The use of natural compounds in the preparation of new materials can improve the biocompatibility of the materials and avoid any potential toxicity of the degradation products when used for biomedical applications. Bile acids are amphiphilic molecules biosynthesized in the liver. They are used to prepare various polymers and oligomers. These polymers made of bile acids are promising materials in both biomedical and pharmaceutical fields.

  20. Effects of bile acid administration on bile acid synthesis and its circadian rhythm in man

    International Nuclear Information System (INIS)

    Pooler, P.A.; Duane, W.C.

    1988-01-01

    In man bile acid synthesis has a distinct circadian rhythm but the relationship of this rhythm to feedback inhibition by bile acid is unknown. We measured bile acid synthesis as release of 14CO2 from [26-14C]cholesterol every 2 hr in three normal volunteers during five separate 24-hr periods. Data were fitted by computer to a cosine curve to estimate amplitude and acrophase of the circadian rhythm. In an additional six volunteers, we measured synthesis every 2 hr from 8:00 a.m. to 4:00 p.m. only. During the control period, amplitude (expressed as percentage of mean synthesis) averaged 52% and acrophase averaged 6:49 a.m. During administration of ursodeoxycholic acid (15 mg per kg per day), synthesis averaged 126% of baseline (p less than 0.1), amplitude averaged 43% and acrophase averaged 6:20 a.m. During administration of chenodeoxycholic acid (15 mg per kg per day), synthesis averaged 43% of baseline (p less than 0.001), amplitude averaged 53% and acrophase averaged 9:04 a.m. Addition of prednisone to this regimen of chenodeoxycholic acid to eliminate release of 14CO2 from corticosteroid hormone synthesis resulted in a mean amplitude of 62% and a mean acrophase of 6:50 a.m., values very similar to those in the baseline period. Administration of prednisone alone also did not significantly alter the baseline amplitude (40%) or acrophase (6:28 a.m.). We conclude that neither chenodeoxycholic acid nor ursodeoxycholic acid significantly alters the circadian rhythm of bile acid synthesis in man

  1. Serum bile acid concentrations in dairy cattle with hepatic lipidosis.

    Science.gov (United States)

    Garry, F B; Fettman, M J; Curtis, C R; Smith, J A

    1994-01-01

    This study was designed to evaluate serum bile acid measurements as indicatory, of liver function and/or hepatic fat infiltration in dairy cattle. Serum bile acid concentrations were measured in healthy dairy cattle at different stages of lactation after fasting or feeding. Bile acid concentrations were compared with liver fat content and sulfobromophthalein (BSP) half-life (T 1/2). Serum bile acid concentrations were higher in cows in early lactation and with higher daily milk production. Compared with prefasting values, bile acid concentrations were decreased at 8, 14, and 24 hours of fasting. Blood samples from fed cows at 1- to 2-hour intervals had wide and inconsistent variations in bile acid concentration. Because serum bile acids correlated well with BSP T 1/2, it is suggested that both measurements evaluate a similar aspect of liver function. Neither bile acids nor BSP T 1/2 correlated with differences in liver fat content among cows. Because of large variability in serum bile acid concentrations in fed cows and the lack of correlation of measured values with liver fat content, bile acid determinations do not appear useful for showing changes in hepatic function in fed cows with subclinical hepatic lipidosis nor serve as a screening test for this condition.

  2. Strong activation of bile acid-sensitive ion channel (BASIC) by ursodeoxycholic acid

    Science.gov (United States)

    Wiemuth, Dominik; Sahin, Hacer; Lefèvre, Cathérine M.T.; Wasmuth, Hermann E.; Gründer, Stefan

    2013-01-01

    Bile acid-sensitive ion channel (BASIC) is a member of the DEG/ENaC gene family of unknown function. Rat BASIC (rBASIC) is inactive at rest. We have recently shown that cholangiocytes, the epithelial cells lining the bile ducts, are the main site of BASIC expression in the liver and identified bile acids, in particular hyo- and chenodeoxycholic acid, as agonists of rBASIC. Moreover, it seems that extracellular divalent cations stabilize the resting state of rBASIC, because removal of extracellular divalent cations opens the channel. In this addendum, we demonstrate that removal of extracellular divalent cations potentiates the activation of rBASIC by bile acids, suggesting an allosteric mechanism. Furthermore, we show that rBASIC is strongly activated by the anticholestatic bile acid ursodeoxycholic acid (UDCA), suggesting that BASIC might mediate part of the therapeutic effects of UDCA. PMID:23064163

  3. 3α-6α-Dihydroxy-7α-fluoro-5β-cholanoate (UPF-680), physicochemical and physiological properties of a new fluorinated bile acid that prevents 17α-ethynyl-estradiol-induced cholestasis in rats

    International Nuclear Information System (INIS)

    Clerici, Carlo; Castellani, Danilo; Asciutti, Stefania; Pellicciari, Roberto; Setchell, Kenneth D.R.; O'Connell, Nancy C.; Sadeghpour, Bahman; Camaioni, Emidio; Fiorucci, Stefano; Renga, Barbara; Nardi, Elisabetta; Sabatino, Giuseppe; Clementi, Mattia; Giuliano, Vittorio; Baldoni, Monia; Orlandi, Stefano; Mazzocchi, Alessandro; Morelli, Antonio; Morelli, Olivia

    2006-01-01

    3α-6α-Dihydroxy-7α-fluoro-5β-cholanoate (UPF-680), the 7α-fluorine analog of hyodeoxycholic acid (HDCA), was synthesized to improve bioavailability and stability of ursodeoxycholic acid (UDCA). Acute rat biliary fistula and chronic cholestasis induced by 17α-ethynyl-estradiol (17EE) models were used to study and compare the effects of UPF-680 (dose range 0.6-6.0 μmol/kg min) with UDCA on bile flow, biliary bicarbonate (HCO 3 - ), lipid output, biliary bile acid composition, hepatic enzymes and organic anion pumps. In acute infusion, UPF-680 increased bile flow in a dose-related manner, by up to 40.9%. Biliary HCO 3 - output was similarly increased. Changes were observed in phospholipid secretion only at the highest doses. Treatment with UDCA and UPF-680 reversed chronic cholestasis induced by 17EE; in this model, UDCA had no effect on bile flow in contrast to UPF-680, which significantly increased bile flow. With acute administration of UPF-680, the biliary bile acid pool became enriched with unconjugated and conjugated UPF-680 (71.7%) at the expense of endogenous cholic acid and muricholic isomers. With chronic administration of UPF-680 or UDCA, the main biliary bile acids were tauro conjugates, but modification of biliary bile acid pool was greater with UPF-680. UPF-680 increased the mRNA for cytochrome P450 7A1 (CYP7A1) and cytochrome P450 8B (CYP8B). Both UDCA and UPF-680 increased the mRNA for Na + taurocholate co-transporting polypeptide (NCTP). In conclusion, UPF-680 prevented 17EE-induced cholestasis and enriched the biliary bile acid pool with less detergent and cytotoxic bile acids. This novel fluorinated bile acid may have potential in the treatment of cholestatic liver disease

  4. Clinical value of bile acids radioimmunoassay

    International Nuclear Information System (INIS)

    Breckwoldt, R.U.

    1981-01-01

    In 50 blood donors, 87 patients with various liver and bile disorders, 50 hemodialyse patients and 50 patients prior to and immediately after cardiac swigery, cholyl glycine (CG) and sulfolithocholyl glycine (SLCG) were determined. Long-term observations were carried out on a further 10 patients with non-A/non-B hepatitis and 10 patients without hepatitis. Correlations were found between the values of alkaline phosphatase, GPT, GOT and bilirubin. Consequently the determination of bile acid, here above all SLCG, constitutes a suitable means to detect subclinical functional liver disorders. The examination of the post-operative functional liver disorders following cardiac swigery showed that there is a distinct time shift between the mostly transitory increase in enzyme activity and the SLCG levels. Surprisingly, the long-term observations showed that increased bile acid levels are already measured during the hepatitis incubation period at normal enzyme activities. It was not possible, however to identify hepatitic patients already during incubation by assay of the bile acid level. Whereas the determination of standard laboratory parameters remains predominant in the description of liver cell damage, the importance of serum bile acid determination is seen in the description of functional liver disorders which are not characterized by increased enzyme activities. (orig.) [de

  5. Bile acid malabsorption in patients with chronic diarrhoea

    Energy Technology Data Exchange (ETDEWEB)

    Eusufzai, S. (Karolinska Inst., Huddinge Univ. Hospital, Stockholm (Sweden))

    1993-10-01

    The presence of bile acid malabsorption was studied in 24 patients with chronic diarrhoea without established cause despite extensive investigations. Bile acid absorption was evaluated with the [sup 75]Se-homocholic acid taurine (SeHCAT) test. A therapeutic trial of cholestyramine was performed in 11 patients. 14 of the patients showed evidence of bile acid malabsorption. Of the 11 patients who were treated with cholestyramine, 3 has no improvement of their diarrhoea and also had a normal SeHCAT test result. Of the other 8 patients, who also had pathologic SeHCAT test result, 5 improved on treatment, whereas 3 had no change of their diarrhoea. 7 of the 24 patients had a previous history of cholecystectomy. 4 of them showed bile acid malabsorption; 3 of these were treated with cholestyramine and responded favourably. The results suggest that bile acid malabsorption may be common in chronic diarrhoea patients, but may not always be the primary cause of diarrhoea. 28 refs., 2 tabs.

  6. Bile acid sequestrants and the treatment of type 2 diabetes mellitus

    NARCIS (Netherlands)

    Staels, Bart; Kuipers, Folkert

    2007-01-01

    Bile acids promote bile formation and facilitate dietary lipid absorption. Animal and human studies showing disturbed bile acid metabolism in diabetes mellitus suggest a link between bile acids and glucose control. Bile acids are activating ligands of the farnesoid X receptor (FXR), a nuclear

  7. Bile acids exert negative feedback control on bile acid synthesis in cultured pig hepatocytes by suppression of cholesterol 7α-hydroxylase activity

    NARCIS (Netherlands)

    Kwekkeboom, J.; Princen, H.M.G.; Voorthuizen, E.M. van; Kempen, H.J.M.

    1990-01-01

    Feedback regulation of bile acid synthesis by its end products was studied in cultured hepatocytes of young weaned pigs. We previously showed that conversion of exogenous [14C] cholesterol into bile acids was suppressed by addition of bile acids to the culture medium. In the present study, the

  8. Endocrine functions of bile acids

    NARCIS (Netherlands)

    Houten, Sander M.; Watanabe, Mitsuhiro; Auwerx, Johan

    2006-01-01

    Bile acids (BAs), a group of structurally diverse molecules that are primarily synthesized in the liver from cholesterol, are the chief components of bile. Besides their well-established roles in dietary lipid absorption and cholesterol homeostasis, it has recently emerged that BAs are also

  9. Fasting Serum Taurine-Conjugated Bile Acids Are Elevated in Type 2 Diabetes and Do Not Change With Intensification of Insulin

    Science.gov (United States)

    Wewalka, Marlene; Patti, Mary-Elizabeth; Barbato, Corinne; Houten, Sander M.

    2014-01-01

    Context: Bile acids (BAs) are newly recognized signaling molecules in glucose and energy homeostasis. Differences in BA profiles with type 2 diabetes mellitus (T2D) remain incompletely understood. Objective: The objective of the study was to assess serum BA composition in impaired glucose-tolerant, T2D, and normal glucose-tolerant persons and to monitor the effects of improving glycemia on serum BA composition in T2D patients. Design and Setting: This was a cross-sectional cohort study in a general population (cohort 1) and nonrandomized intervention (cohort 2). Patients and Interventions: Ninety-nine volunteers underwent oral glucose tolerance testing, and 12 persons with T2D and hyperglycemia underwent 8 weeks of intensification of treatment. Main Outcome Measures: Serum free BA and respective taurine and glycine conjugates were measured by HPLC tandem mass spectrometry. Results: Oral glucose tolerance testing identified 62 normal-, 25 impaired glucose-tolerant, and 12 T2D persons. Concentrations of total taurine-conjugated BA were higher in T2D and intermediate in impaired- compared with normal glucose-tolerant persons (P = .009). Univariate regression revealed a positive association between total taurine-BA and fasting glucose (R = 0.37, P fasting insulin (R = 0.21, P = .03), and homeostatic model assessment-estimated insulin resistance (R = 0.26, P = .01) and an inverse association with oral disposition index (R = −0.36, P fasting serum total BA or BA composition. Conclusion: Fasting taurine-conjugated BA concentrations are higher in T2D and intermediate in impaired compared with normal glucose-tolerant persons and are associated with fasting and postload glucose. Serum BAs are not altered in T2D in response to improved glycemia. Further study may elucidate whether this pattern of taurine-BA conjugation can be targeted to provide novel therapeutic approaches to treat T2D. PMID:24432996

  10. Effect of common polymorphisms of the farnesoid X receptor and bile acid transporters on the pharmacokinetics of ursodeoxycholic acid.

    Science.gov (United States)

    Hu, Miao; Fok, Benny S P; Wo, Siu-Kwan; Lee, Vincent H L; Zuo, Zhong; Tomlinson, Brian

    2016-01-01

    Ursodeoxycholic acid (UDCA), a natural, dihydroxy bile acid, promotes gallstone dissolution and has been attributed with several other beneficial effects. The farnesoid X receptor (FXR) may influence the pharmacokinetics of UDCA by modulating the expression of bile acid transporters. This exploratory study examined whether common functional polymorphisms in FXR and in bile acid transporter genes affect the pharmacokinetics of exogenous UDCA. Polymorphisms in genes for transporters involved in bile acid transport, solute carrier organic anion 1B1 (SLCO1B1) 388A>G and 521T>C, solute carrier 10A1 (SLC10A1) 800 C>T and ATP-binding cassette B11 (ABCB11) 1331T>C, and the FXR -1G>T polymorphism were genotyped in 26 male Chinese subjects who ingested single oral 500-mg doses of UDCA. Plasma concentrations of UDCA and its major conjugate metabolite glycoursodeoxycholic acid (GUDCA) were determined. The mean systemic exposure of UDCA was higher in the five subjects with one copy of the FXR -1G>T variant allele than in those homozygous for the wild-type allele (n = 21) (AUC0-24 h : 38.5 ± 28.2 vs. 20.9 ± 8.0 μg h/mL, P = 0.021), but this difference appeared mainly due to one outlier with the -1GT genotype and elevated baseline and post-treatment UDCA concentrations. After excluding the outlier, body weight was the only factor associated with plasma concentrations of UDCA and there were no significant associations with the other polymorphisms examined. None of the polymorphisms affected the pharmacokinetics of GUDCA. This study showed that the common polymorphisms in bile acid transporters had no significant effect on the pharmacokinetics of exogenous UDCA but an effect of the FXR polymorphism cannot be excluded. © 2015 Wiley Publishing Asia Pty Ltd.

  11. Role of cholangiocyte bile Acid transporters in large bile duct injury after rat liver transplantation.

    Science.gov (United States)

    Cheng, Long; Zhao, Lijin; Li, Dajiang; Liu, Zipei; Chen, Geng; Tian, Feng; Li, Xiaowu; Wang, Shuguang

    2010-07-27

    The pathogenesis of nonanastomotic strictures with a patent hepatic artery remains to be investigated. This study focuses on the role of cholangiocyte bile acid transporters in bile duct injury after liver transplantation. Sprague-Dawley rats were divided into three groups (n=20 for each): the sham-operated group (Sham), the transplant group with 1-hr donor liver cold preservation (CP-1h), and the transplant group with 12-hr donor liver cold preservation (CP-12h). Bile was collected for biochemical analysis. The histopathologic evaluation of bile duct injury was performed and the cholangiocyte bile acid transporters apical sodium-dependent bile acid transporter (ASBT), ileal lipid binding protein (ILBP), and Ostalpha/Ostbeta were investigated. RESULTS.: The immunohistochemical assay suggested that ASBT and ILBP were expressed exclusively on large bile duct epithelial cells, whereas Ostalpha and Ostbeta were expressed on both small and large bile ducts. Western blot and quantitative polymerase chain reaction analysis showed that the expression levels of these transporters dramatically decreased after transplantation. It took seven to 14 days for ILBP, Ostalpha, and Ostbeta to recover, whereas ASBT recovered within 3 days and even reached a peak above the normal level seven days after operation. In the CP-12h group, the ratios of the ASBT/ILBP, ASBT/Ostalpha and ASBT/Ostbeta expression levels were correlated with the injury severity scores of large but not small bile ducts. The results suggest that the unparallel alteration of cholangiocyte bile acid transporters may play a potential role in large bile duct injury after liver transplantation with prolonged donor liver preservation.

  12. Rapid Determination of Bile Acids in Bile from Various Mammals by Reversed-Phase Ultra-Fast Liquid Chromatography.

    Science.gov (United States)

    Si, Gu Leng Ri; Yao, Peng; Shi, Luwen

    2015-08-01

    A valid and efficient reversed-phase ultra-fast liquid chromatography method was developed for the simultaneous determination of 13 bile acids in the bile of three mammal species, including rat, pig and human gallstone patients. Chromatographic separation was performed with a Shim-pack XR-ODS column, and the mobile phase consisted of acetonitrile and potassium phosphate buffer (pH 2.6) at a flow rate of 0.5 mL min(-1). The linear detection range of most bile acids ranged from 2 to 600 ng µL(-1) with a good correlation coefficient (>0.9995). The precision of each bile acid was bile acids were separated in 15 min with satisfactory resolution, and the total analysis time was 18 min, including equilibration. The method was successfully applied in rapid screening of bile samples from the three mammals. Significant metabolic frameworks of bile acids among various species were observed, whereas considerable quantitative variations in both inter- and intraspecies were also observed, especially for gallstone patients. Our results suggest that detecting the change of bile acid profiles could be applied for the diagnosis of gallstone disease. © Crown copyright 2014.

  13. Bile acid aspiration in suspected ventilator-associated pneumonia.

    Science.gov (United States)

    Wu, Yu-Chung; Hsu, Po-Kuei; Su, Kang-Cheng; Liu, Lung-Yu; Tsai, Cheng-Chien; Tsai, Shu-Ho; Hsu, Wen-Hu; Lee, Yu-Chin; Perng, Diahn-Warng

    2009-07-01

    The aims of this study were to measure the levels of bile acids in patients with suspected ventilator-associated pneumonia (VAP) and provide a possible pathway for neutrophilic inflammation to explain its proinflammatory effect on the airway. Bile acid levels were measured by spectrophotometric enzymatic assay, and liquid chromatography mass spectrometry was used to quantify the major bile acids. Alveolar cells were grown on modified air-liquid interface culture inserts, and bile acids were then employed to stimulate the cells. Reverse transcriptase polymerase chain reaction and Western blots were used to determine the involved gene expression and protein levels. The mean (+/- SE) concentration of total bile acids in tracheal aspirates was 6.2 +/- 2.1 and 1.1 +/- 0.4 mumol/L/g sputum, respectively, for patients with and without VAP (p VAP group (p aspiration may reduce the intensity of neutrophilic inflammation in intubated and mechanically ventilated patients in the ICU.

  14. Effect of different pectin on bile acid biosynthesis

    International Nuclear Information System (INIS)

    Khalikova, M.D.; Mukhiddinov, Z.K.; Nuraliev, Yu.N.; Khaydarov, K.Kh.

    2009-01-01

    The objective of the study was to examine the effects of consumption of different pectins from peach, quince, and apricot on bile flow and bile secretion of bile acids, cholesterol, phospholipids and bilirubin in rats. Six groups of nine rats were fed diets containing pectin 20 mg/kg once a day for two weeks. These groups of rats were compared with the group fed on physiological solution as a control and two groups fed on flamenol. Results of our study indicate that pectins, by decreasing cholesterol levels and enhancing bile acid secretion may cause increased hepatic synthesis of bile acids, phospholipids and reduced bilirubin synthesis. Among the studied pectins the apricot pectin shows in a very consistent lowering of cholesterol and bilirubin levels

  15. The role of bile acids in the pathogenesis of bowel diseases

    Directory of Open Access Journals (Sweden)

    Magdalena Panek-Jeziorna

    2017-08-01

    Full Text Available Bile acids not only play a cardinal role in the digestion and absorption of fat and fat-soluble vitamins, but also significantly affect gastrointestinal motor, sensory and secretory functions, intestinal barrier permeability and the regulation of the inflammatory response. The results of recent studies have revealed complex interactions between bile acids and the gut microbiota. In addition, bile acids also play a role of signaling molecules regulating the activity of lipid and glucose metabolic pathways, as well as a role of ligands for transcription factors. Genetic factors associated with the regulation of bile acid synthesis, transport and action may significantly influence gastrointestinal function and predispose to diarrhea resulting from bile acid malabsorption. Methods used in the diagnosis of bile acid malabsorption include 75selenium-homotaurocholic acid test, serum C4 and fibroblast growth factor 19 (FGF19, as well as fecal bile acid levels. The paper presents the latest data on the role of bile acid in the pathogenesis of irritable bowel syndrome, inflammatory bowel diseases and colorectal cancer. Advances in the treatment of disturbances in bile acids absorption and synthesis are also presented. A better understanding of molecular mechanisms regulating bile acid action may have implication for colorectal cancer prevention.

  16. Bile acid metabolism in cirrhosis. VIII. Quantitative evaluation of bile acid synthesis from [7 beta-3H]7 alpha-hydroxycholesterol and [G-3H]26-hydroxycholesterol

    International Nuclear Information System (INIS)

    Goldman, M.; Vlahcevic, Z.R.; Schwartz, C.C.; Gustafsson, J.; Swell, L.

    1982-01-01

    In order to evaluate more definitively the observed aberrations in the synthesis of cholic and chenodeoxycholic acids in patients with advanced cirrhosis, two bile acid biosynthesis pathways were examined by determining the efficiency of conversion of [ 3 H]7 alpha-hydroxycholesterol and [ 3 H] 26-hydroxycholesterol to primary bile acids. Bile acid kinetics were determined by administration of [ 14 C]cholic and [ 14 C]chenodeoxycholic acids. Cholic acid synthesis in cirrhotic patients was markedly depressed (170 vs 927 μmoles per day)( while chenodeoxycholic acid synthesis was reduced to a much lesser degree (227 vs 550 μmoles per day). The administration of [ 3 H]7 alpha-hydroxycholesterol allowed for an evaluation of the major pathway of bile acid synthesis via the 7 alpha-hydroxylation of cholesterol. This compound was efficiently incorporated into primary bile acids by the two normal subjects (88 and 100%) and two cirrhotic patients (77 and 91%). However, the recovery of the label in cholic acid was slightly less in cirrhotic patients than in normal subjects. [ 3 H]26-hydroxycholesterol was administered to ascertain the contribution of the 26-hydroxylation pathway to bile acid synthesis. All study subjects showed poor conversion (9 to 22%) of this intermediate into bile acids. The results of this study suggest that a major block in the bile acid synthesis pathway in cirrhosis is at the level of 7 alpha-hydroxylation of cholesterol (impairment of 7 alpha-hydroxylase) and/or in the feedback triggering mechanism regulating bile acid synthesis. The data also suggest that the 26-hydroxylation pathway in normal subjects and patients with cirrhosis is a minor contributor to synthesis of the primary bile acids. Therefore, the relative sparing of chenodeoxycholic acid synthesis observed in cirrhotic patients is not due to preferential synthesis of this bile acid via the 26-hydroxylation pathway

  17. Ursodeoxycholic Acid and Its Taurine- or Glycine-Conjugated Species Reduce Colitogenic Dysbiosis and Equally Suppress Experimental Colitis in Mice.

    Science.gov (United States)

    Van den Bossche, Lien; Hindryckx, Pieter; Devisscher, Lindsey; Devriese, Sarah; Van Welden, Sophie; Holvoet, Tom; Vilchez-Vargas, Ramiro; Vital, Marius; Pieper, Dietmar H; Vanden Bussche, Julie; Vanhaecke, Lynn; Van de Wiele, Tom; De Vos, Martine; Laukens, Debby

    2017-04-01

    The promising results seen in studies of secondary bile acids in experimental colitis suggest that they may represent an attractive and safe class of drugs for the treatment of inflammatory bowel diseases (IBD). However, the exact mechanism by which bile acid therapy confers protection from colitogenesis is currently unknown. Since the gut microbiota plays a crucial role in the pathogenesis of IBD, and exogenous bile acid administration may affect the community structure of the microbiota, we examined the impact of the secondary bile acid ursodeoxycholic acid (UDCA) and its taurine or glycine conjugates on the fecal microbial community structure during experimental colitis. Daily oral administration of UDCA, tauroursodeoxycholic acid (TUDCA), or glycoursodeoxycholic acid (GUDCA) equally lowered the severity of dextran sodium sulfate-induced colitis in mice, as evidenced by reduced body weight loss, colonic shortening, and expression of inflammatory cytokines. Illumina sequencing demonstrated that bile acid therapy during colitis did not restore fecal bacterial richness and diversity. However, bile acid therapy normalized the colitis-associated increased ratio of Firmicutes to Bacteroidetes Interestingly, administration of bile acids prevented the loss of Clostridium cluster XIVa and increased the abundance of Akkermansia muciniphila , bacterial species known to be particularly decreased in IBD patients. We conclude that UDCA, which is an FDA-approved drug for cholestatic liver disorders, could be an attractive treatment option to reduce dysbiosis and ameliorate inflammation in human IBD. IMPORTANCE Secondary bile acids are emerging as attractive candidates for the treatment of inflammatory bowel disease. Although bile acids may affect the intestinal microbial community structure, which significantly contributes to the course of these inflammatory disorders, the impact of bile acid therapy on the fecal microbiota during colitis has not yet been considered. Here, we

  18. Bile acid sequestrants : more than simple resins

    NARCIS (Netherlands)

    Out, Carolien; Groen, Albert K.; Brufau, Gemma

    Purpose of review Bile acid sequestrants (BAS) have been used for more than 50 years in the treatment of hypercholesterolemia. The last decade, bile acids are emerging as integrated regulators of metabolism via induction of various signal transduction pathways. Consequently, BAS treatment may exert

  19. Human beta-glucuronidase. Measurement of its activity in gallbladder bile devoid of intrinsic interference.

    Science.gov (United States)

    Ho, Y C; Ho, K J

    1988-04-01

    Our purpose is to develop a standard method for preparing the bile for beta-glucuronidase determination by removal of bile acids and conjugated bilirubin which interfere with its activity. The bile acids and conjugated bilirubin in their purified solutions and in the diluted gallbladder biles could be extracted completely with cholestyramine in powder form or tetrahexylammonium chloride (THAC) in chloroform or ethyl acetate. The enzyme was, however, partially precipitated with cholestyramine and denatured by chloroform but not by ethyl acetate. A standard procedure, therefore, includes extraction of the diluted gallbladder bile with THAC in ethyl acetate, followed by determination of the maximal velocity (Vmax) of the enzyme by a kinetic method employing phenolphthalein glucuronide as the substrate. The average Vmax of beta-glucuronidase in the 20 normal gallbladder biles was 165 +/- 86 nmol/min/ml (mean +/- SD), a 23.5-fold increase over the activity before extraction. The measured activity represented the true activity of the enzyme in the bile for recovery of activity of the enzyme added to the bile was practically complete.

  20. Intestinal uptake of bile acids: effect of external abdominal irradiation

    International Nuclear Information System (INIS)

    Thomson, A.B.R.; Cheeseman, C.I.; Walker, K.

    1984-01-01

    Abdominal irradiation has recently been shown to influence the uptake of hexoses, amino acids, fatty acids and cholesterol into the jejunum of rats. The present studies were undertaken with a previously validated in vitro technique to determine the effect of abdominal irradiation from a cesium source on the rates of uptake of six bile acids into the jejunum, ileum, and colon. The results show that: 1) there likely are multiple ileal carriers for bile acids: 2) abdominal irradiation has a variable effect on these carriers; 3) the passive permeability to bile acids varies with the bile acid and with the site along the intestine; and 4) abdominal irradiation is associated with a rise in the colonic permeability to only some bile acids

  1. Acid and bile tolerance of spore-forming lactic acid bacteria.

    Science.gov (United States)

    Hyronimus, B; Le Marrec, C; Sassi, A H; Deschamps, A

    2000-11-01

    Criteria for screening probiotics such as bile tolerance and resistance to acids were studied with 13 spore-forming lactic acid producing bacteria. Different strains of Sporolactobacillus, Bacillus laevolacticus, Bacillus racemilacticus and Bacillus coagulans grown in MRS broth were subjected to low pH conditions (2, 2.5 and 3) and increasing bile concentrations. Among these microorganisms, Bacillus laevolacticus DSM 6475 and all Sporolactobacillus strains tested except Sporolactobacillus racemicus IAM 12395, were resistant to pH 3. Only Bacillus racemilacticus and Bacillus coagulans strains were tolerant to bile concentrations over 0.3% (w/v).

  2. Bile acids induce necrosis in pancreatic stellate cells dependent on calcium entry and sodium‐driven bile uptake

    Science.gov (United States)

    Jakubowska, Monika A.; Gerasimenko, Julia V.; Gerasimenko, Oleg V.; Petersen, Ole H.

    2016-01-01

    Key points Acute biliary pancreatitis is a sudden and severe condition initiated by bile reflux into the pancreas.Bile acids are known to induce Ca2+ signals and necrosis in isolated pancreatic acinar cells but the effects of bile acids on stellate cells are unexplored.Here we show that cholate and taurocholate elicit more dramatic Ca2+ signals and necrosis in stellate cells compared to the adjacent acinar cells in pancreatic lobules; whereas taurolithocholic acid 3‐sulfate primarily affects acinar cells.Ca2+ signals and necrosis are strongly dependent on extracellular Ca2+ as well as Na+; and Na+‐dependent transport plays an important role in the overall bile acid uptake in pancreatic stellate cells.Bile acid‐mediated pancreatic damage can be further escalated by bradykinin‐induced signals in stellate cells and thus killing of stellate cells by bile acids might have important implications in acute biliary pancreatitis. Abstract Acute biliary pancreatitis, caused by bile reflux into the pancreas, is a serious condition characterised by premature activation of digestive enzymes within acinar cells, followed by necrosis and inflammation. Bile acids are known to induce pathological Ca2+ signals and necrosis in acinar cells. However, bile acid‐elicited signalling events in stellate cells remain unexplored. This is the first study to demonstrate the pathophysiological effects of bile acids on stellate cells in two experimental models: ex vivo (mouse pancreatic lobules) and in vitro (human cells). Sodium cholate and taurocholate induced cytosolic Ca2+ elevations in stellate cells, larger than those elicited simultaneously in the neighbouring acinar cells. In contrast, taurolithocholic acid 3‐sulfate (TLC‐S), known to induce Ca2+ oscillations in acinar cells, had only minor effects on stellate cells in lobules. The dependence of the Ca2+ signals on extracellular Na+ and the presence of sodium–taurocholate cotransporting polypeptide (NTCP) indicate a Na

  3. Synthesis, physicochemical properties, and biological activity of bile acids 3-glucuronides: Novel insights into bile acid signalling and detoxification.

    Science.gov (United States)

    Mostarda, Serena; Passeri, Daniela; Carotti, Andrea; Cerra, Bruno; Colliva, Carolina; Benicchi, Tiziana; Macchiarulo, Antonio; Pellicciari, Roberto; Gioiello, Antimo

    2018-01-20

    Glucuronidation is considered an important detoxification pathway of bile acids especially in cholestatic conditions. Glucuronides are less toxic than the parent free forms and are more easily excreted in urine. However, the pathophysiological significance of bile acid glucuronidation is still controversial and debated among the scientific community. Progress in this field has been strongly limited by the lack of appropriate methods for the preparation of pure glucuronides in the amount needed for biological and pharmacological studies. In this work, we have developed a new synthesis of bile acid C3-glucuronides enabling the convenient preparation of gram-scale quantities. The synthesized compounds have been characterized in terms of physicochemical properties and abilities to modulate key nuclear receptors including the farnesoid X receptor (FXR). In particular, we found that C3-glucuronides of chenodeoxycholic acid and lithocholic acid, respectively the most abundant and potentially cytotoxic species formed in patients affected by cholestasis, behave as FXR agonists and positively regulate the gene expression of transporter proteins, the function of which is critical in human conditions related to imbalances of bile acid homeostasis. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  4. Bile acids for liver-transplanted patients

    DEFF Research Database (Denmark)

    Poropat, Goran; Giljaca, Vanja; Stimac, Davor

    2010-01-01

    Liver transplantation has become a widely accepted form of treatment for numerous end-stage liver diseases. Bile acids may decrease allograft rejection after liver transplantation by changing the expression of major histocompatibility complex class molecules in bile duct epithelium and central vein...

  5. Hydrolyzed caseinomacropeptide conjugated galactooligosaccharides support the growth and enhance the bile tolerance in Lactobacillus strains.

    Science.gov (United States)

    Muthaiyan, Arunachalam; Hernandez-Hernandez, Oswaldo; Moreno, F Javier; Sanz, Maria Luz; Ricke, Steven C

    2012-07-11

    In this study bioactive caseinomacropeptide was conjugated with prebiotic galactooligosaccharides (hCMP:GOS) by Maillard reaction to synthesize value added prebiotic compounds to Lactobacillus strains. Growth study showed the ability of hCMP:GOS to serve as a sole carbon source for Lactobacillus strains. A significant amount of acetate and lactate was detected in cell free culture supernatant by HPLC. It demonstrated the ability of Lactobacillus strains to ferment the hCMP:GOS as a carbon source. In addition, hCMP:GOS grown Lactobacillus cells exhibited enhanced bile tolerance and retained 90% viability. Overall results of this study indicate that the hCMP conjugated GOS can be potential multipurpose prebiotic substrates to enhance the growth and bile tolerance in Lactobacillus strains and serve as a fermentable substrate to produce beneficial metabolites in the host.

  6. Radioimmunoassay compared to an enzymatic method for serum bile acid determination

    International Nuclear Information System (INIS)

    Samuelson, K.

    1980-01-01

    Radioimmunoassay (RIA) of cholic and chenodeoxycholic acid was compared to a total bile acid determination with 3α-hydroxysteroid dehydrogenase (3α HSD) and a gas liquid chromatographic (GLC) determination of individual bile acids. When sera from patients with increased bile acid concentration were analysed the results indicated a good correlation between GLC and the other methods. Analysis of sera from healthy subjects indicated a good correlation between GLC and RIA. No correlation existed between RIA and 3α-HSD when serum bile acids were analysed in healthy subjects partly due to the presence of varying amounts of secondary bile acids. (author)

  7. The bile acids, deoxycholic acid and ursodeoxycholic acid, regulate colonic epithelial wound healing.

    Science.gov (United States)

    Mroz, Magdalena S; Lajczak, Natalia K; Goggins, Bridie J; Keely, Simon; Keely, Stephen J

    2018-03-01

    The intestinal epithelium constitutes an innate barrier which, upon injury, undergoes self-repair processes known as restitution. Although bile acids are known as important regulators of epithelial function in health and disease, their effects on wound healing processes are not yet clear. Here we set out to investigate the effects of the colonic bile acids, deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA), on epithelial restitution. Wound healing in T 84 cell monolayers grown on transparent, permeable supports was assessed over 48 h with or without bile acids. Cell migration was measured in Boyden chambers. mRNA and protein expression were measured by RT-PCR and Western blotting. DCA (50-150 µM) significantly inhibited wound closure in cultured epithelial monolayers and attenuated cell migration in Boyden chamber assays. DCA also induced nuclear accumulation of the farnesoid X receptor (FXR), whereas an FXR agonist, GW4064 (10 µM), inhibited wound closure. Both DCA and GW4064 attenuated the expression of CFTR Cl - channels, whereas inhibition of CFTR activity with either CFTR- inh -172 (10 µM) or GlyH-101 (25 µM) also prevented wound healing. Promoter/reporter assays revealed that FXR-induced downregulation of CFTR is mediated at the transcriptional level. In contrast, UDCA (50-150 µM) enhanced wound healing in vitro and prevented the effects of DCA. Finally, DCA inhibited and UDCA promoted mucosal healing in an in vivo mouse model. In conclusion, these studies suggest bile acids are important regulators of epithelial wound healing and are therefore good targets for development of new drugs to modulate intestinal barrier function in disease treatment. NEW & NOTEWORTHY The secondary bile acid, deoxycholic acid, inhibits colonic epithelial wound healing, an effect which appears to be mediated by activation of the nuclear bile acid receptor, FXR, with subsequent downregulation of CFTR expression and activity. In contrast, ursodeoxycholic acid promotes

  8. Restoration of enterohepatic bile acid pathways in pregnant mice following short term activation of Fxr by GW4064

    International Nuclear Information System (INIS)

    Moscovitz, Jamie E.; Kong, Bo; Buckley, Kyle; Buckley, Brian; Guo, Grace L.; Aleksunes, Lauren M.

    2016-01-01

    The farnesoid X receptor (Fxr) controls bile acid homeostasis by coordinately regulating the expression of synthesizing enzymes (Cyp7a1, Cyp8b1), conjugating enzymes (Bal, Baat) and transporters in the ileum (Asbt, Ostα/β) and liver (Ntcp, Bsep, Ostβ). Transcriptional regulation by Fxr can be direct, or through the ileal Fgf15/FGF19 and hepatic Shp pathways. Circulating bile acids are increased during pregnancy due to hormone-mediated disruption of Fxr signaling. While this adaptation enhances lipid absorption, elevated bile acids may predispose women to develop maternal cholestasis. The objective of this study was to determine whether short-term treatment of pregnant mice with GW4064 (a potent FXR agonist) restores Fxr signaling to the level observed in virgin mice. Plasma, liver and ilea were collected from virgin and pregnant mice administered vehicle or GW4064 by oral gavage. Treatment of pregnant mice with GW4064 induced ileal Fgf15, Shp and Ostα/β mRNAs, and restored hepatic Shp, Bal, Ntcp, and Bsep back to vehicle-treated virgin levels. Pregnant mice exhibited 2.5-fold increase in Cyp7a1 mRNA compared to virgin controls, which was reduced by GW4064. Similarly treatment of mouse primary hepatocytes with plasma isolated from pregnant mice induced Cyp7a1 mRNA by nearly 3-fold as compared to virgin plasma, which could be attenuated by co-treatment with either GW4064 or recombinant FGF19 protein. Collectively, these data reveal that repressed activity of intestinal and hepatic Fxr in pregnancy, as previously demonstrated, may be restored by pharmacological activation. This study provides the basis for a novel approach to restore bile acid homeostasis in patients with maternal cholestasis. - Highlights: • Ileal bile acid pathways are altered in pregnancy in an Fxr-dependent manner. • Ileal Fxr/Fgf contributes to changes in hepatic bile acid synthesis and transport. • Treatment of pregnant mice with an Fxr agonist restores bile acid homeostasis.

  9. Restoration of enterohepatic bile acid pathways in pregnant mice following short term activation of Fxr by GW4064

    Energy Technology Data Exchange (ETDEWEB)

    Moscovitz, Jamie E.; Kong, Bo; Buckley, Kyle [Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, 170 Frelinghuysen Rd., Piscataway, NJ 08854 (United States); Buckley, Brian [Environmental and Occupational Health Sciences Institute, 170 Frelinghuysen Rd., Piscataway, NJ 08854 (United States); Guo, Grace L. [Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, 170 Frelinghuysen Rd., Piscataway, NJ 08854 (United States); Environmental and Occupational Health Sciences Institute, 170 Frelinghuysen Rd., Piscataway, NJ 08854 (United States); Aleksunes, Lauren M., E-mail: aleksunes@eohsi.rutgers.edu [Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, 170 Frelinghuysen Rd., Piscataway, NJ 08854 (United States); Environmental and Occupational Health Sciences Institute, 170 Frelinghuysen Rd., Piscataway, NJ 08854 (United States)

    2016-11-01

    The farnesoid X receptor (Fxr) controls bile acid homeostasis by coordinately regulating the expression of synthesizing enzymes (Cyp7a1, Cyp8b1), conjugating enzymes (Bal, Baat) and transporters in the ileum (Asbt, Ostα/β) and liver (Ntcp, Bsep, Ostβ). Transcriptional regulation by Fxr can be direct, or through the ileal Fgf15/FGF19 and hepatic Shp pathways. Circulating bile acids are increased during pregnancy due to hormone-mediated disruption of Fxr signaling. While this adaptation enhances lipid absorption, elevated bile acids may predispose women to develop maternal cholestasis. The objective of this study was to determine whether short-term treatment of pregnant mice with GW4064 (a potent FXR agonist) restores Fxr signaling to the level observed in virgin mice. Plasma, liver and ilea were collected from virgin and pregnant mice administered vehicle or GW4064 by oral gavage. Treatment of pregnant mice with GW4064 induced ileal Fgf15, Shp and Ostα/β mRNAs, and restored hepatic Shp, Bal, Ntcp, and Bsep back to vehicle-treated virgin levels. Pregnant mice exhibited 2.5-fold increase in Cyp7a1 mRNA compared to virgin controls, which was reduced by GW4064. Similarly treatment of mouse primary hepatocytes with plasma isolated from pregnant mice induced Cyp7a1 mRNA by nearly 3-fold as compared to virgin plasma, which could be attenuated by co-treatment with either GW4064 or recombinant FGF19 protein. Collectively, these data reveal that repressed activity of intestinal and hepatic Fxr in pregnancy, as previously demonstrated, may be restored by pharmacological activation. This study provides the basis for a novel approach to restore bile acid homeostasis in patients with maternal cholestasis. - Highlights: • Ileal bile acid pathways are altered in pregnancy in an Fxr-dependent manner. • Ileal Fxr/Fgf contributes to changes in hepatic bile acid synthesis and transport. • Treatment of pregnant mice with an Fxr agonist restores bile acid homeostasis.

  10. In vitro digestion with bile acids enhances the bioaccessibility of kale polyphenols.

    Science.gov (United States)

    Yang, Isabelle; Jayaprakasha, Guddarangavvanahally K; Patil, Bhimanagouda

    2018-02-21

    Kale (Brassica oleracea) is a leafy green vegetable belonging to the Brassicaceae family, and kale leaves have large amounts of dietary fiber and polyphenolics. Dietary fiber can bind bile acids, thus potentially decreasing cholesterol levels; however, whether the polyphenols from kale contribute to in vitro bile acid binding capacity remains unclear. In the present study, kale was extracted with hexane, acetone, and MeOH : water and the dried extracts, as well as the fiber-rich residue, were tested for their bile acid binding capacity. The fiber-rich residue bound total bile acids in amounts equivalent to that bound by raw kale. The lyophilized acetone extract bound significantly more glycochenodeoxycholate and glycodeoxycholate and less of other bile acids. To test whether bile acid binding enhanced the bioaccessibility of polyphenolic compounds from kale, we used ultra-performance liquid chromatography coupled with electrospray ionization/quadrupole-time-of-flight mass spectrometry to identify chemical constituents and measure their bioaccessibility in an in vitro digestion reaction. This identified 36 phenolic compounds in kale, including 18 kaempferol derivatives, 13 quercetin derivatives, 4 sinapoyl derivatives, and one caffeoylquinic acid. The bioaccessibility of these phenolics was significantly higher (69.4%) in digestions with bile acids. Moreover, bile acids enhanced the bioaccessibility of quercetin by 25 times: only 2.7% of quercetin derivatives were bioaccessible in the digestion without bile acids, but with bile acids, their accessibility increased to 69.5%. Bile acids increased the bioaccessibility of kaempferol from 37.7% to 69.2%. The extractability and biostability of total phenolics in the digested residue increased 1.8 fold in the digestions with bile acids. These results demonstrated the potential use of kale to improve human health.

  11. Obeticholic acid, a selective farnesoid X receptor agonist, regulates bile acid homeostasis in sandwich-cultured human hepatocytes.

    Science.gov (United States)

    Zhang, Yuanyuan; Jackson, Jonathan P; St Claire, Robert L; Freeman, Kimberly; Brouwer, Kenneth R; Edwards, Jeffrey E

    2017-08-01

    Farnesoid X receptor (FXR) is a master regulator of bile acid homeostasis through transcriptional regulation of genes involved in bile acid synthesis and cellular membrane transport. Impairment of bile acid efflux due to cholangiopathies results in chronic cholestasis leading to abnormal elevation of intrahepatic and systemic bile acid levels. Obeticholic acid (OCA) is a potent and selective FXR agonist that is 100-fold more potent than the endogenous ligand chenodeoxycholic acid (CDCA). The effects of OCA on genes involved in bile acid homeostasis were investigated using sandwich-cultured human hepatocytes. Gene expression was determined by measuring mRNA levels. OCA dose-dependently increased fibroblast growth factor-19 (FGF-19) and small heterodimer partner (SHP) which, in turn, suppress mRNA levels of cholesterol 7-alpha-hydroxylase (CYP7A1), the rate-limiting enzyme for de novo synthesis of bile acids. Consistent with CYP7A1 suppression, total bile acid content was decreased by OCA (1 μmol/L) to 42.7 ± 20.5% relative to control. In addition to suppressing de novo bile acids synthesis, OCA significantly increased the mRNA levels of transporters involved in bile acid homeostasis. The bile salt excretory pump (BSEP), a canalicular efflux transporter, increased by 6.4 ± 0.8-fold, and the basolateral efflux heterodimer transporters, organic solute transporter α (OST α ) and OST β increased by 6.4 ± 0.2-fold and 42.9 ± 7.9-fold, respectively. The upregulation of BSEP and OST α and OST β, by OCA reduced the intracellular concentrations of d 8 -TCA, a model bile acid, to 39.6 ± 8.9% relative to control. These data demonstrate that OCA does suppress bile acid synthesis and reduce hepatocellular bile acid levels, supporting the use of OCA to treat bile acid-induced toxicity observed in cholestatic diseases. © 2017 Intercept Pharmaceuticals. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and

  12. Effect of bile acids on digestion

    Directory of Open Access Journals (Sweden)

    O. O. Stremoukhov

    2013-12-01

    Full Text Available Studying the effects of different bile acids in the body in recent years significantly increased the understanding of their physiological functions. The role of bile acids is to transfer to Striated border of enterocytes lipids in high micellar concentration and subsequent return them to the water layer in the molecular form. The rate of diffusion of molecules or particles is inversely proportional to the square root of the magnitude of their molecular weight. Main components of the glycoprotein complex (GPC allows to preserve the natural structure of mucosa. Previous physicochemical experiments on GPC established presence of bile acids (3,5 to 10 mg/ml, enzymes (amylase and lipase, amino acids (from 10150 to 29500 ug/ml in the complex. Objective. The aim was to study the influence of bile on fat filtration on the model of GPC. Method and Materials. Soaked filters were put on the tubes: with bile - the first, water - the second group, GPC bile at a dose of 25 mg/kg - the third group. Then on each filter was poured 2 ml of liquid fat. 30 minutes after the start of the experiment the amount of liquid fat that passes through the filter was measured. Results and Discussion. As established in the first group (bile medical, the amount of liquid fat, which passed through the filter amounted to 1,85±0,02 ml. In the second group (water - 0,30 ± 0,03 ml. In the third group (GPC 25 mg/kg - 1,75±0,02 ml. After that the impact of GPC bile in emulsification of fats was studied. 1 ml of vegetable oil and 1,5 ml of purified water were contributed in three series of tubes. The first series of test tubes left unchanged. In the other two 2 ml in 2 series - medical bile in 3 series - GPC bile were added. Tubes were shaken in all series. In the first (control series observed the formation of turbid fluid - emulsion. However, in a few seconds instability of the emulsion was detected. In the second and third series of tubes formation of stable emulsions which are

  13. Bile acids and cardiovascular function in cirrhosis

    DEFF Research Database (Denmark)

    Voiosu, Andrei; Wiese, Signe; Voiosu, Theodor

    2017-01-01

    Cirrhotic cardiomyopathy and the hyperdynamic syndrome are clinically important complications of cirrhosis, but their exact pathogenesis is still partly unknown. Experimental models have proven the cardiotoxic effects of bile acids and recent studies of their varied receptor-mediated functions...... offer new insight into their involvement in cardiovascular dysfunction in cirrhosis. Bile acid receptors such as farnesoid X-activated receptor and TGR5 are currently under investigation as potential therapeutic targets in a variety of pathological conditions. These receptors have also recently been...... identified in cardiomyocytes, vascular endothelial cells and smooth muscle cells where they seem to play an important role in cellular metabolism. Chronic cholestasis leading to abnormal levels of circulating bile acids alters the normal signalling pathways and contributes to the development of profound...

  14. Comparison of the composition of bile acids in bile of patients with adenocarcinoma of the pancreas and benign disease.

    Science.gov (United States)

    Rees, David O; Crick, Peter J; Jenkins, Gareth J; Wang, Yuqin; Griffiths, William J; Brown, Tim H; Al-Sarireh, Bilal

    2017-11-01

    Bile acids have been implicated in the development of gastrointestinal malignancies. Both the specific nature of individual bile acids and their concentration appear key factors in the carcinogenic potency of bile. Using liquid chromatography mass spectrometry (LC-MS) we performed quantitative profiling of bile extracted directly from the common bile duct in 30 patients (15 patients with pancreatic cancer and 15 patients with benign disease). Separation and detection of bile acids was performed using a 1.7μm particle size reversed-phase C 18 LC column at a flow rate of 200μL/min with negative electrospray ionization MS. A significant difference (p=0.018) was seen in the concentration of unconjugated cholic acid in the malignant group (0.643mmol/L) compared to the benign group (0.022mmol/L), with an overall significant difference (p=0.04) seen in the level of total unconjugated bile acids in the malignant group (1.816mmol/L) compared to the benign group (0.069mmol/L). This finding may offer the possibility of both understanding the biology of cancer development in the pancreas, as well as offering a potential diagnostic avenue to explore. However, a larger study is necessary to confirm the alterations in bile acid profiles reported here and explore factors such as diet and microbial populations on the bile acid profiles of these patient groups. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  15. Modification on ursodeoxycholic acid (UDCA) scaffold. discovery of bile acid derivatives as selective agonists of cell-surface G-protein coupled bile acid receptor 1 (GP-BAR1).

    Science.gov (United States)

    Sepe, Valentina; Renga, Barbara; Festa, Carmen; D'Amore, Claudio; Masullo, Dario; Cipriani, Sabrina; Di Leva, Francesco Saverio; Monti, Maria Chiara; Novellino, Ettore; Limongelli, Vittorio; Zampella, Angela; Fiorucci, Stefano

    2014-09-25

    Bile acids are signaling molecules interacting with the nuclear receptor FXR and the G-protein coupled receptor 1 (GP-BAR1/TGR5). GP-BAR1 is a promising pharmacological target for the treatment of steatohepatitis, type 2 diabetes, and obesity. Endogenous bile acids and currently available semisynthetic bile acids are poorly selective toward GP-BAR1 and FXR. Thus, in the present study we have investigated around the structure of UDCA, a clinically used bile acid devoid of FXR agonist activity, to develop a large family of side chain modified 3α,7β-dihydroxyl cholanoids that selectively activate GP-BAR1. In vivo and in vitro pharmacological evaluation demonstrated that administration of compound 16 selectively increases the expression of pro-glucagon 1, a GP-BAR1 target, in the small intestine, while it had no effect on FXR target genes in the liver. Further, compound 16 results in a significant reshaping of bile acid pool in a rodent model of cholestasis. These data demonstrate that UDCA is a useful scaffold to generate novel and selective steroidal ligands for GP-BAR1.

  16. The influence of bile acids homeostasis by cryptotanshinone ...

    African Journals Online (AJOL)

    Background: Herbs might affect the homeostasis of bile acids through influence of multiple metabolic pathways of bile acids. Aim: The present study aims to investigate the inhibition of cryptotanshinone towards the glucuronidation of LCA, trying to indicate the possible influence of cryptotanshinone-containing herbs towards ...

  17. [Simultaneous determination of eight kinds of conjunct bile acids in human bile by R-HPLC].

    Science.gov (United States)

    Dai, Z; Tan, G; Qian, K; Chen, X

    1997-01-01

    A method for the simultaneous determination of eight kinds of conjunct bile acids in human bile was developed by HPLC. They were separated on a YWG-C18 (3 microns) column at 30 degrees C, with methanol/water (65/35, V/V, pH3.0) as mobile phase, and detection wavelength at UV 210 nm. The linear ranges were 50-1,000 microns.ml-1, the recoveries were 91.2%-108.6%. The biles of 30 cases with cholelithiasis cholecystolithiasis and 20 cases without gallstone were detected by HPLC. The results showed that the constitution of bile acids was different between patients with cholelithiasis cholecystolithiasis and patients without gallstone.

  18. The reversed feto-maternal bile acid gradient in intrahepatic cholestasis of pregnancy is corrected by ursodeoxycholic acid.

    Science.gov (United States)

    Geenes, Victoria; Lövgren-Sandblom, Anita; Benthin, Lisbet; Lawrance, Dominic; Chambers, Jenny; Gurung, Vinita; Thornton, Jim; Chappell, Lucy; Khan, Erum; Dixon, Peter; Marschall, Hanns-Ulrich; Williamson, Catherine

    2014-01-01

    Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder associated with an increased risk of adverse fetal outcomes. It is characterised by raised maternal serum bile acids, which are believed to cause the adverse outcomes. ICP is commonly treated with ursodeoxycholic acid (UDCA). This study aimed to determine the fetal and maternal bile acid profiles in normal and ICP pregnancies, and to examine the effect of UDCA treatment. Matched maternal and umbilical cord serum samples were collected from untreated ICP (n = 18), UDCA-treated ICP (n = 46) and uncomplicated pregnancy (n = 15) cases at the time of delivery. Nineteen individual bile acids were measured using HPLC-MS/MS. Maternal and fetal serum bile acids are significantly raised in ICP compared with normal pregnancy (p = acid. There are no differences between the umbilical cord artery and cord vein levels of the major bile acid species. The feto-maternal gradient of bile acids is reversed in ICP. Treatment with UDCA significantly reduces serum bile acids in the maternal compartment (p = acid (LCA) concentrations. ICP is associated with significant quantitative and qualitative changes in the maternal and fetal bile acid pools. Treatment with UDCA reduces the level of bile acids in both compartments and reverses the qualitative changes. We have not found evidence to support the suggestion that UDCA treatment increases fetal LCA concentrations to deleterious levels.

  19. Olfactory sensitivity of Pacific Lampreys to lamprey bile acids

    Science.gov (United States)

    Robinson, T. Craig; Sorensen, Peter W.; Bayer, Jennifer M.; Seelye, James G.

    2009-01-01

    Pacific lampreys Lampetra tridentata are in decline throughout much of their historical range in the Columbia River basin. In support of restoration efforts, we tested whether larval and adult lamprey bile acids serve as migratory and spawning pheromones in adult Pacific lampreys, as they do in sea lampreys Petromyzon marinus. The olfactory sensitivity of adult Pacific lampreys to lamprey bile acids was measured by electro-olfactogram recording from the time of their capture in the spring until their spawning in June of the following year. As controls, we tested L-arginine and a non-lamprey bile acid, taurolithocholic acid 3-sulfate (TLS). Migrating adult Pacific lampreys were highly sensitive to petromyzonol sulfate (a component of the sea lamprey migratory pheromone) and 3-keto petromyzonol sulfate (a component of the sea lamprey sex pheromone) when first captured. This sensitivity persisted throughout their long migratory and overwinter holding period before declining to nearly unmeasurable levels by the time of spawning. The absolute magnitudes of adult Pacific lamprey responses to lamprey bile acids were smaller than those of the sea lamprey, and unlike the sea lamprey, the Pacific lamprey did not appear to detect TLS. No sexual dimorphism was noted in olfactory sensitivity. Thus, Pacific lampreys are broadly similar to sea lampreys in showing sensitivity to the major lamprey bile acids but apparently differ in having a longer period of sensitivity to those acids. The potential utility of bile acid-like pheromones in the restoration of Pacific lampreys warrants their further investigation in this species.

  20. Conformation Control of a Conjugated Polymer through Complexation with Bile Acids Generates Its Novel Spectral and Morphological Properties.

    Science.gov (United States)

    Tsuchiya, Youichi; Noguchi, Takao; Yoshihara, Daisuke; Roy, Bappaditya; Yamamoto, Tatsuhiro; Shinkai, Seiji

    2016-11-29

    Control of higher-order polymer structures attracts a great deal of interest for many researchers when they lead to the development of materials having various advanced functions. Among them, conjugated polymers that are useful as starting materials in the design of molecular wires are particularly attractive. However, an equilibrium existing between isolated chains and bundled aggregates is inevitable and has made their physical properties very complicated. As an attempt to simplify this situation, we previously reported that a polymer chain of a water-soluble polythiophene could be isolated through complexation with a helix-forming polysaccharide. More recently, a covalently self-threading polythiophene was reported, the main chain of which was physically protected from self-folding and chain-chain π-stacking. In this report, we wish to report a new strategy to isolate a water-soluble polythiophene and to control its higher-order structure by a supramolecular approach: that is, among a few bile acids, lithocholate can form stoichiometric complexes with cationic polythiophene to isolate the polymer chain, and the higher-order structure is changeable by the molar ratio. The optical and morphological studies have been thoroughly performed, and the resultant complex has been applied to the selective recognition of two AMP structural isomers.

  1. DIETARY FISH-OIL POTENTIATES BILE ACID-INDUCED CHOLESTEROL SECRETION INTO BILE IN RATS

    NARCIS (Netherlands)

    SMIT, MJ; VERKADE, HJ; HAVINGA, R; VONK, RJ; SCHERPHOF, GL; TVELD, GI; KUIPERS, F

    Recently we demonstrated that dietary fish oil (FO) causes changes in intrahepatic cholesterol transport and hyper secretion of cholesterol into bile in rats V. Clin. Invest. 88: 943-951, 1991). We have now investigated in more detail the relationship between cholesterol and bile acid secretion in

  2. Tests for the absorption of /sup 75/Se-labelled homocholic acid conjugated with taurine (/sup 75/Se-HCAT)

    Energy Technology Data Exchange (ETDEWEB)

    Schroth, H.J.; Berberich, R.; Mueller, K.P.; Feifel, G.; Ecker, K.W.

    1985-05-01

    The absorption of selenomethionine Se 75-labelled homocholic acid conjugated with taurine (/sup 75/-SE-HCAT) was tested in 46 patients. Retention measurements using (1) an uncollimated gamma camera and (2) a measuring arrangement similar to a human-body counter were compared in order to obtain a quantitative assessment of the absorption capacity of the terminal ileum for bile acids. The retention curve obtained after the oral administration of the /sup 75/Se-labelled bile-acid analogue showed a monoexponential decline; in the case of unimpaired absorption, the half-life was greater than 2.5 days. When more than 30 cm of the ileum had been eliminated by inflammatory infection or resection, the measured half-life was below 0.5 days due to malabsorption. We also performed a quantitative determination of the hepatic secretion of /sup 75/-Se-HCAT into the gall bladder. If more than 80% of the activity administered is found in the gall bladder, disturbed absorption of bile acids in the terminal ileum can be excluded. Values smaller than 80%, however, do not provide proof of disturbed absorption.

  3. The interrelationship between bile acid and vitamin A homeostasis

    NARCIS (Netherlands)

    Saeed, Ali; Hoekstra, Mark; Hoeke, Martijn Oscar; Heegsma, Janette; Faber, Klaas Nico

    Vitamin A is a fat-soluble vitamin important for vision, reproduction, embryonic development, cell differentiation, epithelial barrier function and adequate immune responses. Efficient absorption of dietary vitamin A depends on the fat-solubilizing properties of bile acids. Bile acids are

  4. Vectorial transport of unconjugated and conjugated bile salts by monolayers of LLC-PK1 cells doubly transfected with human NTCP and BSEP or with rat Ntcp and Bsep.

    Science.gov (United States)

    Mita, Sachiko; Suzuki, Hiroshi; Akita, Hidetaka; Hayashi, Hisamitsu; Onuki, Reiko; Hofmann, Alan F; Sugiyama, Yuichi

    2006-03-01

    Na(+)-taurocholate-cotransporting peptide (NTCP)/SLC10A1 and bile salt export pump (BSEP)/ABCB11 synergistically play an important role in the transport of bile salts by the hepatocyte. In this study, we transfected human NTCP and BSEP or rat Ntcp and Bsep into LLC-PK1 cells, a cell line devoid of bile salts transporters. Transport by these cells was characterized with a focus on substrate specificity between rats and humans. The basal to apical flux of taurocholate across NTCP- and BSEP-expressing LLC-PK1 monolayers was 10 times higher than that in the opposite direction, whereas the flux across the monolayer of control and NTCP or BSEP single-expressing cells did not show any vectorial transport. The basal to apical flux of taurocholate was saturated with a K(m) value of 20 microM. Vectorial transcellular transport was also observed for cholate, chenodeoxycholate, ursodeoxycholate, their taurine and glycine conjugates, and taurodeoxycholate and glycodeoxycholate, whereas no transport of lithocholate was detected. To evaluate the respective functions of NTCP and BSEP and to compare them with those of rat Ntcp and Bsep, we calculated the clearance by each transporter in this system. A good correlation in the clearance of the examined bile salts (cholate, chenodeoxycholate, ursodeoxycholate, and their taurine or glycine conjugates) was observed between transport by human and that of rat transporters in terms of their rank order: for NTCP, taurine conjugates > glycine conjugates > unconjugated bile salts, and for BSEP, unconjugated bile salts and glycine conjugates > taurine conjugates. In conclusion, the substrate specificity of human and rat NTCP and BSEP appear to be very similar at least for monovalent bile salts under physiological conditions.

  5. Novel type of ornithine-glutathione double conjugate excreted as a major metabolite into the bile of rats administered clebopride

    International Nuclear Information System (INIS)

    Ishizuka, T.; Komiya, I.; Hiratsuka, A.; Watabe, T.

    1990-01-01

    Rats orally given radioactive Clebopride [[14C]CP; N-(1'-benzyl-4'-piperidyl)-2-[14C]methoxy-4-amino-5-chlorobenzamide++ +], an antiulcer agent, excreted a novel type of ornithine (Orn)-GSH double conjugate in the bile as a major metabolite [(14C]BMCP), corresponding to 18% of the dose. The present study provides the first evidence for Orn conjugation of a xenobiotic in mammals and demonstrates that the structure of the radioactive conjugate differs fundamentally from those known in birds and reptiles. The structure of the biliary metabolite, [14C]BMCP, purified to homogeneity by silica gel thin layer and reverse phase high pressure liquid chromatography, was elucidated as S-[2-ornithylamino-4-[14C]methoxy-5-(1'-methyl-4'-piperidylamin o) carboxyphenyl]glutathione, based mainly on the following facts: (1) BMCP showed a protonated molecular ion (M + H)+ peak at m/z 683 in the secondary ion mass spectrum and (2) [14C]BMCP afforded Orn, glutamic acid, glycine, S-(2-amino-4-[14C]methoxy-5-carboxyphenyl)cysteine [( 14C]AMCC), and 1-methyl-4-aminopiperidine (MAP) quantitatively, in an equal molar ratio, by complete hydrolysis with peptidase. Thus, BMCP was a metabolite with three enzymatically hydrolyzable amide bonds in addition to the one existing originally in the parent structure of the drug, which produces MAP by peptic digestion. Of the three additional amide bonds of BMCP, one was a novel type of bond formed by condensation of the alpha-carboxylic acid group of Orn with the primary aromatic amino group of the drug and the other two were in the S-glutathionyl residue, substituted for the chlorine atom vicinal to the Orn-conjugating primary amino group in the aromatic ring and affording glutamic acid, glycine, and the S-cysteine conjugate AMCC by hydrolysis of BMCP with the peptidase

  6. 3 alpha-Hydroxylated bile acid profiles in clinically normal cats, cats with severe hepatic lipidosis, and cats with complete extrahepatic bile duct occlusion.

    Science.gov (United States)

    Center, S A; Thompson, M; Guida, L

    1993-05-01

    Concentrations of 3 alpha-hydroxylated bile acids were measured in serum and urine of clinically normal (healthy) cats (n = 6), cats with severe hepatic lipidosis (n = 9), and cats with complete bile duct occlusion (n = 4). Bile acid concentrations were measured by use of a gradient flow high-performance liquid chromatography procedure with an acetonitrile and ammonium phosphate mobile phase and an in-line postanalytic column containing 3 alpha-hydroxy-steroid dehydrogenase and a fluorescence detector. Specific identification of all bile acid peaks was not completed; unidentified moieties were represented in terms of their elution time (in minutes). Significant differences in serum and urine bile acid concentrations, quantitative and proportional, were determined among groups of cats. Cats with hepatic lipidosis and bile duct occlusion had significantly (P > or = 0.05) greater total serum and urine bile acids concentrations than did healthy cats. The proportion of hydrophobic bile acids in serum, those eluting at > or = 400 minutes, was 1.9% for healthy cats, 3.3% for cats with lipidosis, and 5.4% for bile duct-obstructed cats. Both groups of ill cats had a broader spectrum of unidentified late-eluting serum bile acids than did healthy cats; the largest spectrum developed in bile duct-occluded cats.(ABSTRACT TRUNCATED AT 250 WORDS)

  7. PREPARATIVE ISOLATION AND PURIFICATION OF THREE GLYCINE-CONJUGATED CHOLIC ACIDS FROM PULVIS FELLIS SUIS BY HIGH-SPEED COUNTERCURRENT CHROMATOGRAPHY COUPLED WITH ELSD DETECTION

    OpenAIRE

    He, Jiao; Li, Jing; Sun, Wenji; Zhang, Tianyou; Ito, Yoichiro

    2012-01-01

    Coupled with evaporative light scattering detection, a high-speed counter-current chromatography (HSCCC) method was developed for preparative isolation and purification of three glycine-conjugated cholic acids, glycochenodeoxycholic acid (GCDCA), glycohyodeoxycholic acid (GHDCA) and glycohyocholic acid (GHCA) from Pulvis Fellis Suis (Pig gallbladder bile) for the first time. The separation was performed with a two-phase solvent system consisted of chloroform-methanol-water-acetic acid (65:30:...

  8. Comparison of endogenous and radiolabeled bile acid excretion in patients with idiopathic chronic diarrhea

    International Nuclear Information System (INIS)

    Schiller, L.R.; Bilhartz, L.E.; Santa Ana, C.A.

    1990-01-01

    Fecal recovery of radioactivity after ingestion of a bolus of radiolabeled bile acid is abnormally high in most patients with idiopathic chronic diarrhea. To evaluate the significance of this malabsorption, concurrent fecal excretion of both exogenous radiolabeled bile acid and endogenous (unlabeled) bile acid were measured in patients with idiopathic chronic diarrhea. Subjects received a 2.5-microCi oral dose of taurocholic acid labeled with 14C in the 24th position of the steroid moiety. Endogenous bile acid excretion was measured by a hydroxysteroid dehydrogenase assay on a concurrent 72-h stool collection. Both radiolabeled and endogenous bile acid excretion were abnormally high in most patients with chronic diarrhea compared with normal subjects, even when equivoluminous diarrhea was induced in normal subjects by ingestion of osmotically active solutions. The correlation between radiolabeled and endogenous bile acid excretion was good. However, neither radiolabeled nor endogenous bile acid excretion was as abnormal as is typically seen in patients with ileal resection, and none of these diarrhea patients responded to treatment with cholestyramine with stool weights less than 200 g. These results suggest (a) that this radiolabeled bile acid excretion test accurately reflects excess endogenous bile acid excretion; (b) that excess endogenous bile acid excretion is not caused by diarrhea per se; (c) that spontaneously occurring idiopathic chronic diarrhea is often associated with increased endogenous bile acid excretion; and (d) that bile acid malabsorption is not likely to be the primary cause of diarrhea in most of these patients

  9. The role of membrane cholesterol in determining bile acid cytotoxicity and cytoprotection of ursodeoxycholic acid

    Science.gov (United States)

    Zhou, Yong; Doyen, Rand; Lichtenberger, Lenard M.

    2013-01-01

    In cholestatic liver diseases, the ability of hydrophobic bile acids to damage membranes of hepatocytes/ductal cells contributes to their cytotoxicity. However, ursodeoxycholic acid (UDC), a hydrophilic bile acid, is used to treat cholestasis because it protects membranes. It has been well established that bile acids associate with and solubilize free cholesterol (CHOL) contained within the lumen of the gallbladder because of their structural similarities. However, there is a lack of understanding of how membrane CHOL, which is a well-established membrane stabilizing agent, is involved in cytotoxicity of hydrophobic bile acids and the cytoprotective effect of UDC. We utilized phospholipid liposomes to examine the ability of membrane CHOL to influence toxicity of individual bile acids, such as UDC and the highly toxic sodium deoxycholate (SDC), as well as the cytoprotective mechanism of UDC against SDC-induced cytotoxicity by measuring membrane permeation and intramembrane dipole potential. The kinetics of bile acid solubilization of phosphatidylcholine liposomes containing various levels of CHOL was also characterized. It was found that the presence of CHOL in membranes significantly reduced the ability of bile acids to damage synthetic membranes. UDC effectively prevented damaging effects of SDC on synthetic membranes only in the presence of membrane CHOL, while UDC enhances the damaging effects of SDC in the absence of CHOL. This further demonstrates that the cytoprotective effects of UDC depend upon the level of CHOL in the lipid membrane. Thus, changes in cell membrane composition, such as CHOL content, potentially influence the efficacy of UDC as the primary drug used to treat cholestasis. PMID:19150330

  10. Bile acid sequestrants for cholesterol

    Science.gov (United States)

    ... ency/patientinstructions/000787.htm Bile acid sequestrants for cholesterol To use the sharing features on this page, ... are medicines that help lower your LDL (bad) cholesterol . Too much cholesterol in your blood can stick ...

  11. Semi-Preparative Isolation and Purification of Three Tauro-Conjugated Cholic Acids from Pulvis Fellis Suis by HSCCC Coupled with ELSD Detection

    OpenAIRE

    He, Jiao; Zhang, Yongmin; Ito, Yoichiro; Sun, Wenji

    2011-01-01

    Coupled with evaporative light scattering detection, a high-speed counter-current chromatography (HSCCC) method was applied to the separation and purification of three tauro-conjugated cholic acids of taurochenodeoxycholic acid (TCDCA), taurohyodeoxycholic acid (THDCA) and taurohyocholic acid (THCA) from Pulvis Fellis Suis (Pig gallbladder bile) for the first time. The two-phase solvent system composed of chloroform-methanol-water-acetic acid (4:4:2:0.3, v/v/v/v) was selected for the one-step...

  12. Topochemical approach to efficiently produce main-chain poly(bile acid)s with high molecular weights.

    Science.gov (United States)

    Li, Weina; Li, Xuesong; Zhu, Wei; Li, Changxu; Xu, Dan; Ju, Yong; Li, Guangtao

    2011-07-21

    Based on a topochemical approach, a strategy for efficiently producing main-chain poly(bile acid)s in the solid state was developed. This strategy allows for facile and scalable synthesis of main-chain poly(bile acid)s not only with high molecular weights, but also with quantitative conversions and yields.

  13. [Substrate specificities of bile salt hydrolase 1 and its mutants from Lactobacillus salivarius].

    Science.gov (United States)

    Bi, Jie; Fang, Fang; Qiu, Yuying; Yang, Qingli; Chen, Jian

    2014-03-01

    In order to analyze the correlation between critical residues in the catalytic centre of BSH and the enzyme substrate specificity, seven mutants of Lactobacillus salivarius bile salt hydrolase (BSH1) were constructed by using the Escherichia coli pET-20b(+) gene expression system, rational design and site-directed mutagenesis. These BSH1 mutants exhibited different hydrolytic activities against various conjugated bile salts through substrate specificities comparison. Among the residues being tested, Cys2 and Thr264 were deduced as key sites for BSH1 to catalyze taurocholic acid and glycocholic acid, respectively. Moreover, Cys2 and Thr264 were important for keeping the catalytic activity of BSH1. The high conservative Cys2 was not the only active site, other mutant amino acid sites were possibly involved in substrate binding. These mutant residues might influence the space and shape of the substrate-binding pockets or the channel size for substrate passing through and entering active site of BSH1, thus, the hydrolytic activity of BSH1 was changed to different conjugated bile salt.

  14. New method for the determination of bile acid turnover using /sup 75/Se-homocholic acid taurine

    Energy Technology Data Exchange (ETDEWEB)

    Delhez, H.; Meerwaldt, J.H.; van den Berg, J.W.O.; van Blankenstein, M.

    1982-06-01

    The introduction of /sup 75/Se-homocholic acid taurine (/sup 75/SeHCAT) greatly facilitates the investigation of diarrhoea of unknown origin. By using gamma-labelled bile acids, daily faecal bile acid loss can be measured in total collected stools, thus circumventing laborious mixing and sampling. The /sup 75/SeHCAT method proved to be reliable for the determination of bile acid turnover, giving results identical to the established turnover method using /sup 14/C-taurocholic acid. The new method however, is simpler and faster.

  15. Crosstalk between Bile Acids and Gut Microbiota and Its Impact on Farnesoid X Receptor Signalling

    DEFF Research Database (Denmark)

    Wahlström, Annika; Kovatcheva-Datchary, Petia; Ståhlman, Marcus

    2017-01-01

    Background: The gut microbiota has a substantial impact on health and disease. The human gut microbiota influences the development and progression of metabolic diseases; however, the underlying mechanisms are not fully understood. The nuclear farnesoid X receptor (FXR), which regulates bile acid...... homeostasis and glucose and lipid metabolism, is activated by primary human and murine bile acids, chenodeoxycholic acid and cholic acid, while rodent specific primary bile acids tauromuricholic acids antagonise FXR activation. The gut microbiota deconjugates and subsequently metabolises primary bile acids...... into secondary bile acids in the gut and thereby changes FXR activation and signalling. Key Message: Mouse models have been used to study the crosstalk between bile acids and the gut microbiota, but the substantial differences in bile acid composition between humans and mice need to be considered when...

  16. Therapeutic Mechanisms of Bile Acids and Nor-Ursodeoxycholic Acid in Non-Alcoholic Fatty Liver Disease.

    Science.gov (United States)

    Steinacher, Daniel; Claudel, Thierry; Trauner, Michael

    2017-01-01

    Non-alcoholic fatty liver disease is one of the most rapidly rising clinical problems in the 21st century. So far no effective drug treatment has been established to cure this disease. Bile acids (BAs) have a variety of signaling properties, which can be used therapeutically for modulating hepatic metabolism and inflammation. A side-chain shorted derivative of ursodeoxycholic acid (UDCA) is 24 nor-ursodeoxycholic acid (NorUDCA) and it represents a new class of drugs for treatment of liver diseases. NorUDCA has unique biochemical and therapeutic properties, since it is relatively resistant to conjugation with glycine or taurine compared to UDCA. NorUDCA undergoes cholehepatic shunting, resulting in ductular targeting, bicarbonate-rich hypercholeresis, and cholangiocyte protection. Furthermore, it showed anti-fibrotic, anti-inflammatory, and anti-lipotoxic properties in several animal models. As such, NorUDCA is a promising new approach in the treatment of cholestatic and metabolic liver diseases. This review is a summary of current BA-based therapeutic approaches in the treatment of the fatty liver disease. © 2017 S. Karger AG, Basel.

  17. Akt-dependent NF-κB activation is required for bile acids to rescue colon cancer cells from stress-induced apoptosis

    International Nuclear Information System (INIS)

    Shant, Jasleen; Cheng, Kunrong; Marasa, Bernard S.; Wang Jianying; Raufman, Jean-Pierre

    2009-01-01

    Conjugated secondary bile acids promote human colon cancer cell proliferation by activating EGF receptors (EGFR). We hypothesized that bile acid-induced EGFR activation also mediates cell survival by downstream Akt-regulated activation of NF-κB. Deoxycholyltaurine (DCT) treatment attenuated TNF-α-induced colon cancer cell apoptosis, and stimulated rapid and sustained NF-κB nuclear translocation and transcriptional activity (detected by NF-κB binding to an oligonucleotide consensus sequence and by activation of luciferase reporter gene constructs). Both DCT-induced NF-κB nuclear translocation and attenuation of TNF-α-stimulated apoptosis were dependent on EGFR activation. Inhibitors of nuclear translocation, proteosome activity, and IκBα kinase attenuated NF-κB transcriptional activity. Cell transfection with adenoviral vectors encoding a non-degradable IκBα 'super-repressor' blocked the actions of DCT on both NF-κB activation and TNF-α-induced apoptosis. Likewise, transfection with mutant akt and treatment with a chemical inhibitor of Akt attenuated effects of DCT on NF-κB transcriptional activity and TNF-α-induced apoptosis. Chemical inhibitors of Akt and NF-κB activation also attenuated DCT-induced rescue of H508 cells from ultraviolet radiation-induced apoptosis. Collectively, these observations indicate that, downstream of EGFR, bile acid-induced colon cancer cell survival is mediated by Akt-dependent NF-κB activation. These findings provide a mechanism whereby bile acids increase resistance of colon cancer to chemotherapy and radiation

  18. Ion-neutral Clustering of Bile Acids in Electrospray Ionization Across UPLC Flow Regimes

    Science.gov (United States)

    Brophy, Patrick; Broeckling, Corey D.; Murphy, James; Prenni, Jessica E.

    2018-02-01

    Bile acid authentic standards were used as model compounds to quantitatively evaluate complex in-source phenomenon on a UPLC-ESI-TOF-MS operated in the negative mode. Three different diameter columns and a ceramic-based microfluidic separation device were utilized, allowing for detailed descriptions of bile acid behavior across a wide range of flow regimes and instantaneous concentrations. A custom processing algorithm based on correlation analysis was developed to group together all ion signals arising from a single compound; these grouped signals produce verified compound spectra for each bile acid at each on-column mass loading. Significant adduction was observed for all bile acids investigated under all flow regimes and across a wide range of bile acid concentrations. The distribution of bile acid containing clusters was found to depend on the specific bile acid species, solvent flow rate, and bile acid concentration. Relative abundancies of each cluster changed non-linearly with concentration. It was found that summing all MS level (low collisional energy) ions and ion-neutral adducts arising from a single compound improves linearity across the concentration range (0.125-5 ng on column) and increases the sensitivity of MS level quantification. The behavior of each cluster roughly follows simple equilibrium processes consistent with our understanding of electrospray ionization mechanisms and ion transport processes occurring in atmospheric pressure interfaces. [Figure not available: see fulltext.

  19. [Effect of high blood levels of bile acid on respiratory functions of New Zealand rabbits].

    Science.gov (United States)

    Wang, Fei; Zhao, Cong; Tian, Yinghong; Yin, Yanru

    2013-08-01

    To compare the patterns of respiratory function variations resulting from the classical reflex of blood pressure fall and high blood levels of bile acid, so as to provide evidence for the regulation of respiratory function via bile acids. Seventy New Zealand male Rabbits, under general anesthesia with 20% urethane, were subjected to tracheal intubations and carotid artery cannulations via median incisions of the neck. Using a biological signal acquisition system, the changes in the breathing and blood pressure were observed in response to stimulation of the pneumogastric nerves or to ear vein injections of diluted bile acids or the water solutions of 5 dissociated bile acids. Stimulation of the pneumogastric nerves and injections of diluted bile acids both lowered the blood pressure without significant differences in the total reaction time (T). However, the total respiratory reaction time of bile acids, RT(bile acids), was 9-10 times longer than the total reaction time of blood pressure T(bile acids) (Pacids) were higher than that RR(pneumogastric nerves)resulting from the classical reflex (Pacids), the values of RR(bile acids) were significantly higher than those of RR(bile acids) in RT2(bile acids) interval. UDCA produced no significant influence on blood pressure or respiratory function (Pacid reagents did (Pacids not only act through reflex factors but also have direct effects on respiratory function regulation. Under our experimental conditions, UDCA has no effect on blood pressure or respiratory function, but the other 4 dissociated bile acid reagents can all dose-dependently lower blood pressure and significantly affect respiratory function.

  20. Clinical relevance of the bile acid receptor TGR5 in metabolism

    DEFF Research Database (Denmark)

    van Nierop, F Samuel; Scheltema, Matthijs J; Eggink, Hannah M

    2017-01-01

    The bile acid receptor TGR5 (also known as GPBAR1) is a promising target for the development of pharmacological interventions in metabolic diseases, including type 2 diabetes, obesity, and non-alcoholic steatohepatitis. TGR5 is expressed in many metabolically active tissues, but complex enterohep......The bile acid receptor TGR5 (also known as GPBAR1) is a promising target for the development of pharmacological interventions in metabolic diseases, including type 2 diabetes, obesity, and non-alcoholic steatohepatitis. TGR5 is expressed in many metabolically active tissues, but complex...... enterohepatic bile acid cycling limits the exposure of some of these tissues to the receptor ligand. Profound interspecies differences in the biology of bile acids and their receptors in different cells and tissues exist. Data from preclinical studies show promising effects of targeting TGR5 on outcomes...... such as weight loss, glucose metabolism, energy expenditure, and suppression of inflammation. However, clinical studies are scarce. We give a summary of key concepts in bile acid metabolism; outline different downstream effects of TGR5 activation; and review available data on TGR5 activation, with a focus...

  1. The bile acid-sequestering resin sevelamer eliminates the acute GLP-1 stimulatory effect of endogenously released bile acids in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Brønden, Andreas; Albér, Anders; Rohde, Ulrich

    2018-01-01

    AIMS: The discovery of the specific bile acid receptors farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) in enteroendocrine L cells has prompted research focusing on the impact of bile acids on glucagon-like peptide-1 (GLP-1) secretion and glucose metabolism. The aim of t...

  2. Evidence connecting old, new and neglected glucose-lowering drugs to bile acid-induced GLP-1 secretion

    DEFF Research Database (Denmark)

    Kårhus, Martin L; Brønden, Andreas; Sonne, David P

    2017-01-01

    Bile acids are amphipathic water-soluble steroid-based molecules best known for their important lipid-solubilizing role in the assimilation of fat. Recently, bile acids have emerged as metabolic integrators with glucose-lowering potential. Among a variety of gluco-metabolic effects, bile acids have...... current evidence connecting established glucose-lowering drugs to bile acid-induced GLP-1 secretion and discusses whether bile acid-induced GLP-1 secretion may constitute a new basis for understanding how metformin, inhibitors of the apical sodium-dependent bile acids transporter, and bile acid...... sequestrants - old, new and neglected glucose-lowering drugs - improve glucose metabolism....

  3. Unusual binding of ursodeoxycholic acid to ileal bile acid binding protein: role in activation of FXRα[S

    Science.gov (United States)

    Fang, Changming; Filipp, Fabian V.; Smith, Jeffrey W.

    2012-01-01

    Ursodeoxycholic acid (UDCA, ursodiol) is used to prevent damage to the liver in patients with primary biliary cirrhosis. The drug also prevents the progression of colorectal cancer and the recurrence of high-grade colonic dysplasia. However, the molecular mechanism by which UDCA elicits its beneficial effects is not entirely understood. The aim of this study was to determine whether ileal bile acid binding protein (IBABP) has a role in mediating the effects of UDCA. We find that UDCA binds to a single site on IBABP and increases the affinity for major human bile acids at a second binding site. As UDCA occupies one of the bile acid binding sites on IBABP, it reduces the cooperative binding that is often observed for the major human bile acids. Furthermore, IBABP is necessary for the full activation of farnesoid X receptor α (FXRα) by bile acids, including UDCA. These observations suggest that IBABP may have a role in mediating some of the intestinal effects of UDCA. PMID:22223860

  4. Investigations into the choice of immunogen, ligand, antiserum and assay conditions for the radioimmunoassay of conjugated cholic acid

    Energy Technology Data Exchange (ETDEWEB)

    Beckett, G J; Percy-Robb, I W [Royal Infirmary, Edinburgh (UK); Hunter, W M [Medical Research Council, Edinburgh (UK)

    1978-09-01

    Investigations into the choice of immunogen, ligand, antiserum and assay conditions for the radioimmunoassay of conjugated cholic acid have been performed with a view to producing optimal assay conditions. Cholic acid-BSA was found to be the best immunogen to produce antibodies to conjugated cholic acid and the response was of an IgG type. Incorporating a spacer (hexanoic acid) between hapten and carrier protein resulted in a decrease in antiserum titre. Optimal conditions for the assay were found using (/sup 125/I)histamine-glycocholic acid as ligand with a dilution of antiserum to produce 60% binding of ligand and a pH of 7.4. Using these assay conditions no serum effects were found; extraction of serum prior to assay was therefore unnecessary. The assay was sensitive enough to detect post-prandial increases in serum bile acid concentrations following a liquid test meal; no increase was observed throughout the same time period in a fasting control.

  5. Molecular interactions between selected sodium salts of bile acids and morphine hydrochloride.

    Science.gov (United States)

    Poša, Mihalj; Csanádi, János; Kövér, Katalin E; Guzsvány, Valéria; Batta, Gyula

    2012-06-01

    The objective of this study was to understand the prolonged analgesic action of morphine hydrochloride observed in the presence of sodium 12-oxochenodeoxycholanate. Based on literature, this phenomenon may be due to the formation of aggregates in the cell between the molecules of bile acids and morphine. In addition to the sodium 12-oxochenodeoxycholanate, the present investigation also included salts of cholic and 7-oxodeoxycholic acids. Saturation transfer difference NMR experiments showed that morphine binds to the bile acid molecule close to the aromatic protons H1 and H2 provided that the concentration of the bile acid salt approaches the critical micellar concentration (CMC). The spin-lattice relaxation times (T(1)) of the affected protons decrease significantly in the presence of micellar solutions of the bile acid salts, and the most pronounced change in T(1) was observed for sodium 7-oxodeoxycholate. Diffusion-ordered NMR experiments suggested that morphine hydrochloride can interact only with sodium 7-oxochenodeoxycholate. It can be supposed that the molecular ratio of sodium 7-oxodeoxycholate and morphine hydrochloride in the mixed micelle is 2:1. The CMC values of mixed micelles do not differ from the CMC values of the micelle constituents, which suggests that the binding of morphine hydrochloride does not perturb the hydrophobic domain of the bile acid molecule. In the presence of bile acids, the transfer rate constant (k(12)) of morphine hydrochloride from the buffered aqueous solution to chloroform (model of the cell membrane) shows a decrease. A significant decrease of the k(12) was also observed in the presence of micellar solutions. Kinetic measurements indicated that, in addition to micellar interaction between morphine hydrochloride and sodium salts of bile acids, a complex may also be formed in chloroform via hydrogen bonds formed between the drug and bile acid molecules. Copyright © 2012 Elsevier B.V. All rights reserved.

  6. The Xenobiotic Transporter Mdr1 Enforces T Cell Homeostasis in the Presence of Intestinal Bile Acids.

    Science.gov (United States)

    Cao, Wei; Kayama, Hisako; Chen, Mei Lan; Delmas, Amber; Sun, Amy; Kim, Sang Yong; Rangarajan, Erumbi S; McKevitt, Kelly; Beck, Amanda P; Jackson, Cody B; Crynen, Gogce; Oikonomopoulos, Angelos; Lacey, Precious N; Martinez, Gustavo J; Izard, Tina; Lorenz, Robin G; Rodriguez-Palacios, Alex; Cominelli, Fabio; Abreu, Maria T; Hommes, Daniel W; Koralov, Sergei B; Takeda, Kiyoshi; Sundrud, Mark S

    2017-12-19

    CD4 + T cells are tightly regulated by microbiota in the intestine, but whether intestinal T cells interface with host-derived metabolites is less clear. Here, we show that CD4 + T effector (Teff) cells upregulated the xenobiotic transporter, Mdr1, in the ileum to maintain homeostasis in the presence of bile acids. Whereas wild-type Teff cells upregulated Mdr1 in the ileum, those lacking Mdr1 displayed mucosal dysfunction and induced Crohn's disease-like ileitis following transfer into Rag1 -/- hosts. Mdr1 mitigated oxidative stress and enforced homeostasis in Teff cells exposed to conjugated bile acids (CBAs), a class of liver-derived emulsifying agents that actively circulate through the ileal mucosa. Blocking ileal CBA reabsorption in transferred Rag1 -/- mice restored Mdr1-deficient Teff cell homeostasis and attenuated ileitis. Further, a subset of ileal Crohn's disease patients displayed MDR1 loss of function. Together, these results suggest that coordinated interaction between mucosal Teff cells and CBAs in the ileum regulate intestinal immune homeostasis. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Novel type of ornithine-glutathione double conjugate excreted as a major metabolite into the bile of rats administered clebopride.

    Science.gov (United States)

    Ishizuka, T; Komiya, I; Hiratsuka, A; Watabe, T

    1990-06-01

    Rats orally given radioactive Clebopride [[14C]CP; N-(1'-benzyl-4'-piperidyl)-2-[14C]methoxy-4-amino-5-chlorobenzamide++ +], an antiulcer agent, excreted a novel type of ornithine (Orn)-GSH double conjugate in the bile as a major metabolite [( 14C]BMCP), corresponding to 18% of the dose. The present study provides the first evidence for Orn conjugation of a xenobiotic in mammals and demonstrates that the structure of the radioactive conjugate differs fundamentally from those known in birds and reptiles. The structure of the biliary metabolite, [14C]BMCP, purified to homogeneity by silica gel thin layer and reverse phase high pressure liquid chromatography, was elucidated as S-[2-ornithylamino-4-[14C]methoxy-5-(1'-methyl-4'-piperidylamin o) carboxyphenyl]glutathione, based mainly on the following facts: 1) BMCP showed a protonated molecular ion (M + H)+ peak at m/z 683 in the secondary ion mass spectrum and 2) [14C]BMCP afforded Orn, glutamic acid, glycine, S-(2-amino-4-[14C]methoxy-5-carboxyphenyl)cysteine [( 14C]AMCC), and 1-methyl-4-aminopiperidine (MAP) quantitatively, in an equal molar ratio, by complete hydrolysis with peptidase. Thus, BMCP was a metabolite with three enzymatically hydrolyzable amide bonds in addition to the one existing originally in the parent structure of the drug, which produces MAP by peptic digestion. Of the three additional amide bonds of BMCP, one was a novel type of bond formed by condensation of the alpha-carboxylic acid group of Orn with the primary aromatic amino group of the drug and the other two were in the S-glutathionyl residue, substituted for the chlorine atom vicinal to the Orn-conjugating primary amino group in the aromatic ring and affording glutamic acid, glycine, and the S-cysteine conjugate AMCC by hydrolysis of BMCP with the peptidase. Substitution of a methyl group for the benzyl group at the piperidine ring nitrogen atom, leading to the formation of MAP by peptic digestion, also occurred during metabolism of CP to

  8. Effect of chenodeoxycholic acid and the bile acid sequestrant colesevelam on glucagon-like peptide-1 secretion

    DEFF Research Database (Denmark)

    Hansen, Morten; Scheltema, Matthijs J; Sonne, David P

    2016-01-01

    AIMS: In patients with type 2 diabetes, rectal administration of bile acids increases glucagon-like peptide-1 (GLP-1) secretion and reduces plasma glucose. In addition, oral bile acid sequestrants (BASs) reduce blood glucose by an unknown mechanism. In this study we evaluated the effects...... of the primary human bile acid, chenodeoxycholic acid (CDCA), and the BAS, colesevelam, instilled into the stomach, on plasma levels of GLP-1, glucose-dependent insulinotropic polypeptide, glucose, insulin, C-peptide, glucagon, cholecystokinin and gastrin as well as gastric emptying, gallbladder volume, appetite......, and delayed gastric emptying. We speculate that bile acid-induced activation of TGR5 on L cells increases GLP-1 secretion, which in turn may result in amplification of glucose-stimulated insulin secretion. Furthermore our data suggest that colesevelam does not have an acute effect on GLP-1 secretion in humans....

  9. Selenium- or tellurium- containing bile acids and derivatives thereof

    International Nuclear Information System (INIS)

    Monks, R.; Riley, A.L.M.

    1981-01-01

    This invention relates to the preparation of selenium and tellurium derivatives, particularly γ-emitting radioactive derivatives of bile acids and bile salts. Such compounds are valuable in the examination of body function, especially small bowel function. (author)

  10. HPLC/ELSD analysis of amidated bile acids: an effective and rapid way to assist continuous flow chemistry processes.

    Science.gov (United States)

    Sardella, Roccaldo; Gioiello, Antimo; Ianni, Federica; Venturoni, Francesco; Natalini, Benedetto

    2012-10-15

    The employment of the flow N-acyl amidation of natural bile acids (BAs) required the in-line connection with suitable analytical tools enabling the determination of reaction yields as well as of the purity grade of the synthesized glyco- and tauro-conjugated derivatives. In this framework, a unique HPLC method was successfully established and validated for ursodeoxycholic (UDCA), chenodeoxycholic (CDCA), deoxycholic (DCA) and cholic (CA) acids, as well as the corresponding glyco- and tauro-conjugated forms. Because of the shared absence of relevant chromophoric moieties in the sample structure, an evaporative light scattering detector (ELSD) was profitably utilized for the analysis of such steroidal species. For each of the investigated compounds, all the runs were contemporarily carried out on the acidic free and the two relative conjugated variants. The different ELSD response of the free and the corresponding conjugated BAs, imposed to build-up separate calibration curves. In all the cases, very good precision (RSD% values ranging from 1.04 to 6.40% in the long-period) and accuracy (Recovery% values ranging from 96.03 to 111.14% in the long-period) values along with appreciably low LOD and LOQ values (the former being within the range 1-27 ng mL(-1) and the latter within the range 2-44 ng mL(-1)) turned out. Copyright © 2012 Elsevier B.V. All rights reserved.

  11. Discrimination of bile acids by the rainbow trout olfactory system: Evidence as potential pheromone

    Directory of Open Access Journals (Sweden)

    PERCILIA C GIAQUINTO

    2008-01-01

    Full Text Available Electro-olfactogram recording was used to determine whether the olfactory epithelium of adult rainbow trout is specifically sensitive to bile acids, some of which have been hypothesized to function as pheromones. Of 38 bile acids that had been pre-screened for olfactory activity, 6 were selected. The rainbow trout-specific bile acids, taurocholic acid (TCA, and taurolithocholic acid 3-sulfate (TLS were the most potent compounds tested. TLS had a distinctive dose-response curve. Cross-adaptation experiments demonstrated that sensitivity to bile acids is attributable to at least 3 independent classes of olfactory receptor sites. Our data suggest that bile acids are discriminated by olfaction in rainbow trout, supporting the possibility that these compounds function as pheromones

  12. Comparison of bile acid synthesis determined by isotope dilution versus fecal acidic sterol output in human subjects

    International Nuclear Information System (INIS)

    Duane, W.C.; Holloway, D.E.; Hutton, S.W.; Corcoran, P.J.; Haas, N.A.

    1982-01-01

    Fecal acidic sterol output has been found to be much lower than bile acid synthesis determined by isotope dilution. Because of this confusing discrepancy, we compared these 2 measurements done simultaneously on 13 occasions in 5 normal volunteers. In contrast to previous findings, bile acid synthesis by the Lindstedt isotope dilution method averaged 16.3% lower than synthesis simultaneously determined by fecal acidic sterol output (95% confidence limit for the difference - 22.2 to -10.4%). When one-sample determinations of bile acid pools were substituted for Lindstedt pools, bile acid synthesis by isotope dilution averaged 5.6% higher than synthesis by fecal acidic sterol output (95% confidence limits -4.9 to 16.1%). These data indicate that the 2 methods yield values in reasonably close agreement with one another. If anything, fecal acidic sterol outputs are slightly higher than synthesis by isotope dilution

  13. Intestinal Crosstalk between Bile Acids and Microbiota and Its Impact on Host Metabolism

    DEFF Research Database (Denmark)

    Wahlström, Annika; Sayin, Sama I; Marschall, Hanns-Ulrich

    2016-01-01

    The gut microbiota is considered a metabolic "organ" that not only facilitates harvesting of nutrients and energy from the ingested food but also produces numerous metabolites that signal through their cognate receptors to regulate host metabolism. One such class of metabolites, bile acids......, is produced in the liver from cholesterol and metabolized in the intestine by the gut microbiota. These bioconversions modulate the signaling properties of bile acids via the nuclear farnesoid X receptor and the G protein-coupled membrane receptor 5, which regulate numerous metabolic pathways in the host....... Conversely, bile acids can modulate gut microbial composition both directly and indirectly through activation of innate immune genes in the small intestine. Thus, host metabolism can be affected through microbial modifications of bile acids, which lead to altered signaling via bile acid receptors, but also...

  14. Effect of fat intake on cholesterol turnover and bile acid formation

    International Nuclear Information System (INIS)

    Iritani, Nobuko; Fukuda, Eiko; Ibamoto, Kazuko

    1977-01-01

    Three groups of male rats were maintained on diets containing different amounts of fat. After one week on such regimens, they were injected intraperitoneally with cholesterol- 3 H. During the following 28 days, the radioactivity and quantity of fecal cholesterol and its metabolites were determined. The coprostanol excretion was the about same in all groups and the bile acids excretion increased with increasing fat intake; however, compared to the fat-free group, the excretion of the injected cholesterol- 3 H was greater in the 3% fat group and less in the 10% fat group. Consequently, the specific radioactivity of bile acids was lower in the 10% group than in the others. The half-life of labelled cholesterol was 12.6, 16.0 and 22.2 days for the 3%, 10% fat and fat-free groups, respectively. Rather than a fat-free diet, a low-fat diet of 3% or so, would be of more advantage in eliminating cholesterol by increasing the formation of bile acids to emulsify the fat. In the 10% fat group, however, the enlarged pool size of bile acid probably delayed cholesterol metabolism to bile acids. (auth.)

  15. Formation of C21 bile acids from plant sterols in the rat

    International Nuclear Information System (INIS)

    Boberg, K.M.; Lund, E.; Olund, J.; Bjoerkhem, I.

    1990-01-01

    Formation of bile acids from sitosterol in bile-fistulated female Wistar rats was studied with use of 4-14C-labeled sitosterol and sitosterol labeled with 3H in specific positions. The major part (about 75%) of the 14C radioactivity recovered as bile acids in bile after intravenous administration of [4-14C]sitosterol was found to be considerably more polar than cholic acid, and only trace amounts of radioactivity had chromatographic properties similar to those of cholic acid and chenodeoxycholic acid. It was shown that polar metabolites were formed by intermediate oxidation of the 3 beta-hydroxyl group (loss of 3H from 3 alpha-3H-labeled sitosterol) and that the most polar fraction did not contain a hydroxyl group at C7 (retention of 3H in 7 alpha,7 beta-3H2-labeled sitosterol). Furthermore, the polar metabolites had lost at least the terminal 6 or 7 carbon atoms of the side chain (loss of 3H from 22,23-3H2- and 24,28-3H2-labeled sitosterol). Experiments with 3H-labeled 7 alpha-hydroxysitosterol and 4-14C-labeled 26-hydroxysitosterol showed that none of these compounds was an efficient precursor to the polar metabolites. By analysis of purified most polar products of [4-14C] sitosterol by radio-gas chromatography and the same products of 7 alpha,7 beta-[2H2]sitosterol by combined gas chromatography-mass spectrometry, two major metabolites could be identified as C21 bile acids. One metabolite had three hydroxyl groups (3 alpha, 15, and unknown), and one had two hydroxyl groups (3 alpha, 15) and one keto group. Considerably less C21 bile acids were formed from [4-14C]sitosterol in male than in female Wistar rats. The C21 bile acids formed in male rats did not contain a 15-hydroxyl group. Conversion of a [4-14C]sitosterol into C21 bile acids did also occur in adrenalectomized and ovariectomized rats, indicating that endocrine tissues are not involved

  16. Effects of bile salt deconjugation by probiotic strains on the survival of antibiotic-resistant foodborne pathogens under simulated gastric conditions.

    Science.gov (United States)

    He, Xinlong; Zou, Yunyun; Cho, Youngjae; Ahn, Juhee

    2012-06-01

    This study was designed to evaluate the effects of bile acid deconjugation by probiotic strains on the antibiotic susceptibility of antibiotic-sensitive and multiple antibiotic-resistant Salmonella Typhimurium and Staphylococcus aureus. Eight probiotic strains, Bifidobacterium longum B6, Lactobacillus acidophilus ADH, Lactobacillus brevis KACC 10553, Lactobacillus casei KACC 12413, Lactobacillus paracasei ATCC 25598, Lactobacillus rhamnosus GG, Leuconostoc mesenteroides KACC 12312, and Pediococcus acidilactici KACC 12307, were used to examine bile acid tolerance. The ability to deconjugate bile acids was evaluated using both thin-layer chromatography and high-performance liquid chromatography. The antibiotic susceptibility testing was carried out to determine the synergistic inhibitory activity of deconjugated bile acids. L. acidophilus, L. brevis, and P. acidilactici showed the most tolerance to the conjugated bile acids. P. acidilactici deconjugated glycocholic acid and glycodeoxycholate from 3.18 and 3.09 mM to the detection limits, respectively. The antibiotic susceptibility of selected foodborne pathogens was increased by increasing the concentration of deconjugated bile acids. The study results are useful for understanding the relationship between bile acid deconjugation by probiotic strains and antibiotic susceptibility in the presence of deconjugated bile acids, and they may be useful for designing new probiotic-antibiotic combination therapy based on bile acid deconjugation.

  17. MALDI Mass Spectral Imaging of Bile Acids Observed as Deprotonated Molecules and Proton-Bound Dimers from Mouse Liver Sections

    Science.gov (United States)

    Rzagalinski, Ignacy; Hainz, Nadine; Meier, Carola; Tschernig, Thomas; Volmer, Dietrich A.

    2018-02-01

    Bile acids (BAs) play two vital roles in living organisms, as they are involved in (1) the secretion of cholesterol from liver, and (2) the lipid digestion/absorption in the intestine. Abnormal bile acid synthesis or secretion can lead to severe liver disorders. Even though there is extensive literature on the mass spectrometric determination of BAs in biofluids and tissue homogenates, there are no reports on the spatial distribution in the biliary network of the liver. Here, we demonstrate the application of high mass resolution/mass accuracy matrix-assisted laser desorption/ionization (MALDI)-Fourier-transform ion cyclotron resonance (FTICR) to MS imaging (MSI) of BAs at high spatial resolutions (pixel size, 25 μm). The results show chemical heterogeneity of the mouse liver sections with a number of branching biliary and blood ducts. In addition to ion signals from deprotonation of the BA molecules, MALDI-MSI generated several further intense signals at larger m/z for the BAs. These signals were spatially co-localized with the deprotonated molecules and easily misinterpreted as additional products of BA biotransformations. In-depth analysis of accurate mass shifts and additional electrospray ionization and MALDI-FTICR experiments, however, confirmed them as proton-bound dimers. Interestingly, dimers of bile acids, but also unusual mixed dimers of different taurine-conjugated bile acids and free taurine, were identified. Since formation of these complexes will negatively influence signal intensities of the desired [M - H]- ions and significantly complicate mass spectral interpretations, two simple broadband techniques were proposed for non-selective dissociation of dimers that lead to increased signals for the deprotonated BAs. [Figure not available: see fulltext.

  18. Bile acid composition of gallbladder contents in dogs with gallbladder mucocele and biliary sludge.

    Science.gov (United States)

    Kakimoto, Toshiaki; Kanemoto, Hideyuki; Fukushima, Kenjiro; Ohno, Koichi; Tsujimoto, Hajime

    2017-02-01

    OBJECTIVE To examine bile acid composition of gallbladder contents in dogs with gallbladder mucocele and biliary sludge. ANIMALS 18 dogs with gallbladder mucocele (GBM group), 8 dogs with immobile biliary sludge (i-BS group), 17 dogs with mobile biliary sludge (m-BS group), and 14 healthy dogs (control group). PROCEDURES Samples of gallbladder contents were obtained by use of percutaneous ultrasound-guided cholecystocentesis or during cholecystectomy or necropsy. Concentrations of 15 bile acids were determined by use of highperformance liquid chromatography, and a bile acid compositional ratio was calculated for each group. RESULTS Concentrations of most bile acids in the GBM group were significantly lower than those in the control and m-BS groups. Compositional ratio of taurodeoxycholic acid, which is 1 of 3 major bile acids in dogs, was significantly lower in the GBM and i-BS groups, compared with ratios for the control and m-BS groups. The compositional ratio of taurocholic acid was significantly higher and that of taurochenodeoxycholic acid significantly lower in the i-BS group than in the control group. CONCLUSIONS AND CLINICAL RELEVANCE In this study, concentrations and fractions of bile acids in gallbladder contents were significantly different in dogs with gallbladder mucocele or immobile biliary sludge, compared with results for healthy control dogs. Studies are needed to determine whether changes in bile acid composition are primary or secondary events of gallbladder abnormalities.

  19. Acid, bile, and heat tolerance of free and microencapsulated probiotic bacteria.

    Science.gov (United States)

    Ding, W K; Shah, N P

    2007-11-01

    Eight strains of probiotic bacteria, including Lactobacillus rhamnosus, Bifidobacterium longum, L. salivarius, L. plantarum, L. acidophilus, L. paracasei, B. lactis type Bl-O4, and B. lactis type Bi-07, were studied for their acid, bile, and heat tolerance. Microencapsulation in alginate matrix was used to enhance survival of the bacteria in acid and bile as well as a brief exposure to heat. Free probiotic organisms were used as a control. The acid tolerance of probiotic organisms was tested using HCl in MRS broth over a 2-h incubation period. Bile tolerance was tested using 2 types of bile salts, oxgall and taurocholic acid, over an 8-h incubation period. Heat tolerance was tested by exposing the probiotic organisms to 65 degrees C for up to 1 h. Results indicated microencapsulated probiotic bacteria survived better (P strains. At 30 min of heat treatment, microencapsulated probiotic bacteria survived with an average loss of only 4.17-log CFU/mL, compared to 6.74-log CFU/mL loss with free probiotic bacteria. However, after 1 h of heating both free and microencapsulated probiotic strains showed similar losses in viability. Overall microencapsulation improved the survival of probiotic bacteria when exposed to acidic conditions, bile salts, and mild heat treatment.

  20. Simultaneous determination of nine kinds of dominating bile acids in various snake bile by ultrahigh-performance liquid chromatography with triple quadrupole linear iontrap mass spectrometry.

    Science.gov (United States)

    Zhang, Jie; Fan, Yeqin; Gong, Yajun; Chen, Xiaoyong; Wan, Luosheng; Zhou, Chenggao; Zhou, Jiewen; Ma, Shuangcheng; Wei, Feng; Chen, Jiachun; Nie, Jing

    2017-11-15

    Snake bile is one of the most expensive traditional Chinese medicines (TCMs). However, due to the complicated constitutes of snake bile and the poor ultraviolet absorbance of some trace bile acids (BAs), effective analysis methods for snake bile acids were still unavailable, making it difficult to solve adulteration problems. In present study, ultrahigh-performance liquid chromatography with triple quadrupole linear ion trap mass spectrometry (UHPLC-QqQ-MS/MS) was applied to conduct a quantitative analysis on snake BAs. The mass spectrometer was monitored in the negative ion mode, and multiple-reaction monitoring (MRM) program was used to determine the contents of BAs in snake bile. In all, 61 snake bile from 17 commonly used species of three families (Elapidae, Colubridae and Viperidae), along with five batches of commercial snake bile from four companies, were collected and detected. Nine components, Tauro-3α,12α-dihydroxy-7-oxo-5β-cholenoic acid (T1), Tauro-3α,7α,12α,23R-tetrahydroxy-5β-cholenoic acid (T2), taurocholic acid (TCA), glycocholic acid (GCA), taurochenodeoxycholic acid (TCDCA), taurodeoxycholic acid (TDCA), cholic acid (CA), Tauro-3α,7α-dihydroxy-12-oxo-5β-cholenoic acid (T3), and Tauro-3α,7α,9α,16α-tetrahydroxy-5β-cholenoic acid (T4) were simultaneously and rapidly determined for the first time. In these BAs, T1 and T2, self-prepared with purity above 90%, were first reported with their quantitative determination, and the latter two (T3 and T4) were tentatively determined by quantitative analysis multi-components by single marker (QAMS) method for roughly estimating the components without reference. The developed method was validated with acceptable linearity (r 2 ≥0.995), precision (RSD<6.5%) and recovery (RSD<7.5%). It turned out that the contents of BAs among different species were also significantly different; T1 was one of the principle bile acids in some common snake bile, and also was the characteristic one in Viperidae

  1. Alisol B 23-acetate protects against ANIT-induced hepatotoxity and cholestasis, due to FXR-mediated regulation of transporters and enzymes involved in bile acid homeostasis

    Energy Technology Data Exchange (ETDEWEB)

    Meng, Qiang; Chen, Xin-li; Wang, Chang-yuan; Liu, Qi; Sun, Hui-jun; Sun, Peng-yuan; Huo, Xiao-kui; Liu, Zhi-hao; Yao, Ji-hong; Liu, Ke-xin, E-mail: kexinliu@dlmedu.edu.cn

    2015-03-15

    Intrahepatic cholestasis is a clinical syndrome with systemic and intrahepatic accumulation of excessive toxic bile acids that ultimately cause hepatobiliary injury. Appropriate regulation of bile acids in hepatocytes is critically important for protection against liver injury. In the present study, we characterized the protective effect of alisol B 23-acetate (AB23A), a natural triterpenoid, on alpha-naphthylisothiocyanate (ANIT)-induced liver injury and intrahepatic cholestasis in mice and further elucidated the mechanisms in vivo and in vitro. AB23A treatment dose-dependently protected against liver injury induced by ANIT through reducing hepatic uptake and increasing efflux of bile acid via down-regulation of hepatic uptake transporters (Ntcp) and up-regulation of efflux transporter (Bsep, Mrp2 and Mdr2) expression. Furthermore, AB23A reduced bile acid synthesis through repressing Cyp7a1 and Cyp8b1, increased bile acid conjugation through inducing Bal, Baat and bile acid metabolism through an induction in gene expression of Sult2a1. We further demonstrate the involvement of farnesoid X receptor (FXR) in the hepatoprotective effect of AB23A. The changes in transporters and enzymes, as well as ameliorative liver histology in AB23A-treated mice were abrogated by FXR antagonist guggulsterone in vivo. In vitro evidences also directly demonstrated the effect of AB23A on FXR activation in a dose-dependent manner using luciferase reporter assay in HepG2 cells. In conclusion, AB23A produces protective effect against ANIT-induced hepatotoxity and cholestasis, due to FXR-mediated regulation of transporters and enzymes. - Highlights: • AB23A has at least three roles in protection against ANIT-induced liver injury. • AB23A decreases Ntcp, and increases Bsep, Mrp2 and Mdr2 expression. • AB23A represses Cyp7a1 and Cyp8b1 through inducing Shp and Fgf15 expression. • AB23A increases bile acid metabolism through inducing Sult2a1 expression. • FXR activation is involved

  2. Alisol B 23-acetate protects against ANIT-induced hepatotoxity and cholestasis, due to FXR-mediated regulation of transporters and enzymes involved in bile acid homeostasis

    International Nuclear Information System (INIS)

    Meng, Qiang; Chen, Xin-li; Wang, Chang-yuan; Liu, Qi; Sun, Hui-jun; Sun, Peng-yuan; Huo, Xiao-kui; Liu, Zhi-hao; Yao, Ji-hong; Liu, Ke-xin

    2015-01-01

    Intrahepatic cholestasis is a clinical syndrome with systemic and intrahepatic accumulation of excessive toxic bile acids that ultimately cause hepatobiliary injury. Appropriate regulation of bile acids in hepatocytes is critically important for protection against liver injury. In the present study, we characterized the protective effect of alisol B 23-acetate (AB23A), a natural triterpenoid, on alpha-naphthylisothiocyanate (ANIT)-induced liver injury and intrahepatic cholestasis in mice and further elucidated the mechanisms in vivo and in vitro. AB23A treatment dose-dependently protected against liver injury induced by ANIT through reducing hepatic uptake and increasing efflux of bile acid via down-regulation of hepatic uptake transporters (Ntcp) and up-regulation of efflux transporter (Bsep, Mrp2 and Mdr2) expression. Furthermore, AB23A reduced bile acid synthesis through repressing Cyp7a1 and Cyp8b1, increased bile acid conjugation through inducing Bal, Baat and bile acid metabolism through an induction in gene expression of Sult2a1. We further demonstrate the involvement of farnesoid X receptor (FXR) in the hepatoprotective effect of AB23A. The changes in transporters and enzymes, as well as ameliorative liver histology in AB23A-treated mice were abrogated by FXR antagonist guggulsterone in vivo. In vitro evidences also directly demonstrated the effect of AB23A on FXR activation in a dose-dependent manner using luciferase reporter assay in HepG2 cells. In conclusion, AB23A produces protective effect against ANIT-induced hepatotoxity and cholestasis, due to FXR-mediated regulation of transporters and enzymes. - Highlights: • AB23A has at least three roles in protection against ANIT-induced liver injury. • AB23A decreases Ntcp, and increases Bsep, Mrp2 and Mdr2 expression. • AB23A represses Cyp7a1 and Cyp8b1 through inducing Shp and Fgf15 expression. • AB23A increases bile acid metabolism through inducing Sult2a1 expression. • FXR activation is involved

  3. Structural requirements of the human sodium-dependent bile acid transporter (hASBT): Role of 3- and 7-OH moieties on binding and translocation of bile acids

    Science.gov (United States)

    González, Pablo M.; Lagos, Carlos F.; Ward, Weslyn C.; Polli, James E.

    2014-01-01

    Bile acids (BAs) are the end products of cholesterol metabolism. One of the critical steps in their biosynthesis involves the isomerization of the 3β-hydroxyl (-OH) group on the cholestane ring to the common 3α-configuration on BAs. BAs are actively recaptured from the small intestine by the human Apical Sodium-dependent Bile Acid Transporter (hASBT) with high affinity and capacity. Previous studies have suggested that no particular hydroxyl group on BAs is critical for binding or transport by hASBT, even though 3β-hydroxylated BAs were not examined. The aim of this study was to elucidate the role of the 3α-OH group on BAs binding and translocation by hASBT. Ten 3β-hydroxylated BAs (Iso-bile acids, iBAs) were synthesized, characterized, and subjected to hASBT inhibition and uptake studies. hASBT inhibition and uptake kinetics of iBAs were compared to that of native 3α-OH BAs. Glycine conjugates of native and isomeric BAs were subjected to molecular dynamics simulations in order to identify topological descriptors related to binding and translocation by hASBT. Iso-BAs bound to hASBT with lower affinity and exhibited reduced translocation than their respective 3α-epimers. Kinetic data suggests that, in contrast to native BAs where hASBT binding is the rate-limiting step, iBAs transport was rate-limited by translocation and not binding. Remarkably, 7-dehydroxylated iBAs were not hASBT substrates, highlighting the critical role of 7-OH group on BA translocation by hASBT, especially for iBAs. Conformational analysis of gly-iBAs and native BAs identified topological features for optimal binding as: concave steroidal nucleus, 3-OH “on-” or below-steroidal plane, 7-OH below-plane, and 12-OH moiety towards-plane. Our results emphasize the relevance of the 3α-OH group on BAs for proper hASBT binding and transport and revealed the critical role of 7-OH group on BA translocation, particularly in the absence of a 3α-OH group. Results have implications for BA

  4. The Conjugate Acid-Base Chart.

    Science.gov (United States)

    Treptow, Richard S.

    1986-01-01

    Discusses the difficulties that beginning chemistry students have in understanding acid-base chemistry. Describes the use of conjugate acid-base charts in helping students visualize the conjugate relationship. Addresses chart construction, metal ions, buffers and pH titrations, and the organic functional groups and nonaqueous solvents. (TW)

  5. Functional nanoparticles exploit the bile acid pathway to overcome multiple barriers of the intestinal epithelium for oral insulin delivery

    DEFF Research Database (Denmark)

    Fan, Weiwei; Xia, Dengning; Zhu, Quanlei

    2018-01-01

    , especially to avoid lysosomal degradation, and basolateral release. Here, the functional material, deoxycholic acid-conjugated chitosan, is synthesized and loaded with the model protein drug insulin into deoxycholic acid-modified nanoparticles (DNPs). The DNPs designed in this study are demonstrated......Oral absorption of protein/peptide-loaded nanoparticles is often limited by multiple barriers of the intestinal epithelium. In addition to mucus translocation and apical endocytosis, highly efficient transepithelial absorption of nanoparticles requires successful intracellular trafficking...... to endolysosomal escape of DNPs. Additionally, DNPs can interact with a cytosolic ileal bile acid-binding protein that facilitates the intracellular trafficking and basolateral release of insulin. In rats, intravital two-photon microscopy also reveals that the transport of DNPs into the intestinal villi...

  6. Hormesis in Cholestatic Liver Disease; Preconditioning with Low Bile Acid Concentrations Protects against Bile Acid-Induced Toxicity

    NARCIS (Netherlands)

    Verhaag, Esther M.; Buist-Homan, Manon; Koehorst, Martijn; Groen, Albert K.; Moshage, Han; Faber, Klaas Nico

    2016-01-01

    Introduction Cholestasis is characterized by accumulation of bile acids and inflammation, causing hepatocellular damage. Still, liver damage markers are highest in acute cholestasis and drop when this condition becomes chronic, indicating that hepatocytes adapt towards the hostile environment. This

  7. Hormesis in Cholestatic Liver Disease; Preconditioning with Low Bile Acid Concentrations Protects against Bile Acid-Induced Toxicity

    NARCIS (Netherlands)

    Verhaag, Esther M.; Buist-Homan, Manon; Koehorst, Martijn; Groen, Albert K.; Moshage, Han; Faber, Klaas Nico

    2016-01-01

    Cholestasis is characterized by accumulation of bile acids and inflammation, causing hepatocellular damage. Still, liver damage markers are highest in acute cholestasis and drop when this condition becomes chronic, indicating that hepatocytes adapt towards the hostile environment. This may be

  8. Bile acid treatment alters hepatic disease and bile acid transport in peroxisome-deficient PEX2 Zellweger mice

    NARCIS (Netherlands)

    Keane, Megan H.; Overmars, Henk; Wikander, Thomas M.; Ferdinandusse, Sacha; Duran, Marinus; Wanders, Ronald J. A.; Faust, Phyllis L.

    2007-01-01

    The marked deficiency of peroxisomal organelle assembly in the PEX2(-/-) mouse model for Zellweger syndrome provides a unique opportunity to developmentally and biochemically characterize hepatic disease progression and bile acid products. The postnatal survival of homozygous mutants enabled us to

  9. Bile acids for primary sclerosing cholangitis

    DEFF Research Database (Denmark)

    Poropat, Goran; Giljaca, Vanja; Stimac, Davor

    2011-01-01

    Primary sclerosing cholangitis is a progressive chronic cholestatic liver disease that usually leads to the development of cirrhosis. Studies evaluating bile acids in the treatment of primary sclerosing cholangitis have shown a potential benefit of their use. However, no influence on patients...

  10. Microbiome-mediated bile acid modification: Role in intestinal drug absorption and metabolism.

    Science.gov (United States)

    Enright, Elaine F; Griffin, Brendan T; Gahan, Cormac G M; Joyce, Susan A

    2018-04-13

    Once regarded obscure and underappreciated, the gut microbiota (the microbial communities colonizing the gastrointestinal tract) is gaining recognition as an influencer of many aspects of human health. Also increasingly apparent is the breadth of interindividual variation in these co-evolved microbial-gut associations, presenting novel quests to explore implications for disease and therapeutic response. In this respect, the unearthing of the drug-metabolizing capacity of the microbiota has provided impetus for the integration of microbiological and pharmacological research. This review considers a potential mechanism, 'microbial bile acid metabolism', by which the intricate interplay between the host and gut bacteria may influence drug pharmacokinetics. Bile salts traditionally regarded as biological surfactants, synthesized by the host and biotransformed by gut bacteria, are now also recognized as signalling molecules that affect diverse physiological processes. Accumulating data indicate that bile salts are not equivalent with respect to their physicochemical properties, micellar solubilization capacities for poorly water-soluble drugs, crystallization inhibition tendencies nor potencies for bile acid receptor activation. Herein, the origin, physicochemical properties, physiological functions, plasticity and pharmaceutical significance of the human bile acid pool are discussed. Microbial dependant differences in the composition of the human bile acid pool, simulated intestinal media and commonly used preclinical species is highlighted to better understand in vivo performance predictiveness. While the precise impact of an altered gut microbiome, and consequently bile acid pool, in the biopharmaceutical setting remains largely elusive, the objective of this article is to aid knowledge acquisition through a detailed review of the literature. Copyright © 2018 Elsevier Ltd. All rights reserved.

  11. Alteration of the enterohepatic recirculation of bile acids in rats after exposure to ionizing radiation

    International Nuclear Information System (INIS)

    Scanff, P.; Souidi, M.; Grison, S.; Griffiths, N.M.; Gourmelon, P.

    2004-01-01

    The aim of this work was to study acute alterations of the enterohepatic recirculation (EHR) of bile acids 3 days after an 8-Gy radiation exposure in vivo in the rat by a washout technique. Using this technique in association with HPLC analysis, the EHR of the major individual bile acids was determined in control and irradiated animals. Ex vivo ileal taurocholate absorption was also studied in Ussing chambers. Major hepatic enzyme activities involved in bile acid synthesis were also measured. Measurements of bile acid intestinal content and intestinal absorption efficiency calculation from washout showed reduced intestinal absorption with significant differences from one bile acid to another: absorption of taurocholate and tauromuricholate was decreased, whereas absorption of the more hydrophobic taurochenodeoxycholate was increased, suggesting that intestinal passive diffusion was enhanced, whereas ileal active transport might be reduced. Basal hepatic secretion was increased only for taurocholate, in accordance with the marked increase of CYP8B1 activity in the liver. The results are clearly demonstrate that concomitantly with radiation-induced intestinal bile acid malabsorption, hepatic bile acid synthesis and secretion are also changed. A current working model for pathophysiological changes in enterohepatic recycling after irradiation is thus proposed. (author)

  12. Lytic effects of mixed micelles of fatty acids and bile acids

    NARCIS (Netherlands)

    Lapré, J. A.; Termont, D. S.; Groen, A. K.; van der Meer, R.

    1992-01-01

    It has been hypothesized that bile acids and fatty acids promote colon cancer. A proposed mechanism is a lytic effect of these surfactants on colonic epithelium, resulting in a compensatory proliferation of colonic cells. To investigate the first step of this hypothesis, we studied the lytic

  13. The role of peroxisomal fatty acyl-CoA beta-oxidation in bile acid biosynthesis

    International Nuclear Information System (INIS)

    Hayashi, H.; Miwa, A.

    1989-01-01

    The physiological role of the peroxisomal fatty acyl-CoA beta-oxidizing system (FAOS) is not yet established. We speculated that there might be a relationship between peroxisomal degradation of long-chain fatty acids in the liver and the biosynthesis of bile acids. This was investigated using [1- 14 C]butyric acid and [1- 14 C]lignoceric acid as substrates of FAOS in mitochondria and peroxisomes, respectively. The incorporation of [ 14 C]lignoceric acid into primary bile acids was approximately four times higher than that of [ 14 C]butyric acid (in terms of C-2 units). The pools of these two fatty acids in the liver were exceedingly small. The incorporations of radioactivity into the primary bile acids were strongly inhibited by administration of aminotriazole, which is a specific inhibitor of peroxisomal FAOS in vivo. Aminotriazole inhibited preferentially the formation of cholate, the major primary bile acid, from both [ 14 C]lignoceric acid and [ 14 C]butyric acid, rather than the formation of chenodeoxycholate. The former inhibition was about 70% and the latter was approximately 40-50%. In view of reports that cholate is biosynthesized from endogenous cholesterol, the above results indicate that peroxisomal FAOS may have an anabolic function, supplying acetyl CoA for bile acid biosynthesis

  14. The role of peroxisomal fatty acyl-CoA beta-oxidation in bile acid biosynthesis

    Energy Technology Data Exchange (ETDEWEB)

    Hayashi, H.; Miwa, A. (Josai Univ., Saitama (Japan))

    1989-11-01

    The physiological role of the peroxisomal fatty acyl-CoA beta-oxidizing system (FAOS) is not yet established. We speculated that there might be a relationship between peroxisomal degradation of long-chain fatty acids in the liver and the biosynthesis of bile acids. This was investigated using (1-{sup 14}C)butyric acid and (1-{sup 14}C)lignoceric acid as substrates of FAOS in mitochondria and peroxisomes, respectively. The incorporation of ({sup 14}C)lignoceric acid into primary bile acids was approximately four times higher than that of ({sup 14}C)butyric acid (in terms of C-2 units). The pools of these two fatty acids in the liver were exceedingly small. The incorporations of radioactivity into the primary bile acids were strongly inhibited by administration of aminotriazole, which is a specific inhibitor of peroxisomal FAOS in vivo. Aminotriazole inhibited preferentially the formation of cholate, the major primary bile acid, from both ({sup 14}C)lignoceric acid and ({sup 14}C)butyric acid, rather than the formation of chenodeoxycholate. The former inhibition was about 70% and the latter was approximately 40-50%. In view of reports that cholate is biosynthesized from endogenous cholesterol, the above results indicate that peroxisomal FAOS may have an anabolic function, supplying acetyl CoA for bile acid biosynthesis.

  15. Bile acids destabilise HIF-1α and promote anti-tumour phenotypes in cancer cell models

    International Nuclear Information System (INIS)

    Phelan, J. P.; Reen, F. J.; Dunphy, N.; O'Connor, R.; O'Gara, F.

    2016-01-01

    The role of the microbiome has become synonymous with human health and disease. Bile acids, as essential components of the microbiome, have gained sustained credibility as potential modulators of cancer progression in several disease models. At physiological concentrations, bile acids appear to influence cancer phenotypes, although conflicting data surrounds their precise physiological mechanism of action. Previously, we demonstrated bile acids destabilised the HIF-1α subunit of the Hypoxic-Inducible Factor-1 (HIF-1) transcription factor. HIF-1 overexpression is an early biomarker of tumour metastasis and is associated with tumour resistance to conventional therapies, and poor prognosis in a range of different cancers. Here we investigated the effects of bile acids on the cancer growth and migratory potential of cell lines where HIF-1α is known to be active under hypoxic conditions. HIF-1α status was investigated in A-549 lung, DU-145 prostate and MCF-7 breast cancer cell lines exposed to bile acids (CDCA and DCA). Cell adhesion, invasion, migration was assessed in DU-145 cells while clonogenic growth was assessed in all cell lines. Intracellular HIF-1α was destabilised in the presence of bile acids in all cell lines tested. Bile acids were not cytotoxic but exhibited greatly reduced clonogenic potential in two out of three cell lines. In the migratory prostate cancer cell line DU-145, bile acids impaired cell adhesion, migration and invasion. CDCA and DCA destabilised HIF-1α in all cells and significantly suppressed key cancer progression associated phenotypes; clonogenic growth, invasion and migration in DU-145 cells. These findings suggest previously unobserved roles for bile acids as physiologically relevant molecules targeting hypoxic tumour progression

  16. Crystal structure of a bacterial homologue of the bile acid sodium symporter ASBT

    Science.gov (United States)

    Hu, Nien-Jen; Iwata, So; Cameron, Alexander D.; Drew, David

    2011-01-01

    High cholesterol levels greatly increase the risk of cardiovascular disease. By its conversion into bile acids, about 50% of cholesterol is eliminated from the body. However bile acids released from the bile duct are constantly recycled, being reabsorbed in the intestine via the Apical Sodium dependent Bile acid Transporter (ASBT). It has been shown in animal models that plasma cholesterol levels are significantly lowered by specific inhibitors of ASBT1,2, thus ASBT is a target for hypercholesterolemia drugs. Here, we describe the crystal structure of a bacterial homologue of ASBT from Neisseria meningitidis (ASBTNM) at 2.2Å. ASBTNM contains two inverted structural repeats of five transmembrane helices. A Core domain of six helices harbours two sodium ions while the remaining helices form a Panel-like domain. Overall the architecture of the protein is remarkably similar to the sodium-proton antiporter NhaA3 despite no detectable sequence homology. A bile acid molecule is situated between the Core and Panel domains in a large hydrophobic cavity. Residues near to this cavity have been shown to affect the binding of specific inhibitors of human ASBT4. The position of the bile acid together with the molecular architecture suggests the rudiments of a possible transport mechanism. PMID:21976025

  17. Binding of bile acids by pastry products containing bioactive substances during in vitro digestion.

    Science.gov (United States)

    Dziedzic, Krzysztof; Górecka, Danuta; Szwengiel, Artur; Smoczyńska, Paulina; Czaczyk, Katarzyna; Komolka, Patrycja

    2015-03-01

    The modern day consumer tends to choose products with health enhancing properties, enriched in bioactive substances. One such bioactive food component is dietary fibre, which shows a number of physiological properties including the binding of bile acids. Dietary fibre should be contained in everyday, easily accessible food products. Therefore, the aim of this study was to determine sorption capacities of primary bile acid (cholic acid - CA) and secondary bile acids (deoxycholic - DCA and lithocholic acids - LCA) by muffins (BM) and cookies (BC) with bioactive substances and control muffins (CM) and cookies (CC) in two sections of the in vitro gastrointestinal tract. Variations in gut flora were also analysed in the process of in vitro digestion of pastry products in a bioreactor. Enzymes: pepsin, pancreatin and bile salts: cholic acid, deoxycholic acid and lithocholic acid were added to the culture. Faecal bacteria, isolated from human large intestine, were added in the section of large intestine. The influence of dietary fibre content in cookies and concentration of bile acids in two stages of digestion were analysed. Generally, pastry goods with bioactive substances were characterized by a higher content of total fibre compared with the control samples. These products also differ in the profile of dietary fibre fractions. Principal Component Analysis (PCA) showed that the bile acid profile after two stages of digestion depends on the quality and quantity of fibre. The bile acid profile after digestion of BM and BC forms one cluster, and with the CM and CC forms a separate cluster. High concentration of H (hemicellulose) is positively correlated with LCA (low binding effect) and negatively correlated with CA and DCA contents. The relative content of bile acids in the second stage of digestion was in some cases above the content in the control sample, particularly LCA. This means that the bacteria introduced in the 2nd stage of digestion synthesize the LCA.

  18. Effect of Wheat Dietary Fiber Particle Size during Digestion In Vitro on Bile Acid, Faecal Bacteria and Short-Chain Fatty Acid Content.

    Science.gov (United States)

    Dziedzic, Krzysztof; Szwengiel, Artur; Górecka, Danuta; Gujska, Elżbieta; Kaczkowska, Joanna; Drożdżyńska, Agnieszka; Walkowiak, Jarosław

    2016-06-01

    The influence of bile acid concentration on the growth of Bifidobacterium spp. and Lactobacillus spp. bacteria was demonstrated. Exposing these bacteria to the environment containing bile acid salts, and very poor in nutrients, leads to the disappearance of these microorganisms due to the toxic effect of bile acids. A multidimensional analysis of data in the form of principal component analysis indicated that lactic acid bacteria bind bile acids and show antagonistic effect on E. coli spp. bacteria. The growth in E. coli spp. population was accompanied by a decline in the population of Bifidobacterium spp. and Lactobacillus spp. with a simultaneous reduction in the concentration of bile acids. This is direct proof of acid binding ability of the tested lactic acid bacteria with respect to cholic acid, lithocholic acid and deoxycholic acid. This research demonstrated that the degree of fineness of wheat dietary fibre does not affect the sorption of bile acids and growth of some bacteria species; however, it has an impact on the profile of synthesized short-chained fatty acids. During the digestion of a very fine wheat fibre fraction (WF 90), an increase in the concentration of propionic and butyric acids, as compared with the wheat fiber fraction of larger particles - WF 500, was observed. Our study suggested that wheat fibre did not affect faecal bacteria growth, however, we observed binding of bile acids by Bifidobacterium spp. and Lactobacillus spp.

  19. Impact of oral vancomycin on gut microbiota, bile acid metabolism, and insulin sensitivity

    DEFF Research Database (Denmark)

    Vrieze, Anne; Out, Carolien; Fuentes, Susana

    2014-01-01

    .i.d. At baseline and after 1 week of therapy, fecal microbiota composition (Human Intestinal Tract Chip phylogenetic microarray), fecal and plasma bile acid concentrations as well as insulin sensitivity (hyperinsulinemic euglycemic clamp using [6,6-(2)H2]-glucose tracer) were measured. RESULTS: Vancomycin reduced...... (pinsulin sensitivity (p... of vancomycin significantly impacts host physiology by decreasing intestinal microbiota diversity, bile acid dehydroxylation and peripheral insulin sensitivity in subjects with metabolic syndrome. These data show that intestinal microbiota, particularly of the Firmicutes phylum contributes to bile acid...

  20. Effects of bile acids on human airway epithelial cells: implications for aerodigestive diseases

    Directory of Open Access Journals (Sweden)

    Adil Aldhahrani

    2017-03-01

    Full Text Available Gastro-oesophageal reflux and aspiration have been associated with chronic and end-stage lung disease and with allograft injury following lung transplantation. This raises the possibility that bile acids may cause lung injury by damaging airway epithelium. The aim of this study was to investigate the effect of bile acid challenge using the immortalised human bronchial epithelial cell line (BEAS-2B. The immortalised human bronchial epithelial cell line (BEAS-2B was cultured. A 48-h challenge evaluated the effect of individual primary and secondary bile acids. Post-challenge concentrations of interleukin (IL-8, IL-6 and granulocyte−macrophage colony-stimulating factor were measured using commercial ELISA kits. The viability of the BEAS-2B cells was measured using CellTiter-Blue and MTT assays. Lithocholic acid, deoxycholic acid, chenodeoxycholic acid and cholic acid were successfully used to stimulate cultured BEAS-2B cells at different concentrations. A concentration of lithocholic acid above 10 μmol·L−1 causes cell death, whereas deoxycholic acid, chenodeoxycholic acid and cholic acid above 30 μmol·L−1 was required for cell death. Challenge with bile acids at physiological levels also led to a significant increase in the release of IL-8 and IL6 from BEAS-2B. Aspiration of bile acids could potentially cause cell damage, cell death and inflammation in vivo. This is relevant to an integrated gastrointestinal and lung physiological paradigm of chronic lung disease, where reflux and aspiration are described in both chronic lung diseases and allograft injury.

  1. Synthesis, characterization and biological evaluation of bile acid-aromatic/heteroaromatic amides linked via amino acids as anti-cancer agents.

    Science.gov (United States)

    Agarwal, Devesh S; Anantaraju, Hasitha Shilpa; Sriram, Dharmarajan; Yogeeswari, Perumal; Nanjegowda, Shankara H; Mallu, P; Sakhuja, Rajeev

    2016-03-01

    A series of bile acid (Cholic acid and Deoxycholic acid) aryl/heteroaryl amides linked via α-amino acid were synthesized and tested against 3 human cancer cell-lines (HT29, MDAMB231, U87MG) and 1 human normal cell line (HEK293T). Some of the conjugates showed promising results to be new anticancer agents with good in vitro results. More specifically, Cholic acid derivatives 6a (1.35 μM), 6c (1.41 μM) and 6m (4.52 μM) possessing phenyl, benzothiazole and 4-methylphenyl groups showed fairly good activity against the breast cancer cell line with respect to Cisplatin (7.21 μM) and comparable with respect to Doxorubicin (1 μM), while 6e (2.49μM), 6i (2.46 μM) and 6m (1.62 μM) showed better activity against glioblastoma cancer cell line with respect to both Cisplatin (2.60 μM) and Doxorubicin (3.78 μM) drugs used as standards. Greater than 65% of the compounds were found to be safer on human normal cell line. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Lipoprotein distribution and serum concentrations of 7α-hydroxy-4-cholesten-3-one and bile acids: effects of monogenic disturbances in high-density lipoprotein metabolism

    DEFF Research Database (Denmark)

    Steiner, Carine; Holleboom, Adriaan G; Karuna, Ratna

    2012-01-01

    BA (bile acid) formation is considered an important final step in RCT (reverse cholesterol transport). HDL (high-density lipoprotein) has been reported to transport BAs. We therefore investigated the effects of monogenic disturbances in human HDL metabolism on serum concentrations and lipoprotein...... concentrations of conjugated and secondary BAs differed between heterozygous carriers of SCARB1 (scavenger receptor class B1) mutations and unaffected individuals (P...

  3. Bile Reflux

    Science.gov (United States)

    ... the upper part of your small intestine (duodenum). Bile reflux into the stomach Bile and food mix ... properly, and bile washes back into the stomach. Bile reflux into the esophagus Bile and stomach acid ...

  4. Effect of administration of antibiotics peripartum to wistar rats on bile acid profiles in offspring

    DEFF Research Database (Denmark)

    Clement Thaarup, Ida; Roager, Henrik Munch; Tulstrup, Monica Vera-Lise

    2016-01-01

    Vertical transmission of the maternal microbiota is assumed to be crucial for the offspring’s development. A disrupted microbiota composition leading to an altered metabolic activity of the microbiota can affect bile acid profiles, which are known to influence host metabolism. Here, we examined...... whether perturbation of the maternal gut microbiota during pregnancy, induced by administration of either amoxicillin or vancomycin to pregnant rats, influenced bile acid profiles in the offspring. The dams were treated with antibiotics from 8 days before the dams gave birth and continued until weaning (4...... weeks later). Blood samples were collected from offspring at ages 2, 4 and 14 weeks, and from dams at the end of treatment. From these blood samples, bile acids were extracted and 22 bile acids were quantified by targeted liquid chromatography mass spectrometry. Comparing the serum bile acid profiles...

  5. Sources and Bioactive Properties of Conjugated Dietary Fatty Acids.

    Science.gov (United States)

    Hennessy, Alan A; Ross, Paul R; Fitzgerald, Gerald F; Stanton, Catherine

    2016-04-01

    The group of conjugated fatty acids known as conjugated linoleic acid (CLA) isomers have been extensively studied with regard to their bioactive potential in treating some of the most prominent human health malignancies. However, CLA isomers are not the only group of potentially bioactive conjugated fatty acids currently undergoing study. In this regard, isomers of conjugated α-linolenic acid, conjugated nonadecadienoic acid and conjugated eicosapentaenoic acid, to name but a few, have undergone experimental assessment. These studies have indicated many of these conjugated fatty acid isomers commonly possess anti-carcinogenic, anti-adipogenic, anti-inflammatory and immune modulating properties, a number of which will be discussed in this review. The mechanisms through which these bioactivities are mediated have not yet been fully elucidated. However, existing evidence indicates that these fatty acids may play a role in modulating the expression of several oncogenes, cell cycle regulators, and genes associated with energy metabolism. Despite such bioactive potential, interest in these conjugated fatty acids has remained low relative to the CLA isomers. This may be partly attributed to the relatively recent emergence of these fatty acids as bioactives, but also due to a lack of awareness regarding sources from which they can be produced. In this review, we will also highlight the common sources of these conjugated fatty acids, including plants, algae, microbes and chemosynthesis.

  6. Bile acid changes after high-dose ursodeoxycholic acid treatment in primary sclerosing cholangitis: relation to disease progression

    Science.gov (United States)

    Sinakos, Emmanouil; Marschall, Hanns-Ulrich; Kowdley, Kris V.; Befeler, Alex; Keach, Jill; Lindor, Keith

    2010-01-01

    High-dose (28-30mg/kg/day) ursodeoxycholic acid (UDCA) treatment improves serum liver tests in patients with primary sclerosing cholangitis (PSC) but does not improve survival and is associated with increased rates of serious adverse events. The mechanism for the latter undesired effect remains unclear. High-dose UDCA could result in the production of hepatotoxic bile acids, such as lithocholic acid (LCA), due to limited small bowel absorption of UDCA and conversion of UDCA by bacteria in the colon. We determined the serum bile acid composition in 56 patients with PSC previously enrolled in a randomized, double-blind controlled trial of high dose UDCA versus placebo. Samples for analysis were obtained at baseline and at the end of treatment. The mean changes in UDCA (16.86 vs 0.05 μmol/L) and total bile acid (17.21 vs −0.55 μmol/L) levels were significantly higher in the UDCA group (n=29) compared to placebo (n=27) when pretreatment levels were compared (pacid (CA), deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA). Patients (n=9) in the UDCA group who reached clinical endpoints of disease progression (development of cirrhosis, varices, liver transplantation or death) tend to have greater increase in their post-treatment total bile acid levels (34.99 vs 9.21 μmol/L) (pacid pool including lithocholic acid. PMID:20564380

  7. Experimental Protoporphyria: Effect of Bile Acids on Liver Damage Induced by Griseofulvin

    Directory of Open Access Journals (Sweden)

    María del Carmen Martinez

    2015-01-01

    Full Text Available The effect of bile acids administration to an experimental mice model of Protoporphyria produced by griseofulvin (Gris was investigated. The aim was to assess whether porphyrin excretion could be accelerated by bile acids treatment in an attempt to diminish liver damage induced by Gris. Liver damage markers, heme metabolism, and oxidative stress parameters were analyzed in mice treated with Gris and deoxycholic (DXA, dehydrocholic (DHA, chenodeoxycholic, or ursodeoxycholic (URSO. The administration of Gris alone increased the activities of glutathione reductase (GRed, superoxide dismutase (SOD, alkaline phosphatase (AP, gamma glutamyl transpeptidase (GGT, and glutathione-S-transferase (GST, as well as total porphyrins, glutathione (GSH, and cytochrome P450 (CYP levels in liver. Among the bile acids studied, DXA and DHA increased PROTO IX excretion, DXA also abolished the action of Gris, reducing lipid peroxidation and hepatic GSH and CYP levels, and the activities of GGT, AP, SOD, and GST returned to control values. However, porphyrin accumulation was not prevented by URSO; instead this bile acid reduced ALA-S and the antioxidant defense enzymes system activities. In conclusion, we postulate that DXA acid would be more effective to prevent liver damage induced by Gris.

  8. Mixed micelles of 7,12-dioxolithocholic acid and selected hydrophobic bile acids: interaction parameter, partition coefficient of nitrazepam and mixed micelles haemolytic potential.

    Science.gov (United States)

    Poša, Mihalj; Tepavčević, Vesna

    2011-09-01

    The formation of mixed micelles built of 7,12-dioxolithocholic and the following hydrophobic bile acids was examined by conductometric method: cholic (C), deoxycholic (D), chenodeoxycholic (CD), 12-oxolithocholic (12-oxoL), 7-oxolithocholic (7-oxoL), ursodeoxycholic (UD) and hiodeoxycholic (HD). Interaction parameter (β) in the studied binary mixed micelles had negative value, suggesting synergism between micelle building units. Based on β value, the hydrophobic bile acids formed two groups: group I (C, D and CD) and group II (12-oxoL, 7-oxoL, UD and HD). Bile acids from group II had more negative β values than bile acids from group I. Also, bile acids from group II formed intermolecular hydrogen bonds in aggregates with both smaller (2) and higher (4) aggregation numbers, according to the analysis of their stereochemical (conformational) structures and possible structures of mixed micelles built of these bile acids and 7,12-dioxolithocholic acid. Haemolytic potential and partition coefficient of nitrazepam were higher in mixed micelles built of the more hydrophobic bile acids (C, D, CD) and 7,12-dioxolithocholic acid than in micelles built only of 7,12-dioxolithocholic acid. On the other hand, these mixed micelles still had lower values of haemolytic potential than micelles built of C, D or CD. The mixed micelles that included bile acids: 12-oxoL, 7-oxoL, UD or HD did not significantly differ from the micelles of 7,12-dioxolithocholic acid, observing the values of their haemolytic potential. Copyright © 2011 Elsevier B.V. All rights reserved.

  9. Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis

    Science.gov (United States)

    Gomez-Ospina, Natalia; Potter, Carol J.; Xiao, Rui; Manickam, Kandamurugu; Kim, Mi-Sun; Kim, Kang Ho; Shneider, Benjamin L.; Picarsic, Jennifer L.; Jacobson, Theodora A.; Zhang, Jing; He, Weimin; Liu, Pengfei; Knisely, A. S.; Finegold, Milton J.; Muzny, Donna M.; Boerwinkle, Eric; Lupski, James R.; Plon, Sharon E.; Gibbs, Richard A.; Eng, Christine M.; Yang, Yaping; Washington, Gabriel C.; Porteus, Matthew H.; Berquist, William E.; Kambham, Neeraja; Singh, Ravinder J.; Xia, Fan; Enns, Gregory M.; Moore, David D.

    2016-01-01

    Neonatal cholestasis is a potentially life-threatening condition requiring prompt diagnosis. Mutations in several different genes can cause progressive familial intrahepatic cholestasis, but known genes cannot account for all familial cases. Here we report four individuals from two unrelated families with neonatal cholestasis and mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism. Clinical features of severe, persistent NR1H4-related cholestasis include neonatal onset with rapid progression to end-stage liver disease, vitamin K-independent coagulopathy, low-to-normal serum gamma-glutamyl transferase activity, elevated serum alpha-fetoprotein and undetectable liver bile salt export pump (ABCB11) expression. Our findings demonstrate a pivotal function for FXR in bile acid homeostasis and liver protection. PMID:26888176

  10. Direct measurement of first-pass ileal clearance of a bile acid in humans

    International Nuclear Information System (INIS)

    Galatola, G.; Jazrawi, R.P.; Bridges, C.; Joseph, A.E.; Northfield, T.C.

    1991-01-01

    The purpose of this study was to develop and validate a method of directly measuring ileal bile acid absorption efficiency during a single enterohepatic cycle (first-pass ileal clearance). This has become feasible for the first time because of the availability of the synthetic gamma-labeled bile acid 75Selena-homocholic acid-taurine (75SeHCAT). Together with the corresponding natural bile acid cholic acid-taurine (labeled with 14C), SeHCAT was infused distal to an occluding balloon situated beyond the ampulla of Vater in six healthy subjects. Completion of a single enterohepatic cycle was assessed by obtaining a plateau for 75SeHCAT activity proximal to the occluding balloon, which prevented further cycles. Unabsorbed 75SeHCAT was collected after total gut washout, which was administered distal to the occluding balloon. 75SeHCAT activity in the rectal effluent measured by gamma counter was compared with that of absorbed 75SeHCAT level measured by gamma camera and was used to calculate first-pass ileal clearance. This was very efficient (mean value, 96%) and showed very little variation in the six subjects studied (range, 95%-97%). A parallel time-activity course in hepatic bile for 14C and 75Se during a single enterohepatic cycle, together with a ratio of unity for 14C/75Se in samples obtained at different time intervals, suggests that 75SeHCAT is handled by the ileum like the natural bile acid cholic acid-taurine. Extrapolation of 75SeHCAT first-pass ileal clearance to that of the natural bile acid therefore seems justifiable. In a subsidiary experiment, ileal absorption efficiency per day for 75SeHCAT was also measured by scanning the gallbladder area on 5 successive days after the measurement of first-pass ileal clearance. In contrast with absorption efficiency per cycle, absorption efficiency per day varied widely (49%-86%)

  11. Bile acids for liver-transplanted patients. Protocol for a Cochrane Review

    DEFF Research Database (Denmark)

    Chen, W; Gluud, C

    2003-01-01

    Liver transplantation has become a widely accepted form of treatment for numerous end-stage liver diseases. Bile acids may decrease the degree of allograft rejection after liver transplantation by changing the expression of major histocompatibility complex class molecules in bile duct epithelium...

  12. Highly Sensitive Luminescence Assessment of Bile Acid Using a Balofloxacin-Europium(III) Probe in Micellar Medium

    International Nuclear Information System (INIS)

    Cai, Huan; Zhao, Fang; Si, Hailin; Zhang, Shuaishuai; Wang, Chunchun; Qi, Peirong

    2012-01-01

    A novel and simple method of luminescence enhancement effect for the determination of trace amounts of bile acid was proposed. The procedure was based on the luminescence intensity of the balofloxacin-europium(III) complex that could be strongly enhanced by bile acid in the presence of sodium dodecyl benzene sulfonate (SDBS). Under the optimum conditions, the enhanced luminescence intensity of the system exhibited a good linear relationship with the bile acid concentration in the range 5.0 Χ 10 -9 - 7.0 Χ 10 -7 mol L -1 with a detection limit of 1.3 Χ 10 -9 mol L.1 (3σ). The relative standard deviation (RSD) was 1.7% (n = 11) for 5.0 Χ 10 -8 mol L -1 bile acid. The applicability of the method to the determination of bile acid was demonstrated by investigating the effect of potential interferences and by analyzing human serum and urine samples. The possible enhancement mechanism of luminescence intensity in balofloxacin-europium(III)-bile acid-SDBS system was also discussed briefly

  13. Are bile acid malabsorption and bile acid diarrhoea important causes of loose stool complicating cancer therapy?

    Science.gov (United States)

    Phillips, F; Muls, A C G; Lalji, A; Andreyev, H J N

    2015-08-01

    Gastrointestinal (GI) symptoms during and after cancer therapy can significantly affect quality of life and interfere with treatment. This study assessed whether bile acid malabsorption (BAM) or bile acid diarrhoea (BAD) are important causes of diarrhoea associated with cancer treatment. A retrospective analysis was carried out of consecutive patients assessed for BAM using ((75) Se) Selenium homocholic acid taurocholate (SeHCAT) scanning, after reporting any episodes of loose stool, attending a gastroenterology clinic in a cancer centre. Between 2009 and 2013, 506 consecutive patients (54.5% male; age range: 20-91 years), were scanned. BAM/BAD was diagnosed in 215 (42.5%). It was mild in 25.6%, moderate in 29.3% and severe in 45.1%. Pelvic chemoradiation had induced BAM in > 50% of patients. BAM was also frequent after treatment for conditions not previously associated with BAM, such as anal and colorectal cancer, and was present in > 75% of patients referred after pancreatic surgery. It was also unexpectedly frequent in patients who were treated for malignancy outside the GI tract, such as breast cancer and haematological malignancy. BAM/BAD are very common and under-appreciated causes of GI symptoms after cancer treatment. Health professionals should have a low threshold in suspecting this condition, as diagnosis and treatment can significantly improve quality of life. Colorectal Disease © 2015 The Association of Coloproctology of Great Britain and Ireland.

  14. Bile Acid Signaling Pathways from the Enterohepatic Circulation to the Central Nervous System

    NARCIS (Netherlands)

    Mertens, Kim L.; Kalsbeek, Andries; Soeters, Maarten R.; Eggink, Hannah M.

    2017-01-01

    Bile acids are best known as detergents involved in the digestion of lipids. In addition, new data in the last decade have shown that bile acids also function as gut hormones capable of influencing metabolic processes via receptors such as FXR (farnesoid X receptor) and TGR5 (Takeda G

  15. Increased bile acids in enterohepatic circulation by short-term calorie restriction in male mice

    Energy Technology Data Exchange (ETDEWEB)

    Fu, Zidong Donna [Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, 66160 (United States); Klaassen, Curtis D., E-mail: cklaasse@kumc.edu [Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, 66160 (United States)

    2013-12-15

    Previous studies showed glucose and insulin signaling can regulate bile acid (BA) metabolism during fasting or feeding. However, limited knowledge is available on the effect of calorie restriction (CR), a well-known anti-aging intervention, on BA homeostasis. To address this, the present study utilized a “dose–response” model of CR, where male C57BL/6 mice were fed 0, 15, 30, or 40% CR diets for one month, followed by BA profiling in various compartments of the enterohepatic circulation by UPLC-MS/MS technique. This study showed that 40% CR increased the BA pool size (162%) as well as total BAs in serum, gallbladder, and small intestinal contents. In addition, CR “dose-dependently” increased the concentrations of tauro-cholic acid (TCA) and many secondary BAs (produced by intestinal bacteria) in serum, such as tauro-deoxycholic acid (TDCA), DCA, lithocholic acid, ω-muricholic acid (ωMCA), and hyodeoxycholic acid. Notably, 40% CR increased TDCA by over 1000% (serum, liver, and gallbladder). Interestingly, 40% CR increased the proportion of 12α-hydroxylated BAs (CA and DCA), which correlated with improved glucose tolerance and lipid parameters. The CR-induced increase in BAs correlated with increased expression of BA-synthetic (Cyp7a1) and conjugating enzymes (BAL), and the ileal BA-binding protein (Ibabp). These results suggest that CR increases BAs in male mice possibly through orchestrated increases in BA synthesis and conjugation in liver as well as intracellular transport in ileum. - Highlights: • Dose response effects of short-term CR on BA homeostasis in male mice. • CR increased the BA pool size and many individual BAs. • CR altered BA composition (increased proportion of 12α-hydroxylated BAs). • Increased mRNAs of BA enzymes in liver (Cyp7a1 and BAL) and ileal BA binding protein.

  16. Effects of ionizing radiation on the activity of the major hepatic enzymes implicated in bile acid biosynthesis in the rat

    International Nuclear Information System (INIS)

    Souidi, M.; Scanff, P.; Grison, St.; Gourmelon, P.; Aigueperse, J.

    2007-01-01

    In the days following high-dose radiation exposure, damage to small intestinal mucosa is aggravated by changes in the bile acid pool reaching the gut. Intestinal bile acid malabsorption, as described classically, may be associated with altered hepatic bile acid biosynthesis, which was the objective of this work. The activity of the main rate-limiting enzymes implicated in the bile acid biosynthesis were evaluated in the days following an 8-Gy γ Co 60 total body irradiation of rats, with concomitant determination of biliary bile acid profiles and intestinal bile acid content. Modifications of biliary bile acid profiles, observed as early as the first post-irradiation day, were most marked at the third and fourth day, and resulted in an increased hydrophobicity index. In parallel, the intestinal bile acids' content was enhanced and hepatic enzymatic activities leading to bile acids were changed. A marked increase of sterol 12-hydroxylase and decrease of oxy-sterol 7-hydroxylase activity was observed at day 3, whereas both cholesterol 7-hydroxylase and oxy-sterol 7-hydroxylase activities were decreased at day 4 after irradiation. These results show, for the first time, radiation-induced modifications of hepatic enzymatic activities implicated in bile acid biosynthesis and suggest that they are mainly a consequence of radiation-altered intestinal absorption, which induces a physiological response of the entero-hepatic bile acid recirculation. (authors)

  17. Fluorescence properties of Schiff base - N,N‧-bis(salicylidene) - 1,2-Phenylenediamine in presence of bile acid host

    Science.gov (United States)

    Roy, Nayan; Paul, Pradip C.; Singh, T. Sanjoy

    2015-05-01

    Fluorescence properties of Schiff base - N,N‧-bis(salicylidene) - 1,2-phenylenediamine (LH2) is used to study the micelles formed by aggregation of different important bile acids like cholic acid, deoxycholic acid, chenodeoxycholic acid and glycocholic acid by steady state and picosecond time-resolved fluorescence spectroscopy. The fluorescence band intensity was found out to increase with concomitant red shift with gradual addition of different bile acids. Binding constant of the probe with different bile acids as well as critical micelle concentration was obtained from the variation of fluorescence intensity on increasing concentration of bile acids in the medium. The increase in fluorescence quantum yields, fluorescence decay times and substantial decrease in nonradiative decay rate constants in bile acids micellar environment points to the restricted motion of the fluorophore inside the micellar subdomains.

  18. Effect of a high-fat-high-cholesterol diet on gallbladder bile acid composition and gallbladder motility in dogs.

    Science.gov (United States)

    Kakimoto, Toshiaki; Kanemoto, Hideyuki; Fukushima, Kenjiro; Ohno, Koichi; Tsujimoto, Hajime

    2017-12-01

    OBJCTIVE To investigate the effects of dietary lipid overload on bile acid metabolism and gallbladder motility in healthy dogs. ANIMALS 7 healthy Beagles. PROCEDURES In a crossover study, dogs were fed a high-fat-high-cholesterol diet (HFCD) or a low-fat diet (LFD) for a period of 2 weeks. After a 4-month washout period, dogs were fed the other diet for 2 weeks. Before and at the end of each feeding period, the concentrations of each of the gallbladder bile acids, cholecystokinin (CCK)-induced gallbladder motility, and bile acid metabolism-related hepatic gene expression were examined in all dogs. RESULTS The HFCD significantly increased plasma total cholesterol concentrations. The HFCD also increased the concentration of taurochenodeoxycholic acid and decreased the concentration of taurocholic acid in bile and reduced gallbladder contractility, whereas the LFD significantly decreased the concentration of taurodeoxycholic acid in bile. Gene expression analysis revealed significant elevation of cholesterol 7α-hydroxylase mRNA expression after feeding the HFCD for 2 weeks, but the expression of other genes was unchanged. CONCLUSIONS AND CLINICAL RELEVANCE Feeding the HFCD and LFD for 2 weeks induced changes in gallbladder bile acid composition and gallbladder motility in dogs. In particular, feeding the HFCD caused an increase in plasma total cholesterol concentration, an increase of hydrophobic bile acid concentration in bile, and a decrease in gallbladder sensitivity to CCK. These results suggested that similar bile acid compositional changes and gallbladder hypomotility might be evident in dogs with hyperlipidemia.

  19. Molecular interactions between lecithin and bile salts/acids in oils and their effects on reverse micellization.

    Science.gov (United States)

    Njauw, Ching-Wei; Cheng, Chih-Yang; Ivanov, Viktor A; Khokhlov, Alexei R; Tung, Shih-Huang

    2013-03-26

    It has been known that the addition of bile salts to lecithin organosols induces the formation of reverse wormlike micelles and that the worms are similar to long polymer chains that entangle each other to form viscoelastic solutions. In this study, we further investigated the effects of different bile salts and bile acids on the growth of lecithin reverse worms in cyclohexane and n-decane. We utilized rheological and small-angle scattering techniques to analyze the properties and structures of the reverse micelles. All of the bile salts can transform the originally spherical lecithin reverse micelles into wormlike micelles and their rheological behaviors can be described by the single-relaxation-time Maxwell model. However, their efficiencies to induce the worms are different. In contrast, before phase separation, bile acids can induce only short cylindrical micelles that are not long enough to impart viscoelasticity. We used Fourier transform infrared spectroscopy to investigate the interactions between lecithin and bile salts/acids and found that different bile salts/acids employ different functional groups to form hydrogen bonds with lecithin. Such effects determine the relative positions of the bile salts/acids in the headgroups of lecithin, thus resulting in varying efficiencies to alter the effective critical packing parameter for the formation of wormlike micelles. This work highlights the importance of intermolecular interactions in molecular self-assembly.

  20. Bile acids deoxycholic acid and ursodeoxycholic acid differentially regulate human β-defensin-1 and -2 secretion by colonic epithelial cells.

    Science.gov (United States)

    Lajczak, Natalia K; Saint-Criq, Vinciane; O'Dwyer, Aoife M; Perino, Alessia; Adorini, Luciano; Schoonjans, Kristina; Keely, Stephen J

    2017-09-01

    Bile acids and epithelial-derived human β-defensins (HβDs) are known to be important factors in the regulation of colonic mucosal barrier function and inflammation. We hypothesized that bile acids regulate colonic HβD expression and aimed to test this by investigating the effects of deoxycholic acid (DCA) and ursodeoxycholic acid on the expression and release of HβD1 and HβD2 from colonic epithelial cells and mucosal tissues. DCA (10-150 µM) stimulated the release of both HβD1 and HβD2 from epithelial cell monolayers and human colonic mucosal tissue in vitro In contrast, ursodeoxycholic acid (50-200 µM) inhibited both basal and DCA-induced defensin release. Effects of DCA were mimicked by the Takeda GPCR 5 agonist, INT-777 (50 μM), but not by the farnesoid X receptor agonist, GW4064 (10 μM). INT-777 also stimulated colonic HβD1 and HβD2 release from wild-type, but not Takeda GPCR 5 -/- , mice. DCA stimulated phosphorylation of the p65 subunit of NF-κB, an effect that was attenuated by ursodeoxycholic acid, whereas an NF-κB inhibitor, BMS-345541 (25 μM), inhibited DCA-induced HβD2, but not HβD1, release. We conclude that bile acids can differentially regulate colonic epithelial HβD expression and secretion and discuss the implications of our findings for intestinal health and disease.-Lajczak, N. K., Saint-Criq, V., O'Dwyer, A. M., Perino, A., Adorini, L., Schoonjans, K., Keely, S. J. Bile acids deoxycholic acid and ursodeoxycholic acid differentially regulate human β-defensin-1 and -2 secretion by colonic epithelial cells. © FASEB.

  1. Effect of ursodeoxycholic acid on the kinetics of the major hydrophobic bile acids in health and in chronic cholestatic liver disease

    NARCIS (Netherlands)

    Beuers, U.; Spengler, U.; Zwiebel, F. M.; PAULETZKI, J.; Fischer, S.; Paumgartner, G.

    1992-01-01

    Beneficial effects of ursodeoxycholic acid in chronic cholestatic liver diseases have been attributed to displacement of hydrophobic bile acids from the endogenous bile acid pool. To test this hypothesis, we determined pool sizes, fractional turnover rates, synthesis/input rates and serum levels of

  2. Bile acids modulate glucocorticoid metabolism and the hypothalamic-pituitary-adrenal axis in obstructive jaundice

    DEFF Research Database (Denmark)

    McNeilly, Alison D; Macfarlane, David P; O'Flaherty, Emmett

    2010-01-01

    Suppression of the hypothalamic-pituitary-adrenal axis occurs in cirrhosis and cholestasis and is associated with increased concentrations of bile acids. We investigated whether this was mediated through bile acids acting to impair steroid clearance by inhibiting glucocorticoid metabolism by 5bet...

  3. Effect of ursodeoxycholic acid treatment on the altered progesterone and bile acid homeostasis in the mother-placenta-foetus trio during cholestasis of pregnancy.

    Science.gov (United States)

    Estiú, Maria C; Monte, Maria J; Rivas, Laura; Moirón, Maria; Gomez-Rodriguez, Laura; Rodriguez-Bravo, Tomas; Marin, Jose J G; Macias, Rocio I R

    2015-02-01

    Intrahepatic cholestasis of pregnancy (ICP) is characterized by pruritus and elevated bile acid concentrations in maternal serum. This is accompanied by an enhanced risk of intra-uterine and perinatal complications. High concentrations of sulphated progesterone metabolites (PMS) have been suggested to be involved in the multifactorial aetiopathogenesis of ICP. The aim of this study was to investigate further the mechanism accounting for the beneficial effect of oral administration of ursodeoxycholic acid (UDCA), which is the standard treatment, regarding bile acid and PMS homeostasis in the mother-placenta-foetus trio. Using HPLC-MS/MS bile acids and PMS were determined in maternal and foetal serum and placenta. The expression of ABC proteins in placenta was determined by real time quantitative PCR (RT-QPCR) and immunofluorescence. In ICP, markedly increased concentrations of bile acids (tauroconjugates > glycoconjugates > unconjugated), progesterone and PMS in placenta and maternal serum were accompanied by enhanced concentrations in foetal serum of bile acids, but not of PMS. UDCA treatment reduced bile acid accumulation in the mother-placenta-foetus trio, but had no significant effect on progesterone and PMS concentrations. ABCG2 mRNA abundance was increased in placentas from ICP patients vs. controls and remained stable following UDCA treatment, despite an apparent further increase in ABCG2. UDCA administration partially reduces ICP-induced bile acid accumulation in mothers and foetuses despite the lack of effect on concentrations of progesterone and PMS in maternal serum. Up-regulation of placental ABCG2 may play an important role in protecting the foetus from high concentrations of bile acids and PMS during ICP. © 2014 The British Pharmacological Society.

  4. An inproved synthesis of 24- 13C-labeled bile acids using formyl esters and a modified lead tetraacetate procedure

    International Nuclear Information System (INIS)

    Tserng, K.Y.; Klein, P.D.

    1977-01-01

    An improved synthesis of 24- 13 C-labeled bile acids has been achieved using formyl derivatives of bile acids and a modified lead tetraacetate procedure. The formylated bile acids were degraded by lead tetraacetate and lithium chloride to formylated 23-chloronorcholanes in 72 to 83% yield. Formylated 23-chloronorcholanes were converted to nitriles in dimethylformamide, which were then hydrolyzed to obtain C-24 labeled bile acids in yield of 80 to 90% of labeled sodium cyanide used. This method results in a higher yield and a purer product with less manipulation than previously reported procedures for synthesis of labeled bile acids

  5. Ursodeoxycholic acid lowers bile lithogenicity by regulating SCP2 expression in rabbit cholesterol gallstone models

    Science.gov (United States)

    Cui, Yunfeng; Li, Zhonglian; Zhao, Erpeng; Zhang, Ju; Cui, Naiqiang

    2012-01-01

    Aims: We designed this study to get insight into the disorder of lipid metabolism during cholesterol gallstone formation and evaluate the effect of ursodeoxycholic acid on the improvement of bile lithogenicity and on expression of lipid related genes. Methods: Rabbit cholesterol gallstone models were induced by high cholesterol diet. Bile, blood and liver tissues were obtained from rabbits after 0, 1, 2, 3, 4 and 5 weeks. Bile and blood lipids were measured enzymatically. 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), cytochrome P450, family 7, subfamily A, polypeptide 1 (CYP7A1) and sterol carrier protein 2 (SCP2) mRNA expressions were detected by using quantitative real-time RT-PCR. Cholesterol saturation index (CSI) was calculated by using Carey table to represent the bile lithogenicity. Results: Rates of gallstone formation of the 4 and 5 week treatment groups were 100 %, but that of the ursodeoxycholic acid treatment group was only 33.3 %. Expression of HMGCR and SCP2 mRNA in the 4 week group was upregulated and that of CYP7A1 mRNA decreased as compared with the 0 week group. Ursodeoxycholic acid could significantly extend nucleation time of bile and lower CSI. Ursodeoxycholic acid could reduce the expression of SCP2, but couldn't influence expression of HMGCR and CYP7A1. Conclusions: Abnormal expression of HMGCR, CYP7A1 and SCP2 might lead to high lithogenicity of bile. Ursodeoxycholic acid could improve bile lipids and lower bile lithogenicity, thereby reducing the incidence of gallstones. So it might be a good preventive drug for cholesterol gallstones. PMID:27847447

  6. CYP2E1-dependent elevation of serum cholesterol, triglycerides, and hepatic bile acids by isoniazid

    Energy Technology Data Exchange (ETDEWEB)

    Cheng, Jie; Krausz, Kristopher W. [Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States); Li, Feng; Ma, Xiaochao [Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, 4089 KLSIC, MS 1018, 3901 Rainbow Boulevard, Kansas City, KS 66160 (United States); Gonzalez, Frank J., E-mail: fjgonz@helix.nih.gov [Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States)

    2013-01-15

    Isoniazid is the first-line medication in the prevention and treatment of tuberculosis. Isoniazid is known to have a biphasic effect on the inhibition–induction of CYP2E1 and is also considered to be involved in isoniazid-induced hepatotoxicity. However, the full extent and mechanism of involvement of CYP2E1 in isoniazid-induced hepatotoxicity remain to be thoroughly investigated. In the current study, isoniazid was administered to wild-type and Cyp2e1-null mice to investigate the potential toxicity of isoniazid in vivo. The results revealed that isoniazid caused no hepatotoxicity in wild-type and Cyp2e1-null mice, but produced elevated serum cholesterol and triglycerides, and hepatic bile acids in wild-type mice, as well as decreased abundance of free fatty acids in wild-type mice and not in Cyp2e1-null mice. Metabolomic analysis demonstrated that production of isoniazid metabolites was elevated in wild-type mice along with a higher abundance of bile acids, bile acid metabolites, carnitine and carnitine derivatives; these were not observed in Cyp2e1-null mice. In addition, the enzymes responsible for bile acid synthesis were decreased and proteins involved in bile acid transport were significantly increased in wild-type mice. Lastly, treatment of targeted isoniazid metabolites to wild-type mice led to similar changes in cholesterol, triglycerides and free fatty acids. These findings suggest that while CYP2E1 is not involved in isoniazid-induced hepatotoxicity, while an isoniazid metabolite might play a role in isoniazid-induced cholestasis through enhancement of bile acid accumulation and mitochondria β-oxidation. -- Highlights: ► Isoniazid metabolites were elevated only in wild-type mice. ► Isoniazid caused no hepatotoxicity in wild-type and Cyp2e1-null mice. ► Isoniazid elevated serum cholesterol and triglycerides, and hepatic bile acids. ► Bile acid transporters were significantly decreased in isoniazid-treated mice.

  7. CYP2E1-dependent elevation of serum cholesterol, triglycerides, and hepatic bile acids by isoniazid

    International Nuclear Information System (INIS)

    Cheng, Jie; Krausz, Kristopher W.; Li, Feng; Ma, Xiaochao; Gonzalez, Frank J.

    2013-01-01

    Isoniazid is the first-line medication in the prevention and treatment of tuberculosis. Isoniazid is known to have a biphasic effect on the inhibition–induction of CYP2E1 and is also considered to be involved in isoniazid-induced hepatotoxicity. However, the full extent and mechanism of involvement of CYP2E1 in isoniazid-induced hepatotoxicity remain to be thoroughly investigated. In the current study, isoniazid was administered to wild-type and Cyp2e1-null mice to investigate the potential toxicity of isoniazid in vivo. The results revealed that isoniazid caused no hepatotoxicity in wild-type and Cyp2e1-null mice, but produced elevated serum cholesterol and triglycerides, and hepatic bile acids in wild-type mice, as well as decreased abundance of free fatty acids in wild-type mice and not in Cyp2e1-null mice. Metabolomic analysis demonstrated that production of isoniazid metabolites was elevated in wild-type mice along with a higher abundance of bile acids, bile acid metabolites, carnitine and carnitine derivatives; these were not observed in Cyp2e1-null mice. In addition, the enzymes responsible for bile acid synthesis were decreased and proteins involved in bile acid transport were significantly increased in wild-type mice. Lastly, treatment of targeted isoniazid metabolites to wild-type mice led to similar changes in cholesterol, triglycerides and free fatty acids. These findings suggest that while CYP2E1 is not involved in isoniazid-induced hepatotoxicity, while an isoniazid metabolite might play a role in isoniazid-induced cholestasis through enhancement of bile acid accumulation and mitochondria β-oxidation. -- Highlights: ► Isoniazid metabolites were elevated only in wild-type mice. ► Isoniazid caused no hepatotoxicity in wild-type and Cyp2e1-null mice. ► Isoniazid elevated serum cholesterol and triglycerides, and hepatic bile acids. ► Bile acid transporters were significantly decreased in isoniazid-treated mice.

  8. A Systems Model for Ursodeoxycholic Acid Metabolism in Healthy and Patients With Primary Biliary Cirrhosis.

    Science.gov (United States)

    Zuo, P; Dobbins, R L; O'Connor-Semmes, R L; Young, M A

    2016-08-01

    A systems model was developed to describe the metabolism and disposition of ursodeoxycholic acid (UDCA) and its conjugates in healthy subjects based on pharmacokinetic (PK) data from published studies in order to study the distribution of oral UDCA and potential interactions influencing therapeutic effects upon interruption of its enterohepatic recirculation. The base model was empirically adapted to patients with primary biliary cirrhosis (PBC) based on current understanding of disease pathophysiology and clinical measurements. Simulations were performed for patients with PBC under two competing hypotheses: one for inhibition of ileal absorption of both UDCA and conjugates and the other only of conjugates. The simulations predicted distinctly different bile acid distribution patterns in plasma and bile. The UDCA model adapted to patients with PBC provides a platform to investigate a complex therapeutic drug interaction among UDCA, UDCA conjugates, and inhibition of ileal bile acid transport in this rare disease population. © 2016 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

  9. Inhibition of intestinal bile acid absorption improves cholestatic liver and bile duct injury in a mouse model of sclerosing cholangitis.

    Science.gov (United States)

    Baghdasaryan, Anna; Fuchs, Claudia D; Österreicher, Christoph H; Lemberger, Ursula J; Halilbasic, Emina; Påhlman, Ingrid; Graffner, Hans; Krones, Elisabeth; Fickert, Peter; Wahlström, Annika; Ståhlman, Marcus; Paumgartner, Gustav; Marschall, Hanns-Ulrich; Trauner, Michael

    2016-03-01

    Approximately 95% of bile acids (BAs) excreted into bile are reabsorbed in the gut and circulate back to the liver for further biliary secretion. Therefore, pharmacological inhibition of the ileal apical sodium-dependent BA transporter (ASBT/SLC10A2) may protect against BA-mediated cholestatic liver and bile duct injury. Eight week old Mdr2(-/-) (Abcb4(-/-)) mice (model of cholestatic liver injury and sclerosing cholangitis) received either a diet supplemented with A4250 (0.01% w/w) - a highly potent and selective ASBT inhibitor - or a chow diet. Liver injury was assessed biochemically and histologically after 4weeks of A4250 treatment. Expression profiles of genes involved in BA homeostasis, inflammation and fibrosis were assessed via RT-PCR from liver and ileum homogenates. Intestinal inflammation was assessed by RNA expression profiling and immunohistochemistry. Bile flow and composition, as well as biliary and fecal BA profiles were analyzed after 1week of ASBT inhibitor feeding. A4250 improved sclerosing cholangitis in Mdr2(-/-) mice and significantly reduced serum alanine aminotransferase, alkaline phosphatase and BAs levels, hepatic expression of pro-inflammatory (Tnf-α, Vcam1, Mcp-1) and pro-fibrogenic (Col1a1, Col1a2) genes and bile duct proliferation (mRNA and immunohistochemistry for cytokeratin 19 (CK19)). Furthermore, A4250 significantly reduced bile flow and biliary BA output, which correlated with reduced Bsep transcription, while Ntcp and Cyp7a1 were induced. Importantly A4250 significantly reduced biliary BA secretion but preserved HCO3(-) and biliary phospholipid secretion resulting in an increased HCO3(-)/BA and PL/BA ratio. In addition, A4250 profoundly increased fecal BA excretion without causing diarrhea and altered BA pool composition, resulting in diminished concentrations of primary BAs tauro-β-muricholic acid and taurocholic acid. Pharmacological ASBT inhibition attenuates cholestatic liver and bile duct injury by reducing biliary BA

  10. Semi-Preparative Isolation and Purification of Three Tauro-Conjugated Cholic Acids from Pulvis Fellis Suis by HSCCC Coupled with ELSD Detection.

    Science.gov (United States)

    He, Jiao; Zhang, Yongmin; Ito, Yoichiro; Sun, Wenji

    2011-01-01

    Coupled with evaporative light scattering detection, a high-speed counter-current chromatography (HSCCC) method was applied to the separation and purification of three tauro-conjugated cholic acids of taurochenodeoxycholic acid (TCDCA), taurohyodeoxycholic acid (THDCA) and taurohyocholic acid (THCA) from Pulvis Fellis Suis (Pig gallbladder bile) for the first time. The two-phase solvent system composed of chloroform-methanol-water-acetic acid (4:4:2:0.3, v/v/v/v) was selected for the one-step separation where the lower phase was used as the mobile phase in the head to tail elution mode. The revolution speed of the separation column, flow rate of the mobile phase and separation temperature were 800 rpm, 1.5 ml/min and 25°C respectively. From 100 mg of the crude extract, 10.2 mg of TCDCA, 11.8 mg of THDCA and 5.3 mg of THCA were obtained with the purity of 94.6%, 96.5% and 95.4%, respectively. in one step separation The HSCCC fractions were analyzed by high-performance liquid chromatography (HPLC) and the structures of the three tauro-conjugated cholic acids were identified by ESI-MS, (1)H NMR and (13)C NMR.

  11. Research progress in roles of gut microbiota and bile acid metabolism in development and progression of NAFLD

    Directory of Open Access Journals (Sweden)

    LU Xu

    2014-11-01

    Full Text Available With the prevalence of obesity and metabolic syndrome, the incidence of nonalcoholic fatty liver disease (NAFLD is increasing year by year. Studies have uncovered the important roles of gut microbiota and bile acid metabolism in the development and progression of NAFLD. The roles of gut microbiota, as well bile acid and bile acid receptors, in the development and progression of NAFLD are highlighted.

  12. Perturbation of bile acid homeostasis is an early pathogenesis event of drug induced liver injury in rats

    Energy Technology Data Exchange (ETDEWEB)

    Yamazaki, Makoto; Miyake, Manami; Sato, Hiroko; Masutomi, Naoya; Tsutsui, Naohisa [Mitsubishi Tanabe Pharma Corporation, Kisarazu, Chiba 292-0818 (Japan); Adam, Klaus-Peter; Alexander, Danny C.; Lawton, Kay A.; Milburn, Michael V.; Ryals, John A.; Wulff, Jacob E. [Metabolon Inc., 617 Davis Drive, Suite 400, Durham, NC 27713 (United States); Guo, Lining, E-mail: lguo@metabolon.com [Metabolon Inc., 617 Davis Drive, Suite 400, Durham, NC 27713 (United States)

    2013-04-01

    Drug-induced liver injury (DILI) is a significant consideration for drug development. Current preclinical DILI assessment relying on histopathology and clinical chemistry has limitations in sensitivity and discordance with human. To gain insights on DILI pathogenesis and identify potential biomarkers for improved DILI detection, we performed untargeted metabolomic analyses on rats treated with thirteen known hepatotoxins causing various types of DILI: necrosis (acetaminophen, bendazac, cyclosporine A, carbon tetrachloride, ethionine), cholestasis (methapyrilene and naphthylisothiocyanate), steatosis (tetracycline and ticlopidine), and idiosyncratic (carbamazepine, chlorzoxasone, flutamide, and nimesulide) at two doses and two time points. Statistical analysis and pathway mapping of the nearly 1900 metabolites profiled in the plasma, urine, and liver revealed diverse time and dose dependent metabolic cascades leading to DILI by the hepatotoxins. The most consistent change induced by the hepatotoxins, detectable even at the early time point/low dose, was the significant elevations of a panel of bile acids in the plasma and urine, suggesting that DILI impaired hepatic bile acid uptake from the circulation. Furthermore, bile acid amidation in the hepatocytes was altered depending on the severity of the hepatotoxin-induced oxidative stress. The alteration of the bile acids was most evident by the necrosis and cholestasis hepatotoxins, with more subtle effects by the steatosis and idiosyncratic hepatotoxins. Taking together, our data suggest that the perturbation of bile acid homeostasis is an early event of DILI. Upon further validation, selected bile acids in the circulation could be potentially used as sensitive and early DILI preclinical biomarkers. - Highlights: ► We used metabolomics to gain insights on drug induced liver injury (DILI) in rats. ► We profiled rats treated with thirteen hepatotoxins at two doses and two time points. ► The toxins decreased the

  13. Influence of the structure of bile acids on their partition coefficient in dibutyl ether and chloroform

    Directory of Open Access Journals (Sweden)

    Sebenji Ana S.

    2015-01-01

    Full Text Available Bile acids are well known natural surfactants able to modify the per­meability of biological membranes. The logarithm of partition coefficient between, tradi­tionally used, n-octanol and water is a measure of lipophilicity as a predictor of solute membrane partitioning. The aim of this work was to determine partition coefficients of bile acids in a mixture of water and chloroform and dibutyl ether at different pH values and with addition of different concentrations of sodium ions, and to examine the influence of the structure of bile acid nucleus on measured partition coefficients. Partition coefficients of three bile acid salts were determined using shake-flask method and the concentration of bile acids was determined after twelve hours of shaking at the room temperature in aqueous and organic layer using reversed phase HPLC with DAD detector on 210 nm. For all three analysed bile acid salts values of logP are lower in dibutyl ether than in chloroform. At certain pH values, curves representing the dependence of partition coeffi­cient on pH value intersect, and these are the pH values for which partition coefficients are the same for both solvents. Increasing the solution ionic strength, this intersection is shifted toward lower pH values. It is found that, for both organic solvents, after the addition of hy­droxyl group in the steroid nucleus (i.e. if the bile acid is less hydrophobic the value of logP falls, especially if more hydroxyl groups are present. With chloroform as a solvent, system quickly comes to excess with electrolyte ions than with dibutyl ether. [Projekat Ministarstva nauke Republike Srbije, br. 172021

  14. Irinotecan (CPT-11)-induced elevation of bile acids potentiates suppression of IL-10 expression

    International Nuclear Information System (INIS)

    Fang, Zhong-Ze; Zhang, Dunfang; Cao, Yun-Feng; Xie, Cen; Lu, Dan; Sun, Dong-Xue; Tanaka, Naoki; Jiang, Changtao; Chen, Qianming; Chen, Yu; Wang, Haina; Gonzalez, Frank J.

    2016-01-01

    Irinotecan (CPT-11) is a first-line anti-colon cancer drug, however; CPT-11-induced toxicity remains a key factor limiting its clinical application. To search for clues to the mechanism of CPT-11-induced toxicity, metabolomics was applied using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry. Intraperitoneal injection of 50 mg/kg of CPT-11 induced loss of body weight, and intestine toxicity. Changes in gallbladder morphology suggested alterations in bile acid metabolism, as revealed at the molecular level by analysis of the liver, bile, and ileum metabolomes between the vehicle-treated control group and the CPT-11-treated group. Analysis of immune cell populations further showed that CPT-11 treatment significantly decreased the IL-10-producing CD4 T cell frequency in intestinal lamina propria lymphocytes, but not in spleen or mesenteric lymph nodes. In vitro cell culture studies showed that the addition of bile acids deoxycholic acid and taurodeoxycholic acid accelerated the CPT-11-induced suppression of IL-10 secretion by activated CD4 + naive T cells isolated from mouse splenocytes. These results showed that CPT-11 treatment caused metabolic changes in the composition of bile acids that altered CPT-11-induced suppression of IL-10 expression. - Highlights: • CPT-11 is an effective anticancer drug, but induced toxicity limits its application in the clinic. • CPT-11 decreased IL-10-producing CD4 T cell frequency in intestinal lamina propria lymphocytes. • CPT-11 altered the composition of bile acid metabolites, notably DCA and TDCA in liver, bile and intestine. • DCA and TDCA potentiated CPT-11-induced suppression of IL-10 secretion by active CD4 + naive T cells.

  15. Irinotecan (CPT-11)-induced elevation of bile acids potentiates suppression of IL-10 expression

    Energy Technology Data Exchange (ETDEWEB)

    Fang, Zhong-Ze [Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (United States); Department of Toxicology, School of Public Health, Tianjin Medical University, Tianjin (China); Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences and First Affiliated Hospital of Liaoning Medical University, Dalian (China); Zhang, Dunfang [State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu (China); Cao, Yun-Feng [Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences and First Affiliated Hospital of Liaoning Medical University, Dalian (China); Xie, Cen [Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (United States); Lu, Dan [Department of Immunology, Tianjin Key Laboratory of Cellular and Molecular Immunology, Tianjin Medical University, Tianjin (China); Sun, Dong-Xue; Tanaka, Naoki; Jiang, Changtao [Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (United States); Chen, Qianming; Chen, Yu [State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu (China); Wang, Haina [School of Pharmaceutical Sciences, Shandong University, Jinan (China); Gonzalez, Frank J., E-mail: gonzalef@mail.nih.gov [Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (United States)

    2016-01-15

    Irinotecan (CPT-11) is a first-line anti-colon cancer drug, however; CPT-11-induced toxicity remains a key factor limiting its clinical application. To search for clues to the mechanism of CPT-11-induced toxicity, metabolomics was applied using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry. Intraperitoneal injection of 50 mg/kg of CPT-11 induced loss of body weight, and intestine toxicity. Changes in gallbladder morphology suggested alterations in bile acid metabolism, as revealed at the molecular level by analysis of the liver, bile, and ileum metabolomes between the vehicle-treated control group and the CPT-11-treated group. Analysis of immune cell populations further showed that CPT-11 treatment significantly decreased the IL-10-producing CD4 T cell frequency in intestinal lamina propria lymphocytes, but not in spleen or mesenteric lymph nodes. In vitro cell culture studies showed that the addition of bile acids deoxycholic acid and taurodeoxycholic acid accelerated the CPT-11-induced suppression of IL-10 secretion by activated CD4{sup +} naive T cells isolated from mouse splenocytes. These results showed that CPT-11 treatment caused metabolic changes in the composition of bile acids that altered CPT-11-induced suppression of IL-10 expression. - Highlights: • CPT-11 is an effective anticancer drug, but induced toxicity limits its application in the clinic. • CPT-11 decreased IL-10-producing CD4 T cell frequency in intestinal lamina propria lymphocytes. • CPT-11 altered the composition of bile acid metabolites, notably DCA and TDCA in liver, bile and intestine. • DCA and TDCA potentiated CPT-11-induced suppression of IL-10 secretion by active CD4{sup +} naive T cells.

  16. Use of liquid chromatography hybrid triple-quadrupole mass spectrometry for the detection of emodin metabolites in rat bile and urine.

    Science.gov (United States)

    Wu, Songyan; Zhang, Yaqing; Zhang, Zunjian; Song, Rui

    2017-10-01

    Emodin is the representative form of rhubarb, which is widely used in traditional Chinese medicine for the treatment of purgative, anti-inflammatory, antioxidative and antiviral, etc. Previous reports demonstrated that emodin glucuronide was the major metabolite in plasma. Owing to the extensive conjugation reactions of polyphenols, the aim of this study was to identify the metabolites of emodin in rat bile and urine. Neutral loss and precursor ion scan methods of triple-quadrupole mass spectrometer revealed 13 conjugated metabolites in rat bile and 22 metabolites in rat urine, which included four phase I and 18 phase II metabolites. The major metabolites in rat biosamples were emodin glucuronoconjugates. Moreover, rhein monoglucuronide, chrysophanol monoglucuronide and rhein sulfate were proposed for the first time after oral administration of emodin. Overall, liquid chromatography hybrid triple-quadrupole mass spectrometry analysis leads to the discovery of several novel emodin metabolites in rat bile and urine and underscores that conjugated with glucuronic acid is the main metabolic pathway. Copyright © 2017 John Wiley & Sons, Ltd.

  17. The potential influence of genetic variants in genes along bile acid and bile metabolic pathway on blood cholesterol levels in the population

    NARCIS (Netherlands)

    Lu, Y.; Feskens, E.J.M.; Boer, J.M.A.; Müller, M.R.

    2010-01-01

    The liver is currently known to be the major organ to eliminate excess cholesterol from our body. It accomplishes this function in two ways: conversion of cholesterol molecules into bile acids (BAs) and secretion of unesterified cholesterol molecules into bile. BAs are synthesized in the

  18. Bile acids in experimental colorectal cancer.

    OpenAIRE

    Rainey, J. B.

    1986-01-01

    Cogent epidemiological and experimental data implicate bile acids as endogenous co-carcinogens in colorectal cancer. A series of experiments was designed to test the ability of sodium deoxycholate (SDC) to promote intestinal hyperplasia and neoplasia in rats (n = 265). The intermediary role of faecal anaerobes was explored in animals receiving oral metronidazole. Intrarectal instillation of SDC trebled tumour yield in functioning large bowel and increased both crypt depth and crypt cell produ...

  19. Role of AMACR (α-methylacyl-CoA racemase) and MFE-1 (peroxisomal multifunctional enzyme-1) in bile acid synthesis in mice.

    Science.gov (United States)

    Autio, Kaija J; Schmitz, Werner; Nair, Remya R; Selkälä, Eija M; Sormunen, Raija T; Miinalainen, Ilkka J; Crick, Peter J; Wang, Yuqin; Griffiths, William J; Reddy, Janardan K; Baes, Myriam; Hiltunen, J Kalervo

    2014-07-01

    Cholesterol is catabolized to bile acids by peroxisomal β-oxidation in which the side chain of C27-bile acid intermediates is shortened by three carbon atoms to form mature C24-bile acids. Knockout mouse models deficient in AMACR (α-methylacyl-CoA racemase) or MFE-2 (peroxisomal multifunctional enzyme type 2), in which this β-oxidation pathway is prevented, display a residual C24-bile acid pool which, although greatly reduced, implies the existence of alternative pathways of bile acid synthesis. One alternative pathway could involve Mfe-1 (peroxisomal multifunctional enzyme type 1) either with or without Amacr. To test this hypothesis, we generated a double knockout mouse model lacking both Amacr and Mfe-1 activities and studied the bile acid profiles in wild-type, Mfe-1 and Amacr single knockout mouse line and Mfe-1 and Amacr double knockout mouse lines. The total bile acid pool was decreased in Mfe-1-/- mice compared with wild-type and the levels of mature C24-bile acids were reduced in the double knockout mice when compared with Amacr-deficient mice. These results indicate that Mfe-1 can contribute to the synthesis of mature bile acids in both Amacr-dependent and Amacr-independent pathways.

  20. Greater bile acid excretion with soy bean than with cow milk in infants.

    Science.gov (United States)

    Potter, J M; Nestel, P J

    1976-05-01

    The excretion of fecal sterols and bile acids was measured in five infants from the 1st week of life to 2 or 3 months of age as the composition of their diet was changed from cow milk to soy bean milk. Bile acid excretion, adjusted for body weight, was initially lower during the 1st than during the 3rd week, when it reached adult values. The average excretion of bile acids was 6.8 mg/kg per day with soy bean milk and 3.6 mg/kg per day with cow milk. Net sterol excretion (total sterol output minus cholesterol intake) was also twice as high with soy bean milk and probably reflected enhancement of cholesterol re-excretion as well as of synthesis since the cholesterol content of soy beans is nil. However, net sterol excretion remained higher with soy bean than with cow milk even when egg yolk cholesterol was added to the soy bean milk. It is concluded that the substitution of soy bean milk for cow milk, which lowered the plasma cholesterol in all infants (even in the presence of dietary cholesterol) leads to an increase in bile acids and probably also in cholesterol excretion in young infants.

  1. Pepsin and bile acids in saliva in patients with laryngopharyngeal reflux - a prospective comparative study.

    Science.gov (United States)

    Sereg-Bahar, M; Jerin, A; Jansa, R; Stabuc, B; Hocevar-Boltezar, I

    2015-06-01

    Laryngopharyngeal reflux (LPR) and biliary duodenogastric reflux can cause damage to the laryngeal mucosa and voice disorders. The aim of this study was to find out whether levels of pepsin and bile acids in the saliva can serve as diagnostic markers of LPR. A prospective comparative study. Twenty-eight patients with LPR proven via high-resolution manometry and combined multichannel intraluminal impedance and 24-h pH monitoring and 48 healthy controls without symptoms of LPR were included in the study. In the patients with LPR symptoms, oesophagogastroscopy with oesophageal biopsy was performed. The levels of total pepsin, active pepsin, bile acids and the pH of the saliva were determined in all participants and compared between the groups. Reflux symptom index (RSI) and reflux finding score (RFS) were also obtained and compared. The groups differed significantly in RSI (P = 0.00), RFS (P = 0.00), the levels of bile acids (P = 0.005) and total pepsin in saliva (P = 0.023). The levels of total pepsin and bile acids were about three times higher in the patients with LPR than in the healthy controls. There was a significant correlation between the RSI and RFS score and the level of total pepsin and bile acids in the saliva. Histopathological examination of the oesophageal biopsy taken 5 cm above the lower oesophageal sphincter confirmed reflux in almost 93% of patients with symptoms. The study results show that the levels of total pepsin and bile acids in saliva are significantly higher in patients with LPR than in the controls, thus suggesting this as a useful tool in the diagnosis of LPR and particularly biliary LPR. © 2014 John Wiley & Sons Ltd.

  2. In Vivo Performance of a Novel Fluorinated Magnetic Resonance Imaging Agent for Functional Analysis of Bile Acid Transport

    Science.gov (United States)

    2015-01-01

    A novel trifluorinated cholic acid derivative, CA-lys-TFA, was designed and synthesized for use as a tool to measure bile acid transport noninvasively using magnetic resonance imaging (MRI). In the present study, the in vivo performance of CA-lys-TFA for measuring bile acid transport by MRI was investigated in mice. Gallbladder CA-lys-TFA content was quantified using MRI and liquid chromatography/tandem mass spectrometry. Results in wild-type (WT) C57BL/6J mice were compared to those in mice lacking expression of Asbt, the ileal bile acid transporter. 19F signals emanating from the gallbladders of WT mice 7 h after oral gavage with 150 mg/kg CA-lys-TFA were reproducibly detected by MRI. Asbt-deficient mice administered the same dose had undetectable 19F signals by MRI, and gallbladder bile CA-lys-TFA levels were 30-fold lower compared to WT animals. To our knowledge, this represents the first report of in vivo imaging of an orally absorbed drug using 19F MRI. Fluorinated bile acid analogues have potential as tools to measure and detect abnormal bile acid transport by MRI. PMID:24708306

  3. Effect of Bile Alcohols on the Microbial 7α-dehydroxylation of Chenodeoxycholic acid

    OpenAIRE

    Lindqvist, A.; Midtvedt, T.; Skrede, S.; Sjövall, J.

    2011-01-01

    The effect of bile alcohols on the microbial 7α-dehydroxylation of chenodeoxycholic acid was investigated. Bile alcohols isolated from urine of patients with cerebrotendinous xanthomatosis were added to anaerobic incubations of rat faecal microflora or isolated 'Strain II' with [14C]chenodeoxycholic acid, and the formation of labelled metabolites was measured by high-performance liquid chromatography after 7 d of incubation. The 7α-dehydroxylation by rat faecal microflora was inhi...

  4. Effect of loperamide and delay of bowel motility on bile acid malabsorption caused by late radiation damage and ileal resection

    Energy Technology Data Exchange (ETDEWEB)

    Valdes Olmos, R. (Nederlands Kanker Inst., Amsterdam (Netherlands). Dept. of Nuclear Medicine); Hartog Jager, F. den; Hoefnagel, C.; Taal, B. (Nederlands Kanker Inst., Amsterdam (Netherlands). Dept. of Gastroenterology)

    1991-05-01

    Selenium-75 homocholic acid conjugated with taurine ({sup 75}Se-HCAT) was used during loperamide administration in seven patients suspected of having bile acid malabsorption due to late radiation damage and small-bowel resection in order to document the aetiology of ileal dysfunction and to adjust therapeutic mamagement. In two patients with ileal resection up to 50 cm and in one patient without resection, a reduction of bowel motility by loperamide resulted in marked normalization of the {sup 75}Se-HCAT retention measurements. Sequential scintigraphic {sup 75}Se-HCAT imaging demonstrated a significant improvement in the {sup 75}Se-HCAT reabsorption and recirculation, accompanied in one case by prolongation of colonic retention of the radiopharmaceutical. In four patients with more than 80 cm resection, the {sup 75}Se-HCAT test was abnormal during loperamide administration. In two of these patients for whom baseline values were available, no improvement in the pattern of {sup 75}Se-HCAT absorption was observed. In conclusion, the first results of loperamide {sup 75}Se-HCAT in patients suspected of having bile acid malabsorption and abnormal baseline {sup 75}Se-HCAT are promising. Intervention with loperamide is easy and seems to improve the clinical value of the test with direct therapeutic implications. Sequential {sup 75}Se-HCAT imaging is essential for interpreting changes in the {sup 75}Se-HCAT retention measurements. (orig.).

  5. Absence of bile acid malabsorption as a late effect of pelvic irradiation

    International Nuclear Information System (INIS)

    Schuster, J.J.; Stryker, J.A.; Demers, L.M.; Mortel, R.

    1986-01-01

    The pathophysiology of chronic radiation-induced diarrhea was evaluated in 28 patients who had undergone pelvic irradiation for gynecologic neoplasms 2 to 7 years previously. Twenty-seven patients undergoing radiotherapy with techniques that did not require abdominal or pelvic irradiation served as controls. The glycine conjugates of cholic acid (GC) were measured in serum by radioimmunoassay. Fasting and 2 hr. pp GC levels for the pelvic irradiated patients were 11.0 +/- 11.1 (mean +/- SD) and 24.8 +/- 17.3 micrograms/dl. Fasting and 2 hr. pp GC levels for controls were 12.6 +/- 7.4 and 28.0 +/- 14.7. There were no significant differences in the post-prandial increases in serum GC between pelvic irradiated patients and controls (p = .23, Type II error probability = .13). There was also no significant difference in the 2 hr. pp and fasting GC ratio (p = .39). There was significant difference between the stool frequency (p less than .01) and the prevalence of diarrhea (p less than .02) between pelvic irradiated patients and controls. The data suggest that bile acid malabsorption due to ileal dysfunction is not an inevitable late complication of pelvic irradiation and is not the major determinant in the pathophysiology of chronic radiation-induced diarrhea

  6. Bile acid malabsorption in patients with chronic diarrhoea

    DEFF Research Database (Denmark)

    Wildt, S; Nørby Rasmussen, S; Lysgård Madsen, Jan

    2003-01-01

    Bile acid malabsorption (BAM), a cause of chronic diarrhoea, can be diagnosed by the SeHCAT test. The purpose of this study was to evaluate the usefulness of SeHCAT testing by assessing the extent of BAM and describing the clinical characteristics in a group of patients with chronic diarrhoea...

  7. Acid resistance, bile tolerance and antimicrobial properties of ...

    African Journals Online (AJOL)

    Maari is a fermented food condiment obtained by spontaneous fermentation of seeds from the baobab tree (Adansonia digitata). Nine dominant lactic acid bacteria (LAB) strains, isolated from traditional maari fermentation were examined for their resistance to pH 2.5, their tolerance to 0.3% bile and their antimicrobial ...

  8. Ursodeoxycholic and deoxycholic acids: A good and a bad bile acid for intestinal calcium absorption.

    Science.gov (United States)

    Rodríguez, Valeria; Rivoira, María; Marchionatti, Ana; Pérez, Adriana; Tolosa de Talamoni, Nori

    2013-12-01

    The aim of this study was to investigate the effect of ursodeoxycholic acid (UDCA) on intestinal Ca(2+) absorption and to find out whether the inhibition of this process caused by NaDOC could be prevented by UDCA. Chicks were employed and divided into four groups: (a) controls, (b) treated with 10mM NaDOC, (c) treated with 60 μg UDCA/100g of b.w., and (d) treated with 10mM NaDOC and 60 μg UDCA/100g of b.w. UDCA enhanced intestinal Ca(2+) absorption, which was time and dose-dependent. UDCA avoided the inhibition of intestinal Ca(2+) absorption caused by NaDOC. Both bile acids altered protein and gene expression of molecules involved in the transcellular pathway of intestinal Ca(2+) absorption, but in the opposite way. UDCA aborted the oxidative stress produced by NaDOC in the intestine. UDCA and UDCA plus NaDOC increased vitamin D receptor protein expression. In conclusion, UDCA is a beneficial bile acid for intestinal Ca(2+) absorption. Contrarily, NaDOC inhibits the intestinal cation absorption through triggering oxidative stress. The use of UDCA in patients with cholestasis would be benefited because of the protective effect on the intestinal Ca(2+) absorption, avoiding the inhibition caused by hydrophobic bile acids and neutralizing the oxidative stress. Copyright © 2013 Elsevier Inc. All rights reserved.

  9. Bile acids cycle disruption in patients with nasopharyngeal ...

    African Journals Online (AJOL)

    2014-12-31

    Dec 31, 2014 ... promotes the elevation of interleukin-10 secretion. Cheng-Shi Wang1 ... Nasopharyngeal carcinoma (NPC) is uncommon in the ... Immune function has close relationship with the patho- genesis of ... Liver is the major organ responsible for the synthesis of primary bile acids, and the function of bacteria in the ...

  10. PREPARATIVE ISOLATION AND PURIFICATION OF THREE GLYCINE-CONJUGATED CHOLIC ACIDS FROM PULVIS FELLIS SUIS BY HIGH-SPEED COUNTERCURRENT CHROMATOGRAPHY COUPLED WITH ELSD DETECTION.

    Science.gov (United States)

    He, Jiao; Li, Jing; Sun, Wenji; Zhang, Tianyou; Ito, Yoichiro

    2012-01-01

    Coupled with evaporative light scattering detection, a high-speed counter-current chromatography (HSCCC) method was developed for preparative isolation and purification of three glycine-conjugated cholic acids, glycochenodeoxycholic acid (GCDCA), glycohyodeoxycholic acid (GHDCA) and glycohyocholic acid (GHCA) from Pulvis Fellis Suis (Pig gallbladder bile) for the first time. The separation was performed with a two-phase solvent system consisted of chloroform-methanol-water-acetic acid (65:30:10:1.5, v/v/v/v) by eluting the lower phase in the head-to-tail elution mode. The revolution speed of the separation column, flow rate of the mobile phase and separation temperature were 800 rpm, 2 ml/min and 25 °C, respectively. In a single operation, 33 mg of GCDCA, 38 mg of GHDCA and 23 mg of GHCA were obtained from 200 mg of crude extract with the purity of 95.65%, 96.72% and 96.63%, respectively, in one step separation. The HSCCC fractions were analyzed by high-performance liquid chromatography (HPLC) and the structures of the three glycine-conjugated cholic acids were identified by ESI-MS, (1)H NMR and (13)C NMR.

  11. Serum Bile Acids Are Higher in Humans With Prior Gastric Bypass: Potential Contribution to Improved Glucose and Lipid Metabolism

    Science.gov (United States)

    Patti, Mary-Elizabeth; Houten, Sander M.; Bianco, Antonio C.; Bernier, Raquel; Larsen, P. Reed; Holst, Jens J.; Badman, Michael K.; Maratos-Flier, Eleftheria; Mun, Edward C.; Pihlajamaki, Jussi; Auwerx, Johan; Goldfine, Allison B.

    2015-01-01

    The multifactorial mechanisms promoting weight loss and improved metabolism following Roux-en-Y gastric bypass (GB) surgery remain incompletely understood. Recent rodent studies suggest that bile acids can mediate energy homeostasis by activating the G-protein coupled receptor TGR5 and the type 2 thyroid hormone deiodinase. Altered gastrointestinal anatomy following GB could affect enterohepatic recirculation of bile acids. We assessed whether circulating bile acid concentrations differ in patients who previously underwent GB, which might then contribute to improved metabolic homeostasis. We performed cross-sectional analysis of fasting serum bile acid composition and both fasting and post-meal metabolic variables, in three subject groups: (i) post-GB surgery (n = 9), (ii) without GB matched to preoperative BMI of the index cohort (n = 5), and (iii) without GB matched to current BMI of the index cohort (n = 10). Total serum bile acid concentrations were higher in GB (8.90 ± 4.84 µmol/l) than in both overweight (3.59 ± 1.95, P = 0.005, Ov) and severely obese (3.86 ± 1.51, P = 0.045, MOb). Bile acid subfractions taurochenodeoxycholic, taurodeoxycholic, glycocholic, glycochenodeoxycholic, and glycodeoxycholic acids were all significantly higher in GB compared to Ov (P fasting triglycerides (r = −0.40, P = 0.05), and positively correlated with adiponectin (r = −0.48, P < 0.02) and peak glucagon-like peptide-1 (GLP-1) (r = 0.58, P < 0.003). Total bile acids strongly correlated inversely with thyrotropic hormone (TSH) (r = −0.57, P = 0.004). Together, our data suggest that altered bile acid levels and composition may contribute to improved glucose and lipid metabolism in patients who have had GB. PMID:19360006

  12. Relation between reflux of bile acids into the stomach and gastric mucosal atrophy, intestinal metaplasia in biopsy specimens.

    Science.gov (United States)

    Matsuhisa, Takeshi; Tsukui, Taku

    2012-05-01

    During endoscopic examinations we collected fluid in the stomach that included reflux fluid from the duodenum, and assessed the effect of quantitatively determined bile acids on glandular atrophy and intestinal metaplasia using biopsy specimens. A total of 294 outpatients were enrolled in this study. Total bile acid concentration was measured by an enzyme immunoassay. Glandular atrophy and intestinal metaplasia scores were graded according to the Updated Sydney System. An effect of refluxed bile acids on atrophy and intestinal metaplasia was shown in the high-concentration reflux group in comparison with the control group. However, when the odds ratios (ORs) were calculated according to whether Helicobacter pylori (H. pylori) infection was present, no significant associations were shown between reflux bile acids and atrophy in either the H. pylori-positive cases or -negative cases. The same was true for intestinal metaplasia in the H. pylori-positive cases, whereas intestinal metaplasia was more pronounced in the high-concentration reflux group in the H. pylori-negative cases (OR 2.4, 95%CI 1.1-5.6). We could not clarify the effect of the reflux of bile acids into the stomach in the progression of atrophy. High-concentration bile acids had an effect on the progression of intestinal metaplasia in the H. pylori-negative cases.

  13. Activation of PPARα decreases bile acids in livers of female mice while maintaining bile flow and biliary bile acid excretion.

    Science.gov (United States)

    Zhang, Youcai; Lickteig, Andrew J; Csanaky, Iván L; Klaassen, Curtis D

    2018-01-01

    Fibrates are hypolipidemic drugs that act as activators of peroxisome proliferator-activated receptor α (PPARα). In both humans and rodents, females were reported to be less responsive to fibrates than males. Previous studies on fibrates and PPARα usually involved male mice, but little has been done in females. The present study aimed to provide the first comprehensive analysis of the effects of clofibrate (CLOF) and PPARα on bile acid (BA) homeostasis in female mice. Study in WT male mice showed that a 4-day CLOF treatment increased liver weight, bile flow, and biliary BA excretion, but decreased total BAs in both serum and liver. In contrast, WT female mice were less susceptible to these CLOF-mediated responses observed in males. In WT female mice, CLOF decreased total BAs in the liver, but had little effect on the mRNAs of hepatic BA-related genes. Next, a comparative analysis between WT and PPARα-null female mice showed that lack of PPARα in female mice decreased total BAs in serum, but had little effect on total BAs in liver or bile. However, lack of PPARα in female mice increased mRNAs of BA synthetic enzymes (Cyp7a1, Cyp8b1, Cyp27a1, and Cyp7b1) and transporters (Ntcp, Oatp1a1, Oatp1b2, and Mrp3). Furthermore, the increase of Cyp7a1 in PPARα-null female mice was associated with an increase in liver Fxr-Shp-Lrh-1 signaling. In conclusion, female mice are resistant to CLOF-mediated effects on BA metabolism observed in males, which could be attributed to PPARα-mediated suppression in females on genes involved in BA synthesis and transport. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Promoting effect of bile acids on neoplastic transformation of x-irradiated 10T1/2 cells

    International Nuclear Information System (INIS)

    Han, A.; Hill, C.K.

    1984-01-01

    Experimental studies have raised a concern about a role of bile acids in colo-rectal carcinogenesis. Studies in vivo suggest that bile acids may act as tumor promoters. Using 10T1/2 mouse cells as a model system, the authors explored the effects of cholic and cheno-deoxycholic acid on x-ray-induced neoplastic transformation in these cells. Addition of either cheno-deoxycholic acid or cholic acid to 10T1/2 cells, 24 hours after exposure to x-rays (50kv) increases significantly the frequencies of transformation. The compounds were present in the medium throughout the entire postirradiation refeeding period. At the concentrations used (0.5μg/ml), neither acid was cytotoxic and did not have any effect on cell survival. The enhancement of radiation-induced transformation seems to be greater in the presence of cholic acid, as compared to the effect of cheno-deoxycholic acid. Increase in transformation was relatively greater after low compared to high doses of radiation. The effect of bile acids on transformation of 10T1/2 cells is similar to that of a known tumor promoter TPA. The authors' observations support the conclusion that promotional effect of bile acids is not because of their specific effect on colonic epithelium, but rather due to their general properties as tumor promoters

  15. Incorporation of conjugated linoleic acid (CLA and α-linolenic acid (LNA in pacu fillets

    Directory of Open Access Journals (Sweden)

    Deoclécio José Barilli

    2014-03-01

    Full Text Available The objective of this study was to evaluate the incorporation of conjugated linoleic acid and α-linolenic acid in fillets of pacu fish raised in net cages and fed diets enriched with these acids. The fish were fed for 49 days, and at the end of this period the fatty acid content in the fillets was determined by gas chromatography. Concentrations of α-linolenic acid, eicosapentaenoic acid, and the total omega-3 (n-3 fatty acid in the fillets increased, improving the n-6/n-3 ratio. In addition, the incorporation of conjugated linoleic acid in the fish fillets proved well established. This study showed that the use of diets enriched with conjugated linoleic acid and α-linolenic acid results in the incorporation of these acids in the of pacu fish fillets, improving their nutritional quality.

  16. Survival of Four Probiotic Strains in Acid, Bile Salt and After Spray Drying

    OpenAIRE

    Rawichar Chaipojjana; Suttipong Phosuksirikul; Arunsri Leejeerajumnean

    2014-01-01

    The objective of the study was to select the survival of probiotic strains when exposed to acidic and bile salts condition. Four probiotic strains Lactobacillus casei subsp. rhamnosus TISTR 047, Lactobacillus casei TISTR 1500, Lactobacillus acidophilus TISTR 1338 and Lactobacillus plantarum TISTR 1465 were cultured in MRS broth and incubated at 35ºC for 15 hours before being inoculated into acidic condition 5 M HCl, pH 2 for 2 hours and bile salt 0.3%, pH 5.8 for 8 hour. ...

  17. CHANGES IN THE BILE-ACIDS COMPOSITION OF BILE JUICE AFTER FAT INTAKE

    Directory of Open Access Journals (Sweden)

    CRISTINA DINU

    2009-05-01

    Full Text Available A high fat intake increases the flow of bile or changes the composition of bile acids in refluxed duodenal contents, and then plays an important role in the developmental precancerous lesion of BE and leading to esophageal adenocarcinoma EAC. Wistar rats were divided into three groups based on their diet: a control group (fed with standard diet, containing 4.20% soybean oil, a second group (fed with a low cowfat diet, containing 4.20% cow fat and the third group (fed with a high cow-fat diet, containing 16.8% cow fat. The TCA value detected in the animals fed the high cowfat diet (median concentration, 13.8 ± 2.42 mmol/L was significant increased comparative with those detected of animals fed the standard diet (8.15 ± 1.22 mmol/L. The TDCA value in the high cow-fat group (2.64 ± 0.97 mmol/L was significantly increased comparative with those detected of animals fed the standard diet (1.66 ± 0.50 mmol/L.

  18. Plasma bile acids show a positive correlation with body mass index and are negatively associated with cognitive restraint of eating in obese patients

    Directory of Open Access Journals (Sweden)

    Philip ePrinz

    2015-06-01

    Full Text Available Bile acids may be involved in the regulation of food intake and energy metabolism. The aim of the study was to investigate the association of plasma bile acids with body mass index (BMI and the possible involvement of circulating bile acids in the modulation of physical activity and eating behavior. Blood was obtained in a group of hospitalized patients with normal weight (BMI 18.5-25 kg/m2, underweight (anorexia nervosa, BMI 50 kg/m2, n=14-15/group and plasma bile acid concentrations assessed. Physical activity and plasma bile acids were measured in a group of patients with anorexia nervosa (BMI 14.6±0.3 kg/m2, n=43. Lastly, in a population of obese patients (BMI 48.5±0.9 kg/m2, n=85, psychometric parameters related to disordered eating and plasma bile acids were assessed. Plasma bile acids showed a positive correlation with BMI (r=0.26, p=0.03 in the population of patients with broad range of BMI (9-85 kg/m2, n=74. No associations were observed between plasma bile acids and different parameters of physical activity in anorexic patients (p>0.05. Plasma bile acids were negatively correlated with cognitive restraint of eating (r=-0.30, p=0.008, while no associations were observed with other psychometric eating behavior-related parameters (p>0.05 in obese patients. In conclusion, these data may point towards a role of bile acids in the regulation of body weight. Since plasma bile acids are negatively correlated with the cognitive restraint of eating in obese patients, this may represent a compensatory adaptation to prevent further overeating.

  19. Clinical Study of Ursodeoxycholic Acid in Barrett's Esophagus Patients.

    Science.gov (United States)

    Banerjee, Bhaskar; Shaheen, Nicholas J; Martinez, Jessica A; Hsu, Chiu-Hsieh; Trowers, Eugene; Gibson, Blake A; Della'Zanna, Gary; Richmond, Ellen; Chow, H-H Sherry

    2016-07-01

    Prior research strongly implicates gastric acid and bile acids, two major components of the gastroesophageal refluxate, in the development of Barrett's esophagus and its pathogenesis. Ursodeoxycholic acid (UDCA), a hydrophilic bile acid, has been shown to protect esophageal cells against oxidative stress induced by cytotoxic bile acids. We conducted a pilot clinical study to evaluate the clinical activity of UDCA in patients with Barrett's esophagus. Twenty-nine patients with Barrett's esophagus received UDCA treatment at a daily dose of 13 to 15 mg/kg/day for 6 months. The clinical activity of UDCA was assessed by evaluating changes in gastric bile acid composition and markers of oxidative DNA damage (8-hydroxydeoxyguanosine), cell proliferation (Ki67), and apoptosis (cleaved caspase-3) in Barrett's esophagus epithelium. The bile acid concentrations in gastric fluid were measured by liquid chromatography/mass spectrometry. At baseline, UDCA (sum of unchanged and glycine/taurine conjugates) accounted for 18.2% of total gastric bile acids. After UDCA intervention, UDCA increased significantly to account for 93.4% of total gastric bile acids (P acid composition but did not modulate selected markers of oxidative DNA damage, cell proliferation, and apoptosis in the Barrett's esophagus epithelium. Cancer Prev Res; 9(7); 528-33. ©2016 AACRSee related article by Brian J. Reid, p. 512. ©2016 American Association for Cancer Research.

  20. The role of bile acids in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.

    Science.gov (United States)

    Chow, Monica D; Lee, Yi-Horng; Guo, Grace L

    2017-08-01

    Nonalcoholic fatty liver disease is growing in prevalence worldwide. It is marked by the presence of macrosteatosis on liver histology but is often clinically asymptomatic. However, it can progress into nonalcoholic steatohepatitis which is a more severe form of liver disease characterized by inflammation and fibrosis. Further progression leads to cirrhosis, which predisposes patients to hepatocellular carcinoma or liver failure. The mechanism by which simple steatosis progresses to steatohepatitis is not entirely clear. However, multiple pathways have been proposed. A common link amongst many of these pathways is disruption of the homeostasis of bile acids. Other than aiding in the absorption of lipids and lipid-soluble vitamins, bile acids act as ligands. For example, they bind to farnesoid X receptor, which is critically involved in many of the pathways responsible for maintaining bile acid, glucose, and lipid homeostasis. Alterations to these pathways can lead to dysregulation of energy balance and increased inflammation and fibrosis. Repeated insults over time may be the key to development of steatohepatitis. For this reason, current drug therapies target aspects of these pathways to try to reduce and halt inflammation and fibrosis. This review will focus on the role of bile acids in these various pathways and how changes in these pathways may result in steatohepatitis. While there is no approved pharmaceutical treatment for either hepatic steatosis or steatohepatitis, this review will also touch upon the multitude of potential therapies. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. SeHCAT [tauroselcholic (selenium-75) acid] for the investigation of bile acid malabsorption and measurement of bile acid pool loss: A systematic review and cost-effectiveness analysis

    NARCIS (Netherlands)

    R. Riemsma (Rob); M.J. Al (Maiwenn); I. Corro Ramos (Isaac); S.N. Deshpande; N. Armstrong (Nigel); S. Ryder; C. Noake; M. Krol; M. Oppe (Mark); J. Kleijnen (Jos); J.L. Severens (Hans)

    2013-01-01

    markdownabstractBackground The principal diagnosis/indication for this assessment is chronic diarrhoea due to bile acid malabsorption (BAM). Diarrhoea can be defined as the abnormal passage of loose or liquid stools more than three times daily and/or a daily stool weight > 200 g per day and is

  2. Effects of Bile Acids and Nisin on the Production of Enterotoxin by Clostridium perfringens in a Nutrient-Rich Medium

    Directory of Open Access Journals (Sweden)

    Miseon Park

    2018-01-01

    Full Text Available Clostridium perfringens is the second most common cause of bacterial foodborne illness in the United States, with nearly a million cases each year. C. perfringens enterotoxin (CPE, produced during sporulation, damages intestinal epithelial cells by pore formation, which results in watery diarrhea. The effects of low concentrations of nisin and bile acids on sporulation and toxin production were investigated in C. perfringens SM101, which carries an enterotoxin gene on the chromosome, in a nutrient-rich medium. Bile acids and nisin increased production of enterotoxin in cultures; bile acids had the highest effect. Both compounds stimulated the transcription of enterotoxin and sporulation-related genes and production of spores during the early growth phase. They also delayed spore outgrowth and nisin was more inhibitory. Bile acids and nisin enhanced enterotoxin production in some but not all other C. perfringens isolates tested. Low concentrations of bile acids and nisin may act as a stress signal for the initiation of sporulation and the early transcription of sporulation-related genes in some strains of C. perfringens, which may result in increased strain-specific production of enterotoxin in those strains. This is the first report showing that nisin and bile acids stimulated the transcription of enterotoxin and sporulation-related genes in a nutrient-rich bacterial culture medium.

  3. Effects of Bile Acids and Nisin on the Production of Enterotoxin by Clostridium perfringens in a Nutrient-Rich Medium.

    Science.gov (United States)

    Park, Miseon; Rafii, Fatemeh

    2018-01-01

    Clostridium perfringens is the second most common cause of bacterial foodborne illness in the United States, with nearly a million cases each year. C. perfringens enterotoxin (CPE), produced during sporulation, damages intestinal epithelial cells by pore formation, which results in watery diarrhea. The effects of low concentrations of nisin and bile acids on sporulation and toxin production were investigated in C. perfringens SM101, which carries an enterotoxin gene on the chromosome, in a nutrient-rich medium. Bile acids and nisin increased production of enterotoxin in cultures; bile acids had the highest effect. Both compounds stimulated the transcription of enterotoxin and sporulation-related genes and production of spores during the early growth phase. They also delayed spore outgrowth and nisin was more inhibitory. Bile acids and nisin enhanced enterotoxin production in some but not all other C. perfringens isolates tested. Low concentrations of bile acids and nisin may act as a stress signal for the initiation of sporulation and the early transcription of sporulation-related genes in some strains of C. perfringens , which may result in increased strain-specific production of enterotoxin in those strains. This is the first report showing that nisin and bile acids stimulated the transcription of enterotoxin and sporulation-related genes in a nutrient-rich bacterial culture medium.

  4. Consequences of bile salt biotransformations by intestinal bacteria

    Science.gov (United States)

    Ridlon, Jason M.; Harris, Spencer C.; Bhowmik, Shiva; Kang, Dae-Joong; Hylemon, Phillip B.

    2016-01-01

    ABSTRACT Emerging evidence strongly suggest that the human “microbiome” plays an important role in both health and disease. Bile acids function both as detergents molecules promoting nutrient absorption in the intestines and as hormones regulating nutrient metabolism. Bile acids regulate metabolism via activation of specific nuclear receptors (NR) and G-protein coupled receptors (GPCRs). The circulating bile acid pool composition consists of primary bile acids produced from cholesterol in the liver, and secondary bile acids formed by specific gut bacteria. The various biotransformation of bile acids carried out by gut bacteria appear to regulate the structure of the gut microbiome and host physiology. Increased levels of secondary bile acids are associated with specific diseases of the GI system. Elucidating methods to control the gut microbiome and bile acid pool composition in humans may lead to a reduction in some of the major diseases of the liver, gall bladder and colon. PMID:26939849

  5. Bile acids cycle disruption in patients with nasopharyngeal ...

    African Journals Online (AJOL)

    2014-12-31

    Dec 31, 2014 ... Cite as: Wang C-S, Liu S-H, Peng J, Tang C, Zhu W-G. Bile acids cycle disruption in patients .... stein-Barr virus in the development of nasopharyngeal carcinoma. Chin. J. Cancer 2014; 33(11): 556 PubMed. -568. 2. Mrizak D, Martin N, Barjon C, Jimenez-Pailhes AS,. Mustapha R, Niki T, Guigay J, Pancre V, ...

  6. Barley β-glucan reduces blood cholesterol levels via interrupting bile acid metabolism.

    Science.gov (United States)

    Wang, Yanan; Harding, Scott V; Thandapilly, Sijo J; Tosh, Susan M; Jones, Peter J H; Ames, Nancy P

    2017-11-01

    Underlying mechanisms responsible for the cholesterol-lowering effect of β-glucan have been proposed, yet have not been fully demonstrated. The primary aim of this study was to determine whether the consumption of barley β-glucan lowers cholesterol by affecting the cholesterol absorption, cholesterol synthesis or bile acid synthesis. In addition, this study was aimed to assess whether the underlying mechanisms are related to cholesterol 7α hydroxylase (CYP7A1) SNP rs3808607 as proposed by us earlier. In a controlled, randomised, cross-over study, participants with mild hypercholesterolaemia (n 30) were randomly assigned to receive breakfast containing 3 g high-molecular weight (HMW), 5 g low-molecular weight (LMW), 3 g LMW barley β-glucan or a control diet, each for 5 weeks. Cholesterol absorption was determined by assessing the enrichment of circulating 13C-cholesterol over 96 h following oral administration; fractional rate of synthesis for cholesterol was assessed by measuring the incorporation rate of 2H derived from deuterium oxide within the body water pool into the erythrocyte cholesterol pool over 24 h; bile acid synthesis was determined by measuring serum 7α-hydroxy-4-cholesten-3-one concentrations. Consumption of 3 g HMW β-glucan decreased total cholesterol (TC) levels (P=0·029), but did not affect cholesterol absorption (P=0·25) or cholesterol synthesis (P=0·14). Increased bile acid synthesis after consumption of 3 g HMW β-glucan was observed in all participants (P=0·049), and more pronounced in individuals carrying homozygous G of rs3808607 (P=0·033). In addition, a linear relationship between log (viscosity) of β-glucan and serum 7α-HC concentration was observed in homozygous G allele carriers. Results indicate that increased bile acid synthesis rather than inhibition of cholesterol absorption or synthesis may be responsible for the cholesterol-lowering effect of barley β-glucan. The pronounced TC reduction in G allele carriers of rs

  7. Bile Salt and Acid Tolerant of Lactic Acid Bacteria Isolated from Proventriculus of Broiler Chicken

    Directory of Open Access Journals (Sweden)

    E. Damayanti

    2014-08-01

    Full Text Available The aim of this research was to obtain the lactic acid bacteria (LAB as probiotic candidates which have resistance to bile salt and acid condition. LAB was obtained using isolation method from proventriculus of broiler chicken. Selective MRS media with 0.2% CaCO3 addition were used for LAB isolation using pour plate sampling method under anaerobic condition. The result showed that four selected isolates had morphological and biochemical characteristics as LAB. The selected LAB was characterized as follow: antibacterial activities, antibiotic sensitivity, resistance on bile salt, gastric juice and acid condition, and biochemical identification. Antibacterial activities assay of cell free supernatant was confirmed using disc paper diffusion method which was arranged on factorial design and each treatment consisted of three replications. The cell free supernatant of LAB isolates had antibacterial activities against Escherichia coli, Pseudomonas aerugenosa, and Salmonella pullorum. Molecular identification procedure using 16S rRNA sequence analysis showed that R01 and R02 as Pediococcus acidilactici. The viability of the two isolates were tested by acid pH (pH 1, 2, and 3, gastric juice pH 2, and bile salt condition for digestives tract simulation. The result showed that R01 and R02 had a high viability percentages at pH 1, 2, and 3 (95.45%, 99.49%, 104.01%, and 67.17%, 120.74%, 103.4%, respectively and at bile salt simulation for 1-2 hours (100.35%-102.71% and 100.02%-102.65%, respectively, but at gastric juice simulation for 1-2 hours, the P. acidilactici R01 had higher viability than P. acidilactici R02 (59.69%-76.53% versus 43.57%-40.69%, respectively. In the antibiotic sensitivity test for three antibiotics (i.e. erythromicin 15 µg, penicillin G 10 µg, and streptomycin 10 µg, the P. acidilactici R02 showed resistance to Streptomycin and Penicillin. It is concluded that P. acidilactici R01 and P. acidilactici R02 isolated from proventriculus

  8. Lecithin inhibits fatty acid and bile salt absorption from rat small intestine in vivo.

    Science.gov (United States)

    Saunders, D R; Sillery, J

    1976-12-01

    During digestion of a fatty meal, long chain free fatty acids (FFA) and lecithin are among the lipids solubilized in intestinal contents as mixed micelles with bile salts. We hypothesized that if lecithin were not hydrolyzed, the mixed micelles would be abnormal, and absorption of FFA and bile salts would be depressed. To test this hypothesis, isolated segments of rat small intestine were infused in vivo with micellar solutions of 2 mMolar linoleic acid and 10 mMolar taurocholate to which was added 3 mMolar 1-palmitoyl, 2-oleoyl lecithin (a common lecithin in bile and food), or 1-palmitoyl lysolecithin (the hydrolytic product of lecithin). Absorption of FFA and bile salt was measured under steady state conditions using a single-pass technique. Lecithin depressed the rate of FFA absorption by 40% (p less than 0.025) in jejunal and ileal segments whereas lysolecithin was associated with normal rates of FFA absorption. Lecithin also reduced taurocholate absorption from the ileum by 30% (p less than 0.05). These data support the idea that lecithin may depress FFA and bile salt absorption from the small intestine in pancreatic insufficiency.

  9. Metformin impacts cecal bile acid profiles in mice.

    Science.gov (United States)

    Sillner, Nina; Walker, Alesia; Koch, Wendelin; Witting, Michael; Schmitt-Kopplin, Philippe

    2018-04-15

    Bile acids (BAs) are major components of bile synthesized from cholesterol and take part in the digestion of dietary lipids, as well as having signaling functions. They undergo extensive microbial metabolism inside the gastrointestinal tract. Here, we present a method of ultra-high pressure liquid chromatography coupled to ion trap mass spectrometry for quantification of 45 BAs in mouse cecum. The system was validated in regard to sensitivity with limits of detection and quantification (0.6-24.9 nM), interday accuracy (102.4%), interday precision (15.2%), recovery rate (74.7%), matrix effect (98.2%) and carry-over effect (mice were treated with metformin for 1 day or 14 days. One day of treatment resulted in a significant increase of total BA concentration (2.7-fold increase; db/db metformin 5.32 μmol/g, db/db control mice 1.95 μmol/g), most notable in levels of 7-oxodeoxycholic, 3-dehydrocholic and cholic acid. We observed only minor impact on BA metabolism after 14 days of metformin treatment, compared to the single treatment. Furthermore, healthy wild type mice had elevated concentrations of allocholic and ω-muricholic acid compared to diabetic mice. Our method proved the applicability of profiling BAs in cecum to investigate intestinal BA metabolism in diabetes and pharmacological applications. Copyright © 2018 Elsevier B.V. All rights reserved.

  10. Intrahepatic Cholestasis of Pregnancy with Severe Elevation of Bile Acids in the Setting of Acute Hepatitis C Infection

    Directory of Open Access Journals (Sweden)

    Megan L. Lawlor

    2016-01-01

    Full Text Available Intrahepatic cholestasis of pregnancy (ICP is a complication of pregnancy resulting in elevation of serum bile acid levels. ICP is often associated with underlying liver disease, including hepatitis C. Bile acids in relationship to the acute infection of hepatitis C virus have not yet been delineated in the literature. A 26-year-old gravida 4 para 2103 with dichorionic, diamniotic twin gestation and history of intravenous drug abuse developed ICP in the setting of acute hepatitis C infection. In addition to clinical symptoms of pruritus and right upper quadrant pain, she developed severe elevation in bile acids, 239 micromol/L, and transaminitis aspartate aminotransferase 1033 U/L, and alanine aminotransferase 448 U/L. She received ursodeoxycholic acid and antenatal testing was performed. Patient delivered vaginally at 33-week gestation following preterm rupture of membranes. Neonates were admitted to NICU and had uncomplicated neonatal courses. In the setting of ICP with significant transaminitis and severe elevation of bile acids, consideration of acute viral hepatitis is important, especially considering the worsening opioid epidemic and concurrent increase in intravenous drug use in the United States. Further study is needed regarding the acute form of HCV infection and its effect on ICP and associated bile acids.

  11. Ultra performance liquid chromatography-mass spectrometry profiling of bile acid metabolites in biofluids: application to experimental toxicology studies.

    Science.gov (United States)

    Want, Elizabeth J; Coen, Muireann; Masson, Perrine; Keun, Hector C; Pearce, Jake T M; Reily, Michael D; Robertson, Donald G; Rohde, Cynthia M; Holmes, Elaine; Lindon, John C; Plumb, Robert S; Nicholson, Jeremy K

    2010-06-15

    We have developed an ultra performance liquid chromatography-mass spectrometry (UPLC-MS(E)) method to measure bile acids (BAs) reproducibly and reliably in biological fluids and have applied this approach for indications of hepatic damage in experimental toxicity studies. BAs were extracted from serum using methanol, and an Acquity HSS column coupled to a Q-ToF mass spectrometer was used to separate and identify 25 individual BAs within 5 min. Employing a gradient elution of water and acetonitrile over 21 min enabled the detection of a wide range of endogenous metabolites, including the BAs. The utilization of MS(E) allowed for characteristic fragmentation information to be obtained in a single analytical run, easily distinguishing glycine and taurine BA conjugates. The proportions of these conjugates were altered markedly in an experimental toxic state induced by galactosamine exposure in rats. Principally, taurine-conjugated BAs were greatly elevated ( approximately 50-fold from control levels), and were highly correlated to liver damage severity as assessed by histopathological scoring (r = 0.83), indicating their potential as a sensitive measure of hepatic damage. The UPLC-MS approach to BA analysis offers a sensitive and reproducible tool that will be of great value in exploring both markers and mechanisms of hepatotoxicity and can readily be extended to clinical studies of liver damage.

  12. Bile acids induce glucagon-like peptide 2 secretion with limited effects on intestinal adaptation in early weaned pigs

    DEFF Research Database (Denmark)

    Ipharraguerre, Ignacio R; Tedó, Gemma; Menoyo, David

    2013-01-01

    Early weaning is a stressful event characterized by a transient period of intestinal atrophy that may be mediated by reduced secretion of glucagon-like peptide (GLP) 2. We tested whether enterally fed bile acids or plant sterols could increase nutrient-dependent GLP-2 secretion and improve.......05) but did not affect plasma GLP-1 and feed intake. The intestinal expression of glucagon-like peptide 2 receptor, sodium-dependent bile acid transporter, farnesoid X receptor, and guanosine protein-coupled bile acid receptor genes were not affected by CDC treatment. The intragastric administration of CDC...

  13. Binding domain-driven intracellular trafficking of sterols for synthesis of steroid hormones, bile acids and oxysterols.

    Science.gov (United States)

    Midzak, Andrew; Papadopoulos, Vassilios

    2014-09-01

    Steroid hormones, bioactive oxysterols and bile acids are all derived from the biological metabolism of lipid cholesterol. The enzymatic pathways generating these compounds have been an area of intense research for almost a century, as cholesterol and its metabolites have substantial impacts on human health. Owing to its high degree of hydrophobicity and the chemical properties that it confers to biological membranes, the distribution of cholesterol in cells is tightly controlled, with subcellular organelles exhibiting highly divergent levels of cholesterol. The manners in which cells maintain such sterol distributions are of great interest in the study of steroid and bile acid synthesis, as limiting cholesterol substrate to the enzymatic pathways is the principal mechanism by which production of steroids and bile acids is regulated. The mechanisms by which cholesterol moves within cells, however, remain poorly understood. In this review, we examine the subcellular machinery involved in cholesterol metabolism to steroid hormones and bile acid, relating it to both lipid- and protein-based mechanisms facilitating intracellular and intraorganellar cholesterol movement and delivery to these pathways. In particular, we examine evidence for the involvement of specific protein domains involved in cholesterol binding, which impact cholesterol movement and metabolism in steroidogenesis and bile acid synthesis. A better understanding of the physical mechanisms by which these protein- and lipid-based systems function is of fundamental importance to understanding physiological homeostasis and its perturbation. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  14. Mechanisms Underlying the Anti-Aging and Anti-Tumor Effects of Lithocholic Bile Acid

    Directory of Open Access Journals (Sweden)

    Anthony Arlia-Ciommo

    2014-09-01

    Full Text Available Bile acids are cholesterol-derived bioactive lipids that play essential roles in the maintenance of a heathy lifespan. These amphipathic molecules with detergent-like properties display numerous beneficial effects on various longevity- and healthspan-promoting processes in evolutionarily distant organisms. Recent studies revealed that lithocholic bile acid not only causes a considerable lifespan extension in yeast, but also exhibits a substantial cytotoxic effect in cultured cancer cells derived from different tissues and organisms. The molecular and cellular mechanisms underlying the robust anti-aging and anti-tumor effects of lithocholic acid have emerged. This review summarizes the current knowledge of these mechanisms, outlines the most important unanswered questions and suggests directions for future research.

  15. Circulating bile acids in healthy adults respond differently to a dietary pattern characterized by whole grains, legumes and fruits and vegetables compared to a diet high in refined grains and added sugars: a randomized, controlled, crossover feeding study.

    Science.gov (United States)

    Ginos, Bigina N R; Navarro, Sandi L; Schwarz, Yvonne; Gu, Haiwei; Wang, Dongfang; Randolph, Timothy W; Shojaie, Ali; Hullar, Meredith A J; Lampe, Paul D; Kratz, Mario; Neuhouser, Marian L; Raftery, Daniel; Lampe, Johanna W

    2018-02-16

    -diol, 5-cholanic acid-3β-ol, and glycodeoxycholic acid (GDCA) were statistically significantly positively associated with HOMA-IR individually, and as a group, total, 12α-hydroxylated, primary and secondary bile acids were also significant (FDR < 0.05). When stratifying by BMI, chenodeoxycholic acid (CDCA), cholic acid (CA), UDCA, 5β-cholanic acid-3β, deoxycholic acid, and total, 12α-hydroxylated, primary and secondary bile acid groups were significantly positively associated with HOMA-IR among overweight to obese individuals (FDR <0.05). When stratifying by sex, GCA, CDCA, TCA, CA, UDCA, GDCA, glycolithocholic acid (GLCA), total, primary, 12α-hydroxylated, and glycine-conjugated bile acids were significantly associated with HOMA-IR among women, and CDCA, GDCA, and GLCA were significantly associated among men (FDR < 0.05). There were no significant associations between bile acids and CRP. Diets with comparable macronutrient and energy composition, but differing in carbohydrate source, affected fasting plasma bile acids differently. Specifically, a diet characterized by whole grains, legumes, and fruits and vegetables compared to a diet high in refined grains and added sugars led to modest increases in concentrations of TLCA, TCA and GCA, ligands for FXR and TGR5, which may have beneficial effects on glucose homeostasis. Copyright © 2018. Published by Elsevier Inc.

  16. Suppression of sterol 27-hydroxylase mRNA and transcriptional activity by bile acids in cultured rat hepatocytes

    NARCIS (Netherlands)

    Twisk, J.; Wit, E.C.M. de; Princen, H.M.G.

    1995-01-01

    In previous work we have demonstrated suppression of cholesterol 7α-hydroxylase by bile acids at the level of mRNA and transcription, resulting in a similar decline in bile acid synthesis in cultured rat hepatocytes. In view of the substantial contribution of the 'alternative' or '27-hydroxylase'

  17. Are conjugated linolenic acid isomers an alternative to conjugated linoleic acid isomers in obesity prevention?

    Science.gov (United States)

    Miranda, Jonatan; Arias, Noemi; Fernández-Quintela, Alfredo; del Puy Portillo, María

    2014-04-01

    Despite its benefits, conjugated linoleic acid (CLA) may cause side effects after long-term administration. Because of this and the controversial efficacy of CLA in humans, alternative biomolecules that may be used as functional ingredients have been studied in recent years. Thus, conjugated linolenic acid (CLNA) has been reported to be a potential anti-obesity molecule which may have additional positive effects related to obesity. According to the results reported in obesity, CLNA needs to be given at higher doses than CLA to be effective. However, because of the few studies conducted so far, it is still difficult to reach clear conclusions about the potential use of these CLNAs in obesity and its related changes (insulin resistance, dyslipidemia, or inflammation). Copyright © 2012 SEEN. Published by Elsevier Espana. All rights reserved.

  18. Two distinct etiologies of gastric cardia adenocarcinoma: interactions among pH, Helicobacter pylori, and bile acids

    Directory of Open Access Journals (Sweden)

    Ken-ichi eMukaisho

    2015-05-01

    Full Text Available Gastric cancer can be classified as cardia and noncardia subtypes according to the anatomic site. Although the gastric cancer incidence has decreased steadily in several countries over the past 50 years, the incidence of cardia cancers and esophageal adenocarcinoma (EAC continue to increase. The etiological factors involved in the development of both cardia cancers and EACs are associated with high animal fat intake, which causes severe obesity. Central obesity plays roles in cardiac-type mucosa lengthening and partial hiatus hernia development. There are two distinct etiologies of cardia cancer subtypes: one associated with gastroesophageal reflux (GER, which predominantly occurs in patients without Helicobacter pylori (H. pylori infection and resembles EAC, and the other associated with H. pylori atrophic gastritis, which resembles noncardia cancer. The former can be developed in the environment of high volume duodenal content reflux, including bile acids and a higher acid production in H. pylori–negative patients. N-nitroso compounds, which are generated from the refluxate that includes a large volume of bile acids and are stabilized in the stomach (which has high levels of gastric acid, play a pivotal role in this carcinogenesis. The latter can be associated with the changing colonization of H. pylori from the distal to the proximal stomach with atrophic gastritis because a high concentration of soluble bile acids in an environment of low acid production is likely to act as a bactericide or chemorepellent for H. pylori in the distal stomach with H. pylori infection. The manuscript introduces new insights in causative factors of adenocarcinoma of the cardia about the role of bile acids in gastro-esophageal refluxate based upon robust evidences supporting interactions among pH, H. pylori, and bile acids.

  19. Periodic variation in bile acids controls circadian changes in uric acid via regulation of xanthine oxidase by the orphan nuclear receptor PPARα.

    Science.gov (United States)

    Kanemitsu, Takumi; Tsurudome, Yuya; Kusunose, Naoki; Oda, Masayuki; Matsunaga, Naoya; Koyanagi, Satoru; Ohdo, Shigehiro

    2017-12-29

    Xanthine oxidase (XOD), also known as xanthine dehydrogenase, is a rate-limiting enzyme in purine nucleotide degradation, which produces uric acid. Uric acid concentrations in the blood and liver exhibit circadian oscillations in both humans and rodents; however, the underlying mechanisms remain unclear. Here, we demonstrate that XOD expression and enzymatic activity exhibit circadian oscillations in the mouse liver. We found that the orphan nuclear receptor peroxisome proliferator-activated receptor-α (PPARα) transcriptionally activated the mouse XOD gene and that bile acids suppressed XOD transactivation. The synthesis of bile acids is known to be under the control of the circadian clock, and we observed that the time-dependent accumulation of bile acids in hepatic cells interfered with the recruitment of the co-transcriptional activator p300 to PPARα, thereby repressing XOD expression. This time-dependent suppression of PPARα-mediated transactivation by bile acids caused an oscillation in the hepatic expression of XOD, which, in turn, led to circadian alterations in uric acid production. Finally, we also demonstrated that the anti-hyperuricemic effect of the XOD inhibitor febuxostat was enhanced by administering it at the time of day before hepatic XOD activity increased. These results suggest an underlying mechanism for the circadian alterations in uric acid production and also underscore the importance of selecting an appropriate time of day for administering XOD inhibitors. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  20. Effect of various antibiotics on modulation of intestinal microbiota and bile acid profile in mice

    International Nuclear Information System (INIS)

    Zhang, Youcai; Limaye, Pallavi B.; Renaud, Helen J.; Klaassen, Curtis D.

    2014-01-01

    Antibiotic treatments have been used to modulate intestinal bacteria and investigate the role of intestinal bacteria on bile acid (BA) homeostasis. However, knowledge on which intestinal bacteria and bile acids are modified by antibiotics is limited. In the present study, mice were administered various antibiotics, 47 of the most abundant bacterial species in intestine, as well as individual BAs in plasma, liver, and intestine were quantified. Compared to the two antibiotic combinations (vancomycin + imipenem and cephalothin + neomycin), the three single antibiotics (metronidazole, ciprofloxacin and aztreonam) have less effect on intestinal bacterial profiles, and thus on host BA profiles and mRNA expression of genes that are important for BA homeostasis. The two antibiotic combinations decreased the ratio of Firmicutes to Bacteroidetes in intestine, as well as most secondary BAs in serum, liver and intestine. Additionally, the two antibiotic combinations significantly increased mRNA of the hepatic BA uptake transporters (Ntcp and Oatp1b2) and canalicular BA efflux transporters (Bsep and Mrp2), but decreased mRNA of the hepatic BA synthetic enzyme Cyp8b1, suggesting an elevated enterohepatic circulation of BAs. Interestingly, the two antibiotic combinations tended to have opposite effect on the mRNAs of most intestinal genes, which tended to be inhibited by vancomycin + imipenem but stimulated by cephalothin + neomycin. To conclude, the present study clearly shows that various antibiotics have distinct effects on modulating intestinal bacteria and host BA metabolism. - Highlights: • Various antibiotics have different effects on intestinal bacteria. • Antibiotics alter bile acid composition in mouse liver and intestine. • Antibiotics influence genes involved in bile acid homeostasis. • Clostridia appear to be important for secondary bile acid formation

  1. Effect of various antibiotics on modulation of intestinal microbiota and bile acid profile in mice

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Youcai; Limaye, Pallavi B.; Renaud, Helen J.; Klaassen, Curtis D., E-mail: curtisklaassenphd@gmail.com

    2014-06-01

    Antibiotic treatments have been used to modulate intestinal bacteria and investigate the role of intestinal bacteria on bile acid (BA) homeostasis. However, knowledge on which intestinal bacteria and bile acids are modified by antibiotics is limited. In the present study, mice were administered various antibiotics, 47 of the most abundant bacterial species in intestine, as well as individual BAs in plasma, liver, and intestine were quantified. Compared to the two antibiotic combinations (vancomycin + imipenem and cephalothin + neomycin), the three single antibiotics (metronidazole, ciprofloxacin and aztreonam) have less effect on intestinal bacterial profiles, and thus on host BA profiles and mRNA expression of genes that are important for BA homeostasis. The two antibiotic combinations decreased the ratio of Firmicutes to Bacteroidetes in intestine, as well as most secondary BAs in serum, liver and intestine. Additionally, the two antibiotic combinations significantly increased mRNA of the hepatic BA uptake transporters (Ntcp and Oatp1b2) and canalicular BA efflux transporters (Bsep and Mrp2), but decreased mRNA of the hepatic BA synthetic enzyme Cyp8b1, suggesting an elevated enterohepatic circulation of BAs. Interestingly, the two antibiotic combinations tended to have opposite effect on the mRNAs of most intestinal genes, which tended to be inhibited by vancomycin + imipenem but stimulated by cephalothin + neomycin. To conclude, the present study clearly shows that various antibiotics have distinct effects on modulating intestinal bacteria and host BA metabolism. - Highlights: • Various antibiotics have different effects on intestinal bacteria. • Antibiotics alter bile acid composition in mouse liver and intestine. • Antibiotics influence genes involved in bile acid homeostasis. • Clostridia appear to be important for secondary bile acid formation.

  2. Receptor-mediated uptake of low density lipoprotein stimulates bile acid synthesis by cultured rat hepatocytes

    International Nuclear Information System (INIS)

    Junker, L.H.; Davis, R.A.

    1989-01-01

    The cellular mechanisms responsible for the lipoprotein-mediated stimulation of bile acid synthesis in cultured rat hepatocytes were investigated. Adding 280 micrograms/ml of cholesterol in the form of human or rat low density lipoprotein (LDL) to the culture medium increased bile acid synthesis by 1.8- and 1.6-fold, respectively. As a result of the uptake of LDL, the synthesis of [14C]cholesterol from [2-14C]acetate was decreased and cellular cholesteryl ester mass was increased. Further studies demonstrated that rat apoE-free LDL and apoE-rich high density lipoprotein (HDL) both stimulated bile acid synthesis 1.5-fold, as well as inhibited the formation of [14C]cholesterol from [2-14C]acetate. Reductive methylation of LDL blocked the inhibition of cholesterol synthesis, as well as the stimulation of bile acid synthesis, suggesting that these processes require receptor-mediated uptake. To identify the receptors responsible, competitive binding studies using 125I-labeled apoE-free LDL and 125I-labeled apoE-rich HDL were performed. Both apoE-free LDL and apoE-rich HDL displayed an equal ability to compete for binding of the other, suggesting that a receptor or a group of receptors that recognizes both apolipoproteins is involved. Additional studies show that hepatocytes from cholestyramine-treated rats displayed 2.2- and 3.4-fold increases in the binding of apoE-free LDL and apoE-rich HDL, respectively. These data show for the first time that receptor-mediated uptake of LDL by the liver is intimately linked to processes activating bile acid synthesis

  3. Postprandial Plasma Concentrations of Individual Bile Acids and FGF-19 in Patients With Type 2 Diabetes

    DEFF Research Database (Denmark)

    Sonne, David P; van Nierop, F Samuel; Kulik, Willem

    2016-01-01

    and FGF-19 concentrations. RESULTS: Postprandial total bile acid concentrations increased with increasing meal fat content (P vs controls (oral glucose tolerance test, low and medium fat meals, P fat meal, P = .30). Differences......, Hellerup, Denmark. PARTICIPANTS: Fifteen patients with T2D and 15 healthy matched controls with normal glucose tolerance. INTERVENTIONS: A 75-g oral glucose tolerance test and three isocaloric and isovolemic liquid meals with low, medium, and high fat content, respectively. MAIN OUTCOME MEASURES: Bile acid......CONTEXT: Bile acids regulate lipid and carbohydrate metabolism by interaction with membrane or intracellular proteins including the nuclear farnesoid X receptor (FXR). Postprandial activation of ileal FXR leads to secretion of fibroblast growth factor 19 (FGF-19), a gut hormone that may...

  4. Comparison of linoleic and conjugated linoleic acids in enzymatic acidolysis of tristearin

    DEFF Research Database (Denmark)

    Yang, Tiankui; Xu, Xuebing; Li, L.T.

    2001-01-01

    tristearin (SSS) and linoleic (L) or conjugated linoleic (cL) acids (1:6, mol/mol). The other was between tristearin and the mixture of linoleic and conjugated linoleic acids (1:3:3, mol/mol/mol). Acyl incorporation and migration together with triacylglycerol composition of the products were monitored...... with gas chromatography, pancreatic lipase hydrolysis, and high performance liquid chromatography. Both acyl incorporation and migration of linoleic acid were faster than those of conjugated linoleic acid. At 5 h reaction, there were 13.0% LLL, 46.5% LSL, 27.7% LSS, and 5.6% SSS in the product for a system...... between tristearin and linoleic acid; whereas there were 2.4% cLcLcL, 10.4% cLScL, 50.9% cLSS, and 36.2% SSS in the product for a system between tristearin and conjugated linoleic acid. The results suggest that linoleic acid was more reactive than conjugated linoleic acid in the enzymatic acidolysis...

  5. Viability of Lactic Acid Bacteria Isolated from Kombucha Tea Against Low pH and Bile Salt

    Directory of Open Access Journals (Sweden)

    Ni Nyoman Puspawati

    2016-03-01

    Full Text Available Kombucha tea is a functional drink fermented by various types of microbes. Kombucha tea is also a source of lactic acid bacteria that can maintain the balance of the microflora of the digestive tract which can improve the health of the human body. Lactic acid bacteria can act as a probiotic if it is able to survive to the human gastrointestinal tract, where in order to reach the digestive tract, lactic acid bacteria has to be resistant to the low pH in the stomach and bile salts. The purpose of this study was to determine the level of resistance of lactic acid bacteria in kombucha tea against low pH and bile salts. This study uses 20 isolates, each of these isolates were tested to the resistance of low pH 2.0 and 0.5 % bile salts with incubation time of 4 hours. The results indicated that from 20 isolates of lactic acid bacteria that were obtained from kombucha tea, 15 isolates were resistant to low pH and 13 isolates were resistant to bile salts. The isolates have a huge potential to be developed as a probiotic candidate that can contribute greatly to the health of the digestive tract.

  6. Occurrence of Conjugated Linolenic Acids in Purified Soybean Oil

    OpenAIRE

    Kinami, Tomohisa; Horii, Naoto; Narayan, Bhaskar; Arato, Shingo; Hosokawa, Masashi; Miyashita, Kazuo; Negishi, Hironori; Ikuina, Junichi; Noda, Ryuji; Shirasawa, Seiichi

    2007-01-01

    A high-performance liquid chromatographic (HPLC) method is described for the determination of conjugated linoleic acids (CLA) and conjugated linolenic acids (CLN). Methyl esters prepared from purified lipid fractions of soybean oil were analyzed using an HPLC system equipped with photodiode-array detector to detect peaks having maximum absorption around 233 and 275 nm. These peaks were concentrated by AgNO3-silicic acid column chromatography and reversed-phase HPLC. The structural analysis, o...

  7. Electro-chromograms of human bile

    NARCIS (Netherlands)

    Verschure, J.C.M.

    1956-01-01

    Fivefold diagrams of concentrated samples of human bile were obtained with paper electrophoresis. In these diagrams were distinguished by means of various staining methods: proteins, lipids, bile pigments, bile acids and cholesterol. The series of diagrams from each bile sample thus obtained is

  8. Irritable bowel syndrome-diarrhea: characterization of genotype by exome sequencing, and phenotypes of bile acid synthesis and colonic transit

    Science.gov (United States)

    Klee, Eric W.; Shin, Andrea; Carlson, Paula; Li, Ying; Grover, Madhusudan; Zinsmeister, Alan R.

    2013-01-01

    The study objectives were: to mine the complete exome to identify putative rare single nucleotide variants (SNVs) associated with irritable bowel syndrome (IBS)-diarrhea (IBS-D) phenotype, to assess genes that regulate bile acids in IBS-D, and to explore univariate associations of SNVs with symptom phenotype and quantitative traits in an independent IBS cohort. Using principal components analysis, we identified two groups of IBS-D (n = 16) with increased fecal bile acids: rapid colonic transit or high bile acids synthesis. DNA was sequenced in depth, analyzing SNVs in bile acid genes (ASBT, FXR, OSTα/β, FGF19, FGFR4, KLB, SHP, CYP7A1, LRH-1, and FABP6). Exome findings were compared with those of 50 similar ethnicity controls. We assessed univariate associations of each SNV with quantitative traits and a principal components analysis and associations between SNVs in KLB and FGFR4 and symptom phenotype in 405 IBS, 228 controls and colonic transit in 70 IBS-D, 71 IBS-constipation. Mining the complete exome did not reveal significant associations with IBS-D over controls. There were 54 SNVs in 10 of 11 bile acid-regulating genes, with no SNVs in FGF19; 15 nonsynonymous SNVs were identified in similar proportions of IBS-D and controls. Variations in KLB (rs1015450, downstream) and FGFR4 [rs434434 (intronic), rs1966265, and rs351855 (nonsynonymous)] were associated with colonic transit (rs1966265; P = 0.043), fecal bile acids (rs1015450; P = 0.064), and principal components analysis groups (all 3 FGFR4 SNVs; P transit (P = 0.066). Thus exome sequencing identified additional variants in KLB and FGFR4 associated with bile acids or colonic transit in IBS-D. PMID:24200957

  9. [Blood serum level of primary bile acids in cattle, horses, swine and dogs].

    Science.gov (United States)

    Karsai, F; Szaniszló, F; Pethes, G

    1991-02-01

    The levels of the two primary bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA), were determined by radioimmunoassay in cattle, horse, pig and dog serum. The mean serum cholic acid (SCA) and deoxycholic acid (SCDCA) levels of cows varied with their reproductive status, being 7.8 (+/- 3.3) and 1.5 (+/- 1.0) mumol/l in dry cows, 17.8 (+/- 6.9) and 2.3 (+/- 1.0) mumol/l in freshly calved dams, and 15.8 (+/- 5.7) and 2.3 (+/- 0.8) mumol/l, respectively, in lactating cows. The SCA level found in the immediate prepartal period and also on the day of calving corresponded to those found during the dry period, then, they tended to rise 2 days after calving and attained the peak characteristic for freshly calved dams on day 3 or 4 post partum. Feed consumption had no influence on the serum levels of primary bile acids, and circadian variations of SCA and SCDCA were also negligible. Suckling calves had much lower SCA levels (2.3 (+/- 1.0) mumol/l before feeding than cows. This initial concentration rose to 10.3 (+/- 2.9) mumol/l 1 h after feeding and returned to 5.0 (+/- 2.1) mumol/l 3 h later. Like cows, horses showed no appreciate difference between pre- and post-feeding levels of SCA (2.2 (+/- 1.2) mumol/l) and SCDCA (1.1 (+/- 0.3) mumol/l). Unlike bovines, pigs and dogs showed a considerable increase in the serum levels of the primary bile acids after feeding.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Functional Intestinal Bile Acid 7α-Dehydroxylation by Clostridium scindens Associated with Protection from Clostridium difficile Infection in a Gnotobiotic Mouse Model.

    Science.gov (United States)

    Studer, Nicolas; Desharnais, Lyne; Beutler, Markus; Brugiroux, Sandrine; Terrazos, Miguel A; Menin, Laure; Schürch, Christian M; McCoy, Kathy D; Kuehne, Sarah A; Minton, Nigel P; Stecher, Bärbel; Bernier-Latmani, Rizlan; Hapfelmeier, Siegfried

    2016-01-01

    Bile acids, important mediators of lipid absorption, also act as hormone-like regulators and as antimicrobial molecules. In all these functions their potency is modulated by a variety of chemical modifications catalyzed by bacteria of the healthy gut microbiota, generating a complex variety of secondary bile acids. Intestinal commensal organisms are well-adapted to normal concentrations of bile acids in the gut. In contrast, physiological concentrations of the various intestinal bile acid species play an important role in the resistance to intestinal colonization by pathogens such as Clostridium difficile . Antibiotic therapy can perturb the gut microbiota and thereby impair the production of protective secondary bile acids. The most important bile acid transformation is 7α-dehydroxylation, producing deoxycholic acid (DCA) and lithocholic acid (LCA). The enzymatic pathway carrying out 7α-dehydroxylation is restricted to a narrow phylogenetic group of commensal bacteria, the best-characterized of which is Clostridium scindens . Like many other intestinal commensal species, 7-dehydroxylating bacteria are understudied in vivo . Conventional animals contain variable and uncharacterized indigenous 7α-dehydroxylating organisms that cannot be selectively removed, making controlled colonization with a specific strain in the context of an undisturbed microbiota unfeasible. In the present study, we used a recently established, standardized gnotobiotic mouse model that is stably associated with a simplified murine 12-species "oligo-mouse microbiota" (Oligo-MM 12 ). It is representative of the major murine intestinal bacterial phyla, but is deficient for 7α-dehydroxylation. We find that the Oligo-MM 12 consortium carries out bile acid deconjugation, a prerequisite for 7α-dehydroxylation, and confers no resistance to C. difficile infection (CDI). Amendment of Oligo-MM 12 with C. scindens normalized the large intestinal bile acid composition by reconstituting 7

  11. Thyroid hormone reduces PCSK9 and stimulates bile acid synthesis in humans[S

    Science.gov (United States)

    Bonde, Ylva; Breuer, Olof; Lütjohann, Dieter; Sjöberg, Stefan; Angelin, Bo; Rudling, Mats

    2014-01-01

    Reduced plasma LDL-cholesterol is a hallmark of hyperthyroidism and is caused by transcriptional stimulation of LDL receptors in the liver. Here, we investigated whether thyroid hormone (TH) actions involve other mechanisms that may also account for the reduction in LDL-cholesterol, including effects on proprotein convertase subtilisin/kexin type 9 (PCSK9) and bile acid synthesis. Twenty hyperthyroid patients were studied before and after clinical normalization, and the responses to hyperthyroidism were compared with those in 14 healthy individuals after 14 days of treatment with the liver-selective TH analog eprotirome. Both hyperthyroidism and eprotirome treatment reduced circulating PCSK9, lipoprotein cholesterol, apoB and AI, and lipoprotein(a), while cholesterol synthesis was stable. Hyperthyroidism, but not eprotirome treatment, markedly increased bile acid synthesis and reduced fibroblast growth factor (FGF) 19 and dietary cholesterol absorption. Eprotirome treatment, but not hyperthyroidism, reduced plasma triglycerides. Neither hyperthyroidism nor eprotirome treatment altered insulin, glucose, or FGF21 levels. TH reduces circulating PSCK9, thereby likely contributing to lower plasma LDL-cholesterol in hyperthyroidism. TH also stimulates bile acid synthesis, although this response is not critical for its LDL-lowering effect. PMID:25172631

  12. Whey protein isolate improves acid and bile tolerances of Streptococcus thermophilus ST-M5 and Lactobacillus delbrueckii ssp. bulgaricus LB-12.

    Science.gov (United States)

    Vargas, Luis A; Olson, Douglas W; Aryana, Kayanush J

    2015-04-01

    Acid tolerance and bile tolerance are important probiotic characteristics. Whey proteins contain branched-chain amino acids, which play a role in muscle building and are popular among athletes. Increasing emphasis is being placed on diets containing less carbohydrate, less fat, and more protein. The effect of incremental additions of whey protein isolate (WPI) on probiotic characteristics of pure cultures is not known. The objective of this study was to determine the influence of added WPI on acid tolerance and bile tolerance of pure cultures of Streptococcus thermophilus ST-M5 and Lactobacillus bulgaricus LB-12. The WPI was used at 0 (control), 1, 2 and 3% (wt/vol). Assessment of acid tolerance was conducted on pure cultures at 30-min intervals for 2h of acid exposure and bile tolerance at 1-h intervals for 5h of bile exposure. Use of 1, 2, and 3% WPI improved acid tolerance of Strep. thermophilus ST-M5 and Lb. bulgaricus LB-12. The highest counts for acid tolerance of Strep. thermophilus ST-M5 and Lb. bulgaricus LB-12 were obtained when 3% WPI was used. Use of 2 and 3% WPI improved bile tolerance of Strep. thermophilus ST-M5 and Lb. bulgaricus LB-12 over 5h of bile exposure. The use of WPI is recommended to improve acid and bile tolerance of the yogurt culture bacteria Strep. thermophilus ST-M5 and Lb. bulgaricus LB-12. Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

  13. Bile acid effects are mediated by ATP release and purinergic signalling in exocrine pancreatic cells

    DEFF Research Database (Denmark)

    Kowal, Justyna Magdalena; Haanes, Kristian Agmund; Christensen, Nynne

    2015-01-01

    BACKGROUND: In many cells, bile acids (BAs) have a multitude of effects, some of which may be mediated by specific receptors such the TGR5 or FXR receptors. In pancreas systemic BAs, as well as intra-ductal BAs from bile reflux, can affect pancreatic secretion. Extracellular ATP and purinergic...

  14. Mechanisms of triglyceride metabolism in patients with bile acid diarrhea.

    Science.gov (United States)

    Sagar, Nidhi Midhu; McFarlane, Michael; Nwokolo, Chuka; Bardhan, Karna Dev; Arasaradnam, Ramesh Pulendran

    2016-08-14

    Bile acids (BAs) are essential for the absorption of lipids. BA synthesis is inhibited through intestinal farnesoid X receptor (FXR) activity. BA sequestration is known to influence BA metabolism and control serum lipid concentrations. Animal data has demonstrated a regulatory role for the FXR in triglyceride metabolism. FXR inhibits hepatic lipogenesis by inhibiting the expression of sterol regulatory element binding protein 1c via small heterodimer primer activity. Conversely, FXR promotes free fatty acids oxidation by inducing the expression of peroxisome proliferator-activated receptor α. FXR can reduce the expression of microsomal triglyceride transfer protein, which regulates the assembly of very low-density lipoproteins (VLDL). FXR activation in turn promotes the clearance of circulating triglycerides by inducing apolipoprotein C-II, very low-density lipoproteins receptor (VLDL-R) and the expression of Syndecan-1 together with the repression of apolipoprotein C-III, which increases lipoprotein lipase activity. There is currently minimal clinical data on triglyceride metabolism in patients with bile acid diarrhoea (BAD). Emerging data suggests that a third of patients with BAD have hypertriglyceridemia. Further research is required to establish the risk of hypertriglyceridaemia in patients with BAD and elicit the mechanisms behind this, allowing for targeted treatment.

  15. The synthesis and biological activity of some bile acid derivatives

    International Nuclear Information System (INIS)

    Kadirov, A.Kh.; Khaydarov, K.Kh.; Giyosov, A.Sh.

    2000-01-01

    In this monograph authors present the modified technologic scheme of receiving of 3α, 7α, 12α-three hydro xi cholanic acid with using of available raw materials for the synthesis products and for receiving on its base drugs diluent cholesterol gallstones of gall-bladder and bile-ducts

  16. Inhibition of bile salt transport by drugs associated with liver injury in primary hepatocytes from human, monkey, dog, rat, and mouse.

    Science.gov (United States)

    Zhang, Jie; He, Kan; Cai, Lining; Chen, Yu-Chuan; Yang, Yifan; Shi, Qin; Woolf, Thomas F; Ge, Weigong; Guo, Lei; Borlak, Jürgen; Tong, Weida

    2016-08-05

    Interference of bile salt transport is one of the underlying mechanisms for drug-induced liver injury (DILI). We developed a novel bile salt transport activity assay involving in situ biosynthesis of bile salts from their precursors in primary human, monkey, dog, rat, and mouse hepatocytes in suspension as well as LC-MS/MS determination of extracellular bile salts transported out of hepatocytes. Glycine- and taurine-conjugated bile acids were rapidly formed in hepatocytes and effectively transported into the extracellular medium. The bile salt formation and transport activities were time‒ and bile-acid-concentration‒dependent in primary human hepatocytes. The transport activity was inhibited by the bile salt export pump (BSEP) inhibitors ketoconazole, saquinavir, cyclosporine, and troglitazone. The assay was used to test 86 drugs for their potential to inhibit bile salt transport activity in human hepatocytes, which included 35 drugs associated with severe DILI (sDILI) and 51 with non-severe DILI (non-sDILI). Approximately 60% of the sDILI drugs showed potent inhibition (with IC50 values monkey, dog, rat and mouse hepatocytes. Species differences in potency were observed with mouse being less sensitive than other species to inhibition of bile salt transport. In summary, a novel assay has been developed using hepatocytes in suspension from human and animal species that can be used to assess the potential for drugs and/or drug-derived metabolites to inhibit bile salt transport and/or formation activity. Drugs causing sDILI, except those by immune-mediated mechanism, are highly associated with potent inhibition of bile salt transport. Published by Elsevier Ireland Ltd.

  17. Studies of Se-75 labelled bile acid analogue absorption in different forms of gastrointestinal diseases using a whole body counter

    International Nuclear Information System (INIS)

    Grebe, S.F.; Sattler, E.L.; Rinkenberger, C.; Bodenmueller, D.; Grebe, S.K.G.; Mueller, K.D.; Mueller, H.; Faengewisch, G.L.; Heckers, H.; Steckenmesser, R.

    1996-01-01

    It is possible to detect disturbances of bile acid absorption using a whole body counter after administration of Se-75 labelled bile acid analogues. We scrutinized the benefit of a modification of the test method. We investigated 77 patients with different forms of a gastrointestinal disease. After application of Se 75 homotaurocholic acid we measured patient-activity up to 7 days later including whole-body profile scans in the first 6 h. The fractional retention after 7 days was between 20 and 67%. In cases of impaired absorption it was below 12%. Patients with liver diseases and afer cholecystectomy (without bile acid resorption disturbance) showed normal values. Patients with Crohn's disease of the ileum or with intestinal ileas by-pass or with colestyramine treatment or with disturbance of vitamin B12-absorption or with cystic fibrosis showed a disturbance of bile acid absorption. The normal whole-body half-life was more than 2.8 days. The 24 and 72 h values were 62 and 31% in cases with normal absorption. Smaller values are signs of bile acid malabsorption. Impulse rates measured with the whole body counter are of an order of magnitude that allows to reduce the usually administered dose of 37 kBq to 9.25 kBq. This is an efficient method to detect disturbances of bile acid absorption. The usually adminstered activity of 37 kBq can be reduced to 9.25 kBq. (orig./MG) [de

  18. Increases in plasma motilin follow each episode of gallbladder emptying during the interdigestive period, and changes in serum bile acid concentration correlate to plasma motilin

    DEFF Research Database (Denmark)

    Qvist, N; Oster-Jørgensen, E; Pedersen, S A

    1995-01-01

    concentration of bile acids also showed a cyclic variation in relation to gallbladder motility. During periods of gallbladder emptying serum bile acid concentration had a median value of 1.78 mumol/l, as compared with a median value of 1.17 mumol/l during periods of gallbladder filling. This difference did......, and in cases of two or more emptying periods during the MMC cycle the concentration decreased in between. The shape of the serum bile acid profile is dependent on the intestinal transport and absorption of bile acids, and the significance of the cyclic variation in serum concentration of bile acids in relation...

  19. Synthesis and biological activity of amino acid conjugates of abscisic acid.

    Science.gov (United States)

    Todoroki, Yasushi; Narita, Kenta; Muramatsu, Taku; Shimomura, Hajime; Ohnishi, Toshiyuki; Mizutani, Masaharu; Ueno, Kotomi; Hirai, Nobuhiro

    2011-03-01

    We prepared 19 amino acid conjugates of the plant hormone abscisic acid (ABA) and investigated their biological activity, enzymatic hydrolysis by a recombinant Arabidopsis amidohydrolases GST-ILR1 and GST-IAR3, and metabolic fate in rice seedlings. Different sets of ABA-amino acids induced ABA-like responses in different plants. Some ABA-amino acids, including some that were active in bioassays, were hydrolyzed by recombinant Arabidopsis GST-IAR3, although GST-ILR1 did not show hydrolysis activity for any of the ABA-amino acids. ABA-L-Ala, which was active in all the bioassays, an Arabidopsis seed germination, spinach seed germination, and rice seedling elongation assays, except in a lettuce seed germination assay and was hydrolyzed by GST-IAR3, was hydrolyzed to free ABA in rice seedlings. These findings suggest that some plant amidohydrolases hydrolyze some ABA-amino acid conjugates. Because our study indicates the possibility that different plants have hydrolyzing activity toward different ABA-amino acids, an ABA-amino acid may function as a species-selective pro-hormone of ABA. Copyright © 2011 Elsevier Ltd. All rights reserved.

  20. Enteral bile acid treatment improves parenteral nutrition-related liver disease and intestinal mucosal atrophy in neonatal pigs

    DEFF Research Database (Denmark)

    Jain, Ajay Kumar; Stoll, Barbara; Burrin, Douglas G

    2012-01-01

    Total parenteral nutrition (TPN) is essential for patients with impaired gut function but leads to parenteral nutrition-associated liver disease (PNALD). TPN disrupts the normal enterohepatic circulation of bile acids, and we hypothesized that it would decrease intestinal expression of the newly...... described metabolic hormone fibroblast growth factor-19 (FGF19) and also glucagon-like peptides-1 and -2 (GLP-1 and GLP-2). We tested the effects of restoring bile acids by treating a neonatal piglet PNALD model with chenodeoxycholic acid (CDCA). Neonatal pigs received enteral feeding (EN), TPN, or TPN...... + CDCA for 14 days, and responses were assessed by serum markers, histology, and levels of key regulatory peptides. Cholestasis and steatosis were demonstrated in the TPN group relative to EN controls by elevated levels of serum total and direct bilirubin and also bile acids and liver triglyceride (TG...

  1. Mig-6 plays a critical role in the regulation of cholesterol homeostasis and bile acid synthesis.

    Directory of Open Access Journals (Sweden)

    Bon Jeong Ku

    Full Text Available The disruption of cholesterol homeostasis leads to an increase in cholesterol levels which results in the development of cardiovascular disease. Mitogen Inducible Gene 6 (Mig-6 is an immediate early response gene that can be induced by various mitogens, stresses, and hormones. To identify the metabolic role of Mig-6 in the liver, we conditionally ablated Mig-6 in the liver using the Albumin-Cre mouse model (Alb(cre/+Mig-6(f/f; Mig-6(d/d. Mig-6(d/d mice exhibit hepatomegaly and fatty liver. Serum levels of total, LDL, and HDL cholesterol and hepatic lipid were significantly increased in the Mig-6(d/d mice. The daily excretion of fecal bile acids was significantly decreased in the Mig-6(d/d mice. DNA microarray analysis of mRNA isolated from the livers of these mice showed alterations in genes that regulate lipid metabolism, bile acid, and cholesterol synthesis, while the expression of genes that regulate biliary excretion of bile acid and triglyceride synthesis showed no difference in the Mig-6(d/d mice compared to Mig-6(f/f controls. These results indicate that Mig-6 plays an important role in cholesterol homeostasis and bile acid synthesis. Mice with liver specific conditional ablation of Mig-6 develop hepatomegaly and increased intrahepatic lipid and provide a novel model system to investigate the genetic and molecular events involved in the regulation of cholesterol homeostasis and bile acid synthesis. Defining the molecular mechanisms by which Mig-6 regulates cholesterol homeostasis will provide new insights into the development of more effective ways for the treatment and prevention of cardiovascular disease.

  2. Tauroursodeoxycholate Protects Rat Hepatocytes from Bile Acid-Induced Apoptosis via β1-Integrin- and Protein Kinase A-Dependent Mechanisms

    Directory of Open Access Journals (Sweden)

    Annika Sommerfeld

    2015-05-01

    Full Text Available Background/Aims: Ursodeoxycholic acid, which in vivo is rapidly converted into its taurine conjugate, is frequently used for the treatment of cholestatic liver disease. Apart from its choleretic effects, tauroursodeoxycholate (TUDC can protect hepatocytes from bile acid-induced apoptosis, but the mechanisms underlying its anti-apoptotic effects are poorly understood. Methods: These mechanisms were investigated in perfused rat liver and isolated rat hepatocytes. Results: It was found that TUDC inhibited the glycochenodeoxycholate (GCDC-induced activation of the CD95 death receptor at the level of association between CD95 and the epidermal growth factor receptor. This was due to a rapid TUDC-induced β1-integrin-dependent cyclic AMP (cAMP signal with induction of the dual specificity mitogen-activated protein (MAP kinase phosphatase 1 (MKP-1, which prevented GCDC-induced phosphorylation of mitogen-activated protein kinase kinase 4 (MKK4 and c-jun-NH2-terminal kinase (JNK activation. Furthermore, TUDC induced a protein kinase A (PKA-mediated serine/threonine phosphorylation of the CD95, which was recently identified as an internalization signal for CD95. Furthermore, TUDC inhibited GCDC-induced CD95 targeting to the plasma membrane in a β1-integrin-and PKA-dependent manner. In line with this, the β1-integrin siRNA knockdown in sodium taurocholate cotransporting polypeptide (Ntcp-transfected HepG2 cells abolished the protective effect of TUDC against GCDC-induced apoptosis. Conclusion: TUDC exerts its anti-apoptotic effect via a β1-integrin-mediated formation of cAMP, which prevents CD95 activation by hydrophobic bile acids at the levels of JNK activation and CD95 serine/threonine phosphorylation.

  3. Influence of diet or intrarectal bile acid injections on colon epithelial cell proliferation in rats previously injected with 1,2-dimethylhydrazine

    International Nuclear Information System (INIS)

    Glauert, H.P.; Bennink, M.R.

    1983-01-01

    The effects of varying colon bile acid concentrations on rat colon epithelial cell proliferation were studied. Bile acid concentrations were altered by intrarectally injecting either deoxycholic or lithocholic acid for 4 weeks or by increasing the dietary fat or fiber (wheat bran, agar, or carrageenan) intake for 4 weeks. 1,2-Dimethylhydrazine (DMH) was s.c. injected into half of the rats 1 week before treatments began. Colon epithelial cell proliferation was measured by [ 3 H]thymidine autoradiography of colon crypts. Rats injected with DMH had more DNA-synthesizing cells per crypt. Neither bile acid injection nor any of the diets altered the number of DNA-synthesizing cells per crypt. DMH injections, deoxycholic and lithocholic acid intrarectal injections, and dietary agar and wheat bran all increased the total number of cells per crypt. High fat diets and dietary carrageenan did not affect cell number. All diets containing fiber lowered total fecal bile acid concentrations, but increasing the fat content of the diet did not affect them. These results indicate that the bile acid injections and dietary agar and wheat bran induce a slight hyperplasia in the colon

  4. Differential feedback regulation of cholesterol 7α-hydroxylase mRNA and transcriptional activity by rat bile acids in primary monolayer cultures of rat hepatocytes

    NARCIS (Netherlands)

    Twisk, J.; Lehmann, E.M.; Princen, H.M.G.

    1993-01-01

    We have used primary monolayer cultures of rat hepatocytes to study the effects of physiological concentrations of various bile acids, commonly found in bile of normal rats, on the mechanism of regulation of cholesterol 7α-hydroxylase and bile acid synthesis. Addition of taurocholic acid, the most

  5. Metformin protects rat hepatocytes against bile acid-induced apoptosis.

    Directory of Open Access Journals (Sweden)

    Titia E Woudenberg-Vrenken

    Full Text Available BACKGROUND: Metformin is used in the treatment of Diabetes Mellitus type II and improves liver function in patients with non-alcoholic fatty liver disease (NAFLD. Metformin activates AMP-activated protein kinase (AMPK, the cellular energy sensor that is sensitive to changes in the AMP/ATP-ratio. AMPK is an inhibitor of mammalian target of rapamycin (mTOR. Both AMPK and mTOR are able to modulate cell death. AIM: To evaluate the effects of metformin on hepatocyte cell death. METHODS: Apoptotic cell death was induced in primary rat hepatocytes using either the bile acid glycochenodeoxycholic acid (GCDCA or TNFα in combination with actinomycin D (actD. AMPK, mTOR and phosphoinositide-3 kinase (PI3K/Akt were inhibited using pharmacological inhibitors. Apoptosis and necrosis were quantified by caspase activation, acridine orange staining and Sytox green staining respectively. RESULTS: Metformin dose-dependently reduces GCDCA-induced apoptosis, even when added 2 hours after GCDCA, without increasing necrotic cell death. Metformin does not protect against TNFα/ActD-induced apoptosis. The protective effect of metformin is dependent on an intact PI3-kinase/Akt pathway, but does not require AMPK/mTOR-signaling. Metformin does not inhibit NF-κB activation. CONCLUSION: Metformin protects against bile acid-induced apoptosis and could be considered in the treatment of chronic liver diseases accompanied by inflammation.

  6. Ibuprofen-conjugated hyaluronate/polygalacturonic acid hydrogel for the prevention of epidural fibrosis.

    Science.gov (United States)

    Lin, Cheng-Yi; Peng, Hsiu-Hui; Chen, Mei-Hsiu; Sun, Jui-Sheng; Chang, Chih-Ju; Liu, Tse-Ying; Chen, Ming-Hong

    2016-05-01

    The formation of fibrous tissue is part of the natural healing response following a laminectomy. Severe scar tissue adhesion, known as epidural fibrosis, is a common cause of failed back surgery syndrome. In this study, by combining the advantages of drug treatment with a physical barrier, an ibuprofen-conjugated crosslinkable polygalacturonic acid and hyaluronic acid hydrogel was developed for epidural fibrosis prevention. Conjugation was confirmed and measured by 1D(1)H NMR spectroscopy.In vitroanalysis showed that the ibuprofen-conjugated polygalacturonic acid-hyaluronic acid hydrogel showed low cytotoxicity. In addition, the conjugated ibuprofen decreased prostaglandin E2production of the lipopolysaccharide-induced RAW264.7 cells. Histological data inin vivostudies indicated that the scar tissue adhesion of laminectomized male adult rats was reduced by the application of our ibuprofen-conjugated polygalacturonic acid-hyaluronic acid hydrogel. Its use also reduced the population of giant cells and collagen deposition of scar tissue without inducing extensive cell recruitment. The results of this study therefore suggest that the local delivery of ibuprofenviaa polygalacturonic acid-hyaluronic acid-based hydrogel reduces the possibility of epidural fibrosis. © The Author(s) 2016.

  7. Bile acids override steatosis in farnesoid X receptor deficient mice in a model of non-alcoholic steatohepatitis

    International Nuclear Information System (INIS)

    Wu, Weibin; Liu, Xijun; Peng, Xiaomin; Xue, Ruyi; Ji, Lingling; Shen, Xizhong; Chen, She; Gu, Jianxin; Zhang, Si

    2014-01-01

    Highlights: • FXR deficiency enhanced MCD diet-induced hepatic fibrosis. • FXR deficiency attenuated MCD diet-induced hepatic steatosis. • FXR deficiency repressed genes involved in fatty acid uptake and triglyceride accumulation. - Abstract: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, and the pathogenesis is still not well known. The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily and plays an essential role in maintaining bile acid and lipid homeostasis. In this study, we study the role of FXR in the pathogenesis of NFALD. We found that FXR deficient (FXR −/− ) mice fed methionine- and choline-deficient (MCD) diet had higher serum ALT and AST activities and lower hepatic triglyceride levels than wild-type (WT) mice fed MCD diet. Expression of genes involved in inflammation (VCAM-1) and fibrosis (α-SMA) was increased in FXR −/− mice fed MCD diet (FXR −/− /MCD) compared to WT mice fed MCD diet (WT/MCD). Although MCD diet significantly induced hepatic fibrosis in terms of liver histology, FXR −/− /MCD mice showed less degree of hepatic steatosis than WT/MCD mice. Moreover, FXR deficiency synergistically potentiated the elevation effects of MCD diet on serum and hepatic bile acids levels. The super-physiological concentrations of hepatic bile acids in FXR −/− /MCD mice inhibited the expression of genes involved in fatty acid uptake and triglyceride accumulation, which may be an explanation for less steatosis in FXR −/− /MCD mice in contrast to WT/MCD mice. These results suggest that hepatic bile acids accumulation could override simple steatosis in hepatic injury during the progression of NAFLD and further emphasize the role of FXR in maintaining hepatic bile acid homeostasis in liver disorders and in hepatic protection

  8. Bile acids override steatosis in farnesoid X receptor deficient mice in a model of non-alcoholic steatohepatitis

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Weibin; Liu, Xijun; Peng, Xiaomin [Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Xue, Ruyi [Department of Gastroenterology and Hepatology, Zhongshan Hospital, Shanghai Institute of Liver Disease, Fudan University, Shanghai 200032 (China); Ji, Lingling [Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Shen, Xizhong [Department of Gastroenterology and Hepatology, Zhongshan Hospital, Shanghai Institute of Liver Disease, Fudan University, Shanghai 200032 (China); Chen, She, E-mail: shechen@fudan.edu.cn [Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Gu, Jianxin [Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Zhang, Si, E-mail: zhangsi@fudan.edu.cn [Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China)

    2014-05-23

    Highlights: • FXR deficiency enhanced MCD diet-induced hepatic fibrosis. • FXR deficiency attenuated MCD diet-induced hepatic steatosis. • FXR deficiency repressed genes involved in fatty acid uptake and triglyceride accumulation. - Abstract: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, and the pathogenesis is still not well known. The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily and plays an essential role in maintaining bile acid and lipid homeostasis. In this study, we study the role of FXR in the pathogenesis of NFALD. We found that FXR deficient (FXR{sup −/−}) mice fed methionine- and choline-deficient (MCD) diet had higher serum ALT and AST activities and lower hepatic triglyceride levels than wild-type (WT) mice fed MCD diet. Expression of genes involved in inflammation (VCAM-1) and fibrosis (α-SMA) was increased in FXR{sup −/−} mice fed MCD diet (FXR{sup −/−}/MCD) compared to WT mice fed MCD diet (WT/MCD). Although MCD diet significantly induced hepatic fibrosis in terms of liver histology, FXR{sup −/−}/MCD mice showed less degree of hepatic steatosis than WT/MCD mice. Moreover, FXR deficiency synergistically potentiated the elevation effects of MCD diet on serum and hepatic bile acids levels. The super-physiological concentrations of hepatic bile acids in FXR{sup −/−}/MCD mice inhibited the expression of genes involved in fatty acid uptake and triglyceride accumulation, which may be an explanation for less steatosis in FXR{sup −/−}/MCD mice in contrast to WT/MCD mice. These results suggest that hepatic bile acids accumulation could override simple steatosis in hepatic injury during the progression of NAFLD and further emphasize the role of FXR in maintaining hepatic bile acid homeostasis in liver disorders and in hepatic protection.

  9. In vitro bile acid binding of mustard greens, kale, broccoli, cabbage and green bell pepper improves with sautéing compared with raw or other methods of preparation.

    Science.gov (United States)

    Bile acid binding capacity has been related to cholesterol-lowering potential of foods and food fractions. Lowered recirculating bile acids results in utilization of cholesterol to synthesize bile acid and reduced fat absorption. Secondary bile acids have been associated with increased risk of can...

  10. Independent Activation of Hepatitis B Virus Biosynthesis by Retinoids, Peroxisome Proliferators, and Bile Acids

    Science.gov (United States)

    Reese, Vanessa C.; Oropeza, Claudia E.

    2013-01-01

    In the human hepatoma cell line HepG2, retinoic acid, clofibric acid, and bile acid treatment can only modestly increase hepatitis B virus (HBV) biosynthesis. Utilizing the human embryonic kidney cell line 293T, it was possible to demonstrate that the retinoid X receptor α (RXRα) plus its ligand can support viral biosynthesis independently of additional nuclear receptors. In addition, RXRα/peroxisome proliferator-activated receptor α (PPARα) and RXRα/farnesoid X receptor α (FXRα) heterodimeric nuclear receptors can also mediate ligand-dependent HBV transcription and replication when activated by clofibric acid and bile acid, respectively, independently of a requirement for the ligand-dependent activation of RXRα. These observations indicate that there are at least three possible modes of ligand-mediated activation of HBV transcription and replication existing within hepatocytes, suggesting that multiple independent mechanisms control viral production in the livers of infected individuals. PMID:23135717

  11. How bad is bile acid diarrhoea: an online survey of patient-reported symptoms and outcomes.

    Science.gov (United States)

    Bannaga, Ayman; Kelman, Lawrence; O'Connor, Michelle; Pitchford, Claire; Walters, Julian R F; Arasaradnam, Ramesh P

    2017-01-01

    Bile acid diarrhoea (BAD) is an underdiagnosed condition producing diarrhoea, urgency and fear of faecal incontinence. How patients experience these symptoms has not previously been studied. Bile Acid Malabsorption (BAM) Support UK was established in 2015 as a national charity with objectives including to provide details regarding how BAD affects patients, to improve earlier recognition and clinical management. A questionnaire was collected anonymously by BAM Support UK and the Bile Salt Malabsorption Facebook group over 4 weeks at the end of 2015. It comprised 56 questions and aimed to inform patients and clinicians about how BAD affects the respondents. The first 100 responses were analysed. 91% of the respondents reported a diagnosis of BAD. 58% of total respondents diagnosed following a Selenium-homocholic acid taurine scan, 69% were diagnosed by a gastroenterologist, with type 2 and 3 BAD comprising 38% and 37%, respectively, of total respondents. Symptoms had been experienced for more than 5 years before diagnosis in 44% of respondents. Following treatment, usually with bile acid sequestrants, 60% of participants reported improvement of diarrhoea and most reported their mental health has been positively impacted. Just over half of the cohort felt as though their symptoms had been dismissed during clinical consultations and 28% felt their GPs were unaware of BAD. BAD requires more recognition by clinicians to address the current delays in diagnosis. Treatment improves physical and mental symptoms in the majority of participants.

  12. Role of farnesoid X receptor and bile acids in alcoholic liver disease

    Directory of Open Access Journals (Sweden)

    Sharon Manley

    2015-03-01

    Full Text Available Alcoholic liver disease (ALD is one of the major causes of liver morbidity and mortality worldwide. Chronic alcohol consumption leads to development of liver pathogenesis encompassing steatosis, inflammation, fibrosis, cirrhosis, and in extreme cases, hepatocellular carcinoma. Moreover, ALD may also associate with cholestasis. Emerging evidence now suggests that farnesoid X receptor (FXR and bile acids also play important roles in ALD. In this review, we discuss the effects of alcohol consumption on FXR, bile acids and gut microbiome as well as their impacts on ALD. Moreover, we summarize the findings on FXR, FoxO3a (forkhead box-containing protein class O3a and PPARα (peroxisome proliferator-activated receptor alpha in regulation of autophagy-related gene transcription program and liver injury in response to alcohol exposure.

  13. Long-term effect of medical treatment of diarrhoea in 594 patients with SeHCAT scan diagnosed bile acid malabsorption from 2003 to 2016; a retrospective study

    DEFF Research Database (Denmark)

    Damsgaard, B; Dalby, H R; Krogh, K

    2018-01-01

    Background Excessive amounts of bile acids entering the colon due to bile acid malabsorption cause chronic bile acid diarrhoea. Diagnosis is possible by measuring the retention fraction of orally ingested 75Selenium homotaurocholic acid (SeHCAT). The knowledge of long-term effects of medical trea...

  14. Differential effects of 17 alpha-ethinylestradiol on the neutral and acidic pathways of bile salt synthesis in the rat

    NARCIS (Netherlands)

    Koopen, NR; Post, SM; Wolters, H; Havinga, R; Stellaard, F; Boverhof, R; Kuipers, F; Princen, HMG

    Effects of 17 alpha-ethinylestradiol (EE) on the neutral and acidic biosynthetic pathways of bile salt (BS) synthesis were evaluated in rats with an intact enterohepatic circulation and in rats with long-term bile diversion to induce BS synthesis, For this purpose, bile salt pool composition,

  15. New fluorescent bile acids: synthesis, chemical characterization, and disastereoselective uptake by Caco-2 cells of 3-deoxy 3-NBD-amino deoxycholic and ursodeoxycholic acid.

    Science.gov (United States)

    Májer, Ferenc; Salomon, Johanna J; Sharma, Ruchika; Etzbach, Simona V; Najib, Mohd Nadzri Mohd; Keaveny, Ray; Long, Aideen; Wang, Jun; Ehrhardt, Carsten; Gilmer, John F

    2012-03-01

    Deoxycholic acid (DCA), a secondary bile acid (BA), and ursodeoxycholic acid (UDCA), a tertiary BA, cause opposing effects in vivo and in cell suspensions. Fluorescent analogues of DCA and UDCA could help investigate important questions about their cellular interactions and distribution. We have prepared a set of isomeric 3α- and 3β-amino analogues of UDCA and DCA and derivatised these with the discrete fluorophore, 4-nitrobenzo-2-oxa-1,3-diazol (NBD), forming the corresponding four fluorescent adducts. These absorb in the range 465-470 nm and fluoresce at approx. 535 nm. In order to determine the ability of the new fluorescent bile acids to mimic the parents, their uptake was studied using monolayers of Caco-2 cells, which are known to express multiple proteins of the organic anion-transporting peptide (OATP) subfamily of transporters. Cellular uptake was monitored over time at 4 and 37°C to distinguish between passive and active transport. All four BA analogues were taken up but in a strikingly stereo- and structure-specific manner, suggesting highly discriminatory interactions with transporter protein(s). The α-analogues of DCA and to a lesser extent UDCA were actively transported, whereas the β-analogues were not. The active transport process was saturable, with Michaelis-Menten constants for 3α-NBD DCA (5) being K(m)=42.27±12.98 μM and V(max)=2.8 ± 0.4 nmol/(mg protein*min) and for 3α-NBD UDCA (3) K(m)=28.20 ± 7.45 μM and V(max)=1.8 ± 0.2 nmol/(mg protein*min). These fluorescent bile acids are promising agents for investigating questions of bile acid biology and for detection of bile acids and related organic anion transport processes. Copyright © 2012 Elsevier Ltd. All rights reserved.

  16. The utility of 5-aminolevulinic acid-mediated photodynamic diagnosis in the detection of intraoperative bile leakage.

    Science.gov (United States)

    Inoue, Yoshihiro; Imai, Yoshiro; Fujii, Kensuke; Hirokawa, Fumitoshi; Hayashi, Michihiro; Uchiyama, Kazuhisa

    2017-06-01

    The purpose of this retrospective study was to evaluate the utility of the new intraoperative bile leakage test as a preventive measure of postoperative bile leakage. 737 patients were retrospectively analyzed with respect to the management of intra- and post-operative bile leakage. Nine (8.3%) of 109 patients evaluated using conventional white light fluorescent imaging were recognized as having intra-operative bile leakage. However, performance of 5-aminolevulinic acid (5-ALA)-mediated PDD detected bile leakage intraoperatively not only in these 9 patients, but also in an additional 6 patients, such that 'red fluorescence' at the cut surface of the liver, was visualized in a total of 15 patients. The postoperative courses of most patients were uneventful, and postoperative bile leakages occurred in only one (0.9%) patient. 5-ALA fluorescence imaging may be needed to prevent postoperative bile leakage in patients at high risk for this surgical complication after hepatic resection. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. A Standard Structure for Bile Acids and Derivatives

    Directory of Open Access Journals (Sweden)

    Francisco Meijide

    2018-02-01

    Full Text Available The crystal structures of two ester compounds (a monomer in its methyl ester form, with an amino isophthalic group, and a dimer in which the two steroid units are linked by a urea bridge recrystallized from ethyl acetate/methanol derived from cholic acid are described. Average bond lengths and bond angles from the crystal structures of 26 monomers and four dimers (some of them in several solvents of bile acids and esters (and derivatives are used for proposing a standard steroid nucleus. The hydrogen bond network and conformation of the lateral chain are also discussed. This standard structure was used to compare with the structures of both progesterone and cholesterol.

  18. Influence of dietary tender cluster beans (Cyamopsis tetragonoloba) on biliary proteins, bile acid synthesis and cholesterol crystal growth in rat bile.

    Science.gov (United States)

    Raghavendra, Chikkanna K; Srinivasan, Krishnapura

    2015-02-01

    Tender cluster beans (CBs; Cyamopsis tetragonoloba) are observed to possess anti-lithogenic potential in experimental mice. Formation of cholesterol gallstones in gallbladder is controlled by procrystallizing and anticrystallizing factors present in bile in addition to supersaturation of cholesterol. This study aimed at evaluating the influence of CB on biliary glycoproteins, low molecular weight (LMW) and high molecular weight (HMW) proteins, cholesterol nucleation time, and cholesterol crystal growth in rat hepatic bile. Groups of rats were fed for 10 weeks with 0.5% cholesterol to render the bile lithogenic. Experimental dietary interventions were: 10% freeze-dried CB, 1% garlic powder or their combination. Incorporation of CB into HCD decreased the cholesterol saturation index in bile, increased bile flow and biliary glycoproteins. Dietary CB prolonged cholesterol nucleation time in bile. Electrophoresis of biliary proteins showed the presence of high concentration of 27 kDa protein which might be responsible for the prolongation of cholesterol nucleation time in the CB fed group. Proteins of 20 kDa and 18 kDa were higher in CB treated animals, while the same were less expressed in HCD group. Biliary proteins from CB fed animals reduced cholesterol crystal growth index which was elevated in the presence of proteins from HCD group. Cholesterol-7α-hydroxylase and cholesterol-27-hydroxylase mRNA expression was increased in CB treated animals contributing to the bile acid synthesis. Thus, the beneficial anti-lithogenic effect of dietary CB which primarily is due to reduced cholesterol saturation index was additionally affected through a modulation of the nucleating and anti-nucleating proteins that affect cholesterol crystallization. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. Mechanisms of triglyceride metabolism in patients with bile acid diarrhea

    Science.gov (United States)

    Sagar, Nidhi Midhu; McFarlane, Michael; Nwokolo, Chuka; Bardhan, Karna Dev; Arasaradnam, Ramesh Pulendran

    2016-01-01

    Bile acids (BAs) are essential for the absorption of lipids. BA synthesis is inhibited through intestinal farnesoid X receptor (FXR) activity. BA sequestration is known to influence BA metabolism and control serum lipid concentrations. Animal data has demonstrated a regulatory role for the FXR in triglyceride metabolism. FXR inhibits hepatic lipogenesis by inhibiting the expression of sterol regulatory element binding protein 1c via small heterodimer primer activity. Conversely, FXR promotes free fatty acids oxidation by inducing the expression of peroxisome proliferator-activated receptor α. FXR can reduce the expression of microsomal triglyceride transfer protein, which regulates the assembly of very low-density lipoproteins (VLDL). FXR activation in turn promotes the clearance of circulating triglycerides by inducing apolipoprotein C-II, very low-density lipoproteins receptor (VLDL-R) and the expression of Syndecan-1 together with the repression of apolipoprotein C-III, which increases lipoprotein lipase activity. There is currently minimal clinical data on triglyceride metabolism in patients with bile acid diarrhoea (BAD). Emerging data suggests that a third of patients with BAD have hypertriglyceridemia. Further research is required to establish the risk of hypertriglyceridaemia in patients with BAD and elicit the mechanisms behind this, allowing for targeted treatment. PMID:27570415

  20. In Vitro bile acid binding of kale, mustard greens, broccoli, cabbage and green bell pepper improves with microwave cooking

    Science.gov (United States)

    Bile acid binding potential of foods and food fractions has been related to lowering the risk of heart disease and that of cancer. Sautéing or steam cooking has been observed to significantly improve bile acid binding of green/leafy vegetables. It was hypothesized that microwave cooking could impr...

  1. Selective fluorescent detection of aspartic acid and glutamic acid employing dansyl hydrazine dextran conjugate.

    Science.gov (United States)

    Nasomphan, Weerachai; Tangboriboonrat, Pramuan; Tanapongpipat, Sutipa; Smanmoo, Srung

    2014-01-01

    Highly water soluble polymer (DD) was prepared and evaluated for its fluorescence response towards various amino acids. The polymer consists of dansyl hydrazine unit conjugated into dextran template. The conjugation enhances higher water solubility of dansyl hydrazine moiety. Of screened amino acids, DD exhibited selective fluorescence quenching in the presence of aspartic acid (Asp) and glutamic acid (Glu). A plot of fluorescence intensity change of DD against the concentration of corresponding amino acids gave a good linear relationship in the range of 1 × 10(-4) M to 25 × 10(-3) M. This establishes DD as a potential polymeric sensor for selective sensing of Asp and Glu.

  2. Cancer Chemopreventive Ability of Conjugated Linolenic Acids

    Directory of Open Access Journals (Sweden)

    Kazuo Miyashita

    2011-11-01

    Full Text Available Conjugated fatty acids (CFA have received increased interest because of their beneficial effects on human health, including preventing cancer development. Conjugated linoleic acids (CLA are such CFA, and have been reviewed extensively for their multiple biological activities. In contrast to other types of CFAs including CLA that are found at low concentrations (less than 1% in natural products, conjugated linolenic acids (CLN are the only CFAs that occur in higher quantities in natural products. Some plant seeds contain a considerably high concentration of CLN (30 to 70 wt% lipid. Our research group has screened CLN from different plant seed oils to determine their cancer chemopreventive ability. This review describes the physiological functions of CLN isomers that occur in certain plant seeds. CLN are able to induce apoptosis through decrease of Bcl-2 protein in certain human cancer cell lines, increase expression of peroxisome proliferator-activated receptor (PPAR-γ, and up-regulate gene expression of p53. Findings in our preclinical animal studies have indicated that feeding with CLN resulted in inhibition of colorectal tumorigenesis through modulation of apoptosis and expression of PPARγ and p53. In this review, we summarize chemopreventive efficacy of CLN against cancer development, especially colorectal cancer.

  3. Plasma bile acids are not associated with energy metabolism in humans

    NARCIS (Netherlands)

    Brufau, Gemma; Bahr, Matthias J.; Staels, Bart; Claudel, Thierry; Ockenga, Johann; Boker, Klaus H. W.; Murphy, Elizabeth J.; Prado, Kris; Stellaard, Frans; Manns, Michael P.; Kuipers, Folkert; Tietge, Uwe J. F.

    2010-01-01

    Bile acids (BA) have recently been shown to increase energy expenditure in mice, but this concept has not been tested in humans. Therefore, we investigated the relationship between plasma BA levels and energy expenditure in humans. Type 2 diabetic (T2DM) patients (n = 12) and gender, age and

  4. Quantification of 15 bile acids in lake charr feces by ultra-high performance liquid chromatography–tandem mass spectrometry

    Science.gov (United States)

    Li, Ke; Buchinger, Tyler J.; Bussy, Ugo; Fissette, Skye D.; Johnson, Nicholas; Li, Weiming

    2015-01-01

    Many fishes are hypothesized to use bile acids (BAs) as chemical cues, yet quantification of BAs in biological samples and the required methods remain limited. Here, we present an UHPLC–MS/MS method for simultaneous, sensitive, and rapid quantification of 15 BAs, including free, taurine, and glycine conjugated BAs, and application of the method to fecal samples from lake charr (Salvelinus namaycush). The analytes were separated on a C18 column with acetonitrile–water (containing 7.5 mM ammonium acetate and 0.1% formic acid) as mobile phase at a flow rate of 0.25 mL/min for 12 min. BAs were monitored with a negative electrospray triple quadrupole mass spectrometer (Xevo TQ-S™). Calibration curves of 15 BAs were linear over the concentration range of 1.00–5,000 ng/mL. Validation revealed that the method was specific, accurate, and precise. The method was applied to quantitative analysis of feces extract of fry lake charr and the food they were eating. The concentrations of analytes CA, TCDCA, TCA, and CDCA were 242.3, 81.2, 60.7, and 36.2 ng/mg, respectively. However, other taurine conjugated BAs, TUDCA, TDCA, and THDCA, were not detected in feces of lake charr. Interestingly, TCA and TCDCA were detected at high concentrations in food pellets, at 71.9 and 38.2 ng/mg, respectively. Application of the method to feces samples from lake charr supported a role of BAs as chemical cues, and will enhance further investigation of BAs as chemical cues in other fish species.

  5. Serum bile acids are higher in humans with prior gastric bypass: potential contribution to improved glucose and lipid metabolism

    DEFF Research Database (Denmark)

    Patti, Mary-Elizabeth; Houten, Sander M; Bianco, Antonio C

    2009-01-01

    , glycochenodeoxycholic, and glycodeoxycholic acids were all significantly higher in GB compared to Ov (P glucose (r = -0.59, P triglycerides (r = -0.40, P = 0.05), and positively correlated with adiponectin (r = -0.48, P ... performed cross-sectional analysis of fasting serum bile acid composition and both fasting and post-meal metabolic variables, in three subject groups: (i) post-GB surgery (n = 9), (ii) without GB matched to preoperative BMI of the index cohort (n = 5), and (iii) without GB matched to current BMI...... of the index cohort (n = 10). Total serum bile acid concentrations were higher in GB (8.90 +/- 4.84 micromol/l) than in both overweight (3.59 +/- 1.95, P = 0.005, Ov) and severely obese (3.86 +/- 1.51, P = 0.045, MOb). Bile acid subfractions taurochenodeoxycholic, taurodeoxycholic, glycocholic...

  6. The effect of conjugated linoleic acid on the fatty acid composition of ...

    African Journals Online (AJOL)

    rahim aydin

    Dietary conjugated linoleic acid (CLA) was reported to increase the levels of saturated fatty ... Hence, the objective of this study was to determine the effects of dietary CLA on the fatty acid ..... silver ion-high performance liquid chromatography.

  7. Effects of clofibric acid on the biliary excretion of benoxaprofen glucuronide and taurine conjugate in rats.

    Science.gov (United States)

    Okada, K; Kanoh, H; Mohri, K

    2011-10-01

    Benoxaprofen (BOP) is a 2-methyl propionic acid derivative with anti-inflammatory activity. BOP has an asymmetric carbon, and receives chiral inversion from R to S in vivo. BOP is metabolized to glucuronide (BOP-G) and taurine conjugate (BOP-T). The configuration of BOP-G is mainly S, and that of BOP-T is R. Chiral inversion of R to S of the propionic acid moiety and amino acid conjugation of carboxyl compounds proceed via an acyl CoA intermediate. It is known that fibrates, used in hyperlipidemia, induce acyl CoA synthetase and increase CoA concentration. We administered racemic BOP (10 mg/kg body weight) to rats (CFA+) pre-administered clofibric acid (CFA, 280 mg/kg/day), and studied BOP, BOP-G, and BOP-T enantiomer concentrations in plasma and bile up to 12 h after administration. The findings were compared with those in rats (CFA-) that had not received CFA. Furthermore, we studied the amounts of BOP-G enantiomer produced by glucuronidation in vitro using microsomes pretreated with CFA. The amounts of (S)-BOP-G in CFA+ rats were 2.7-fold larger than that in CFA- rats. Although (R)-BOP-T was excreted in CFA- rats, BOP-T could not be detected in CFA+ rats. Plasma clearance values of racemic BOP and (S)-BOP in CFA+ rats were 5-fold and 6-fold larger than those in CFA- rats, respectively. (S)-BOP-G formation activities were higher than (R)-BOP-G formation activities in both CFA+and CFA- microsomes. These findings suggest that CFA increases biliary excretion of (S)-BOP-G and facilitates plasma elimination of BOP, and further suggests that CFA predominantly induces chiral inversion to S rather than metabolic reaction to (R)-BOP-T, resulting in an increase of (S)-BOP-G.

  8. Lactobacillus acidophilus NCFM affects vitamin E acetate metabolism and intestinal bile acid signature in monocolonized mice

    DEFF Research Database (Denmark)

    Roager, Henrik Munch; Sulek, Karolina; Skov, Kasper

    2014-01-01

    (NCFM) on the intestinal metabolome (jejunum, caecum, and colon) in mice by comparing NCFM mono-colonized (MC) mice with GF mice using liquid chromatography coupled to mass-spectrometry (LC-MS). The study adds to existing evidence that NCFM in vivo affects the bile acid signature of mice...... by deconjugation and dehydroxylation of bile acids. Furthermore, we confirmed that carbohydrate metabolism is affected by NCFM in the mouse intestine. Especially, the digestion of larger carbohydrates (penta- and tetrasaccharides) was increased in MC mice. Interestingly, we also found vitamin E (α...

  9. Production of carrier-peptide conjugates using chemically reactive unnatural amino acids

    Science.gov (United States)

    Young, Travis; Schultz, Peter G

    2013-12-17

    Provided are methods of making carrier polypeptide that include incorporating a first unnatural amino acid into a carrier polypeptide variant, incorporating a second unnatural amino acid into a target polypeptide variant, and reacting the first and second unnatural amino acids to produce the conjugate. Conjugates produced using the provided methods are also provided. In addition, orthogonal translation systems in methylotrophic yeast and methods of using these systems to produce carrier and target polypeptide variants comprising unnatural amino acids are provided.

  10. Profile of preoperative fecal organic acids closely predicts the incidence of postoperative infectious complications after major hepatectomy with extrahepatic bile duct resection: Importance of fecal acetic acid plus butyric acid minus lactic acid gap.

    Science.gov (United States)

    Yokoyama, Yukihiro; Mizuno, Takashi; Sugawara, Gen; Asahara, Takashi; Nomoto, Koji; Igami, Tsuyoshi; Ebata, Tomoki; Nagino, Masato

    2017-10-01

    To investigate the association between preoperative fecal organic acid concentrations and the incidence of postoperative infectious complications in patients undergoing major hepatectomy with extrahepatic bile duct resection for biliary malignancies. The fecal samples of 44 patients were collected before undergoing hepatectomy with bile duct resection for biliary malignancies. The concentrations of fecal organic acids, including acetic acid, butyric acid, and lactic acid, and representative fecal bacteria were measured. The perioperative clinical characteristics and the concentrations of fecal organic acids were compared between patients with and without postoperative infectious complications. Among 44 patients, 13 (30%) developed postoperative infectious complications. Patient age and intraoperative bleeding were significantly greater in patients with postoperative infectious complications compared with those without postoperative infectious complications. The concentrations of fecal acetic acid and butyric acid were significantly less, whereas the concentration of fecal lactic acid tended to be greater in the patients with postoperative infectious complications. The calculated gap between the concentrations of fecal acetic acid plus butyric acid minus lactic acid gap was less in the patients with postoperative infectious complications (median 43.5 vs 76.1 μmol/g of feces, P = .011). Multivariate analysis revealed that an acetic acid plus butyric acid minus lactic acid gap acid profile (especially low acetic acid, low butyric acid, and high lactic acid) had a clinically important impact on the incidence of postoperative infectious complications in patients undergoing major hepatectomy with extrahepatic bile duct resection. Copyright © 2017. Published by Elsevier Inc.

  11. Conjugated linolenic acids (CLnA, super CLA – natural sources and biological activity

    Directory of Open Access Journals (Sweden)

    Agnieszka Białek

    2014-11-01

    Full Text Available Polyunsaturated fatty acids (PUFA have a wide range of biological activity. Among them conjugated fatty acids are of great interest. Conjugated linoleic acids (CLA, which exert a multidirectional health-benefiting influence, and conjugated linolenic acids (CLnA, super CLA are examples of this group of fatty acids. CLnA are a group of positional and geometric isomers of octadecatrienoic acid (C18:3, which possess double bonds at positions 9, 11, 13 or 8, 10, 12 of their chain. Some vegetable oils are rich sources of CLnA, e.g. bitter melon oil (from Momordica charantia seeds and pomegranate oil (from Punica granatum seeds. The aim of this paper was to present information concerning natural sources and health-promoting activities of conjugated linolenic acids.The presented data reveal that conjugated linolenic acids may be very useful in prevention and treatment of many diseases, especially diabetes, arteriosclerosis , obesity and cancers (mammary, prostate and colon cancer. Among many potential mechanisms of their action, the fact that some CLnA are converted by oxidoreductases into CLA is very important. It seems to be very reasonable to conduct research concerning the possibility of CLnA use in prevention of many diseases.

  12. Crystal structure of bile salt hydrolase from Lactobacillus salivarius.

    Science.gov (United States)

    Xu, Fuzhou; Guo, Fangfang; Hu, Xiao Jian; Lin, Jun

    2016-05-01

    Bile salt hydrolase (BSH) is a gut-bacterial enzyme that negatively influences host fat digestion and energy harvesting. The BSH enzyme activity functions as a gateway reaction in the small intestine by the deconjugation of glycine-conjugated or taurine-conjugated bile acids. Extensive gut-microbiota studies have suggested that BSH is a key mechanistic microbiome target for the development of novel non-antibiotic food additives to improve animal feed production and for the design of new measures to control obesity in humans. However, research on BSH is still in its infancy, particularly in terms of the structural basis of BSH function, which has hampered the development of BSH-based strategies for improving human and animal health. As an initial step towards the structure-function analysis of BSH, C-terminally His-tagged BSH from Lactobacillus salivarius NRRL B-30514 was crystallized in this study. The 1.90 Å resolution crystal structure of L. salivarius BSH was determined by molecular replacement using the structure of Clostridium perfringens BSH as a starting model. It revealed this BSH to be a member of the N-terminal nucleophile hydrolase superfamily. Crystals of apo BSH belonged to space group P21212, with unit-cell parameters a = 90.79, b = 87.35, c = 86.76 Å (PDB entry 5hke). Two BSH molecules packed perfectly as a dimer in one asymmetric unit. Comparative structural analysis of L. salivarius BSH also identified potential residues that contribute to catalysis and substrate specificity.

  13. Production of a conjugated fatty acid by Bifidobacterium breve LMC520 from α-linolenic acid: conjugated linolenic acid (CLnA).

    Science.gov (United States)

    Park, Hui Gyu; Cho, Hyung Taek; Song, Myoung-Chong; Kim, Sang Bum; Kwon, Eung Gi; Choi, Nag Jin; Kim, Young Jun

    2012-03-28

    This study was performed to characterize natural CLnA isomer production by Bifidobacterium breve LMC520 of human origin in comparison to conjugated linoleic acid (CLA) production. B. breve LMC520 was found to be highly active in terms of CLnA production, of which the major portion was identified as cis-9,trans-11,cis-15 CLnA isomer by GC-MS and NMR analysis. B. breve LMC520 was incubated for 48 h using MRS medium (containing 0.05% L-cysteine · HCl) under different environmental conditions such as atmosphere, pH, and substrate concentration. The high conversion rate of α-linolenic acid (α-LNA) to CLnA (99%) was retained up to 2 mM α-LNA, and the production was proportionally increased nearly 7-fold with 8 mM by the 6 h of incubation under anaerobic conditions at a wide range of pH values (between 5 and 9). When α-LNA was compared with linoleic acid (LA) as a substrate for isomerization by B. breve LMC520, the conversion of α-LNA was higher than that of LA. These results demonstrated that specific CLnA isomer could be produced through active bacterial conversion at an optimized condition. Because many conjugated octadecatrienoic acids in nature are shown to play many positive roles, the noble isomer found in this study has potential as a functional source.

  14. Bile Routing Modification Reproduces Key Features of Gastric Bypass in Rat.

    Science.gov (United States)

    Goncalves, Daisy; Barataud, Aude; De Vadder, Filipe; Vinera, Jennifer; Zitoun, Carine; Duchampt, Adeline; Mithieux, Gilles

    2015-12-01

    To evaluate the role of bile routing modification on the beneficial effects of gastric bypass surgery on glucose and energy metabolism. Gastric bypass surgery (GBP) promotes early improvements in glucose and energy homeostasis in obese diabetic patients. A suggested mechanism associates a decrease in hepatic glucose production to an enhanced intestinal gluconeogenesis. Moreover, plasma bile acids are elevated after GBP and bile acids are inhibitors of gluconeogenesis. In male Sprague-Dawley rats, we performed bile diversions from the bile duct to the midjejunum or the mid-ileum to match the modified bile delivery in the gut occurring in GBP. Body weight, food intake, glucose tolerance, insulin sensitivity, and food preference were analyzed. The expression of gluconeogenesis genes was evaluated in both the liver and the intestine. Bile diversions mimicking GBP promote an increase in plasma bile acids and a marked improvement in glucose control. Bile bioavailability modification is causal because a bile acid sequestrant suppresses the beneficial effects of bile diversions on glucose control. In agreement with the inhibitory role of bile acids on gluconeogenesis, bile diversions promote a blunting in hepatic glucose production, whereas intestinal gluconeogenesis is increased in the gut segments devoid of bile. In rats fed a high-fat-high-sucrose diet, bile diversions improve glucose control and dramatically decrease food intake because of an acquired disinterest in fatty food. This study shows that bile routing modification is a key mechanistic feature in the beneficial outcomes of GBP.

  15. Characterization of biliary conjugates of 4,4'-methylenedianiline in male versus female rats

    International Nuclear Information System (INIS)

    Chen, Kan; Cole, Richard B.; Santa Cruz, Vicente; Blakeney, Ernest W.; Kanz, Mary F.; Dugas, Tammy R.

    2008-01-01

    4,4'-Methylenedianiline (4,4'-diaminodiphenylmethane; DAPM) is an aromatic diamine used in the production of numerous polyurethane foams and epoxy resins. Previous studies in rats revealed that DAPM initially injures biliary epithelial cells of the liver, that the toxicity is greater in female than in male rats, and that the toxic metabolites of DAPM are excreted into bile. Since male and female rats exhibit differences in the expression of both phase I and phase II enzymes, our hypothesis was that female rats either metabolize DAPM to more toxic metabolites or have a decreased capacity to conjugate metabolites to less toxic intermediates. Our objective was thus to isolate, characterize, and quantify DAPM metabolites excreted into bile in both male and female bile duct-cannulated Sprague Dawley rats. The rats were gavaged with [ 14 C]-DAPM, and the collected bile was subjected to reversed-phase HPLC with radioisotope detection. Peaks eluting from HPLC were collected and analyzed using electrospray MS and NMR spectroscopy. HPLC analysis indicated numerous metabolites in both sexes, but male rats excreted greater amounts of glutathione and glucuronide conjugates than females. Electrospray MS and NMR spectra of HPLC fractions revealed that the most prominent metabolite found in bile of both sexes was a glutathione conjugate of an imine metabolite of a 4'-nitroso-DAPM. Seven other metabolites were identified, including acetylated, cysteinyl-glycine, glutamyl-cysteine, glycine, and glucuronide conjugates. While our prior studies demonstrated increased covalent binding of DAPM in the liver and bile of female compared to male rats, in these studies, SDS-PAGE with autoradiography revealed 4-5 radiolabeled protein bands in the bile of rats treated with [ 14 C]-DAPM. In addition, these bands were much more prominent in female than in male rats. These studies thus suggest that a plausible mechanism for the increased sensitivity of female rats to DAPM toxicity may be decreased

  16. Glucose-lowering effects and mechanisms of the bile acid-sequestering resin sevelamer

    DEFF Research Database (Denmark)

    Brønden, Andreas; Mikkelsen, Kristian; Sonne, David P

    2018-01-01

    AIMS: Sevelamer, a non-absorbable amine-based resin used for treatment of hyperphosphatemia, has been demonstrated to hold a marked bile acid-binding potential alongside beneficial effects on lipid and glucose metabolism. The aim of this study was to investigate the glucose-lowering effect and me...

  17. Analyses of bile from gallbladders of Arius platystomus, Arius tenuispinis, Pomadasys commersonni and Kishinoella tonggol.

    Science.gov (United States)

    Hassan, Amir; Ahmed, Mansoor; Rasheed, Munawwer; Mansoor, Najia; Khan, Rafeeq Alam; Kamal, Mustafa; Rashid, Mohammad Abdur

    2015-07-01

    Bile from gallbladders of Arius platystomus (Singhara), Arius tenuispinis (Khagga), Pomadasys commersonni (Holoola) and Kishinoella tonggol (Dawan) were derivatised and analysed by GC-MS for identification of bile acids and bile alcohols. Cholic acid and Chenodeoxycholic acid were found as major bile acids in Arius platystomus, Arius tenuispinis and Pomadasys commersonni. Other bile acids identified in Arius platystomus were allochenodeoxycholic acid, allodeoxycholic acid, 3α,7α,12α-trihydroxy-24-methyl-5β-cholestane-26-oic acid, and 3α,7α,12α, 24-tetrahydroxy-5α-cholestane-26-oic acid. Cholesterol was found as major bile alcohol in Arius platystomus, Arius tenuispinis and Pomadasys commersonni. Cholic acid was the major bile acid identified in the bile of Kishinoella tonggol while other bile acids included 3α,7α,12α-tridydroxy-5α-cholestanoic acid and 3α,7α,12α-tridydroxy-5β-cholestanoic acid. Bile alcohol 5β-cyprinol was present in significant amounts with 5β-cholestane-3α,7α,12α,24-tetrol being the other contributors in the bile of Kishinoella tonggol.

  18. Potential of nor-Ursodeoxycholic Acid in Cholestatic and Metabolic Disorders.

    Science.gov (United States)

    Trauner, Michael; Halilbasic, Emina; Claudel, Thierry; Steinacher, Daniel; Fuchs, Claudia; Moustafa, Tarek; Pollheimer, Marion; Krones, Elisabeth; Kienbacher, Christian; Traussnigg, Stefan; Kazemi-Shirazi, Lili; Munda, Petra; Hofer, Harald; Fickert, Peter; Paumgartner, Gustav

    2015-01-01

    24-nor-ursodeoxycholic acid (norUDCA) is a side-chain shortened derivate of ursodeoxycholic acid (UDCA). Since norUDCA is only ineffectively conjugated with glycine or taurine, it has specific physicochemical and therapeutic properties distinct from UDCA. Nonamidated norUDCA undergoes cholehepatic shunting enabling 'ductular targeting' and inducing a bicarbonate-rich hypercholeresis, with cholangioprotective effects. At the same time it has direct anti-inflammatory, antilipotoxic, anti fibrotic, and antiproliferative properties targeting various liver cell populations. norUDCA appears to be one of the most promising novel treatment approaches targeting the liver and the bile duct system at multifactorial and multicellular levels. This review article is a summary of a lecture given at the XXIII International Bile Acid Meeting (Falk Symposium 194) on 'Bile Acids as Signal Integrators and Metabolic Modulators' held in Freiburg, October 8-9, 2014, and summarizes the recent progress with norUDCA as a novel therapeutic approach in cholestatic and metabolic (liver) disorders. 2015 S. Karger AG, Basel.

  19. Bile acid synthesis is increased in Chilean Hispanics with gallstones and in gallstone high-risk Mapuche Indians.

    Science.gov (United States)

    Gälman, Cecilia; Miquel, Juan Francisco; Pérez, Rosa Maria; Einarsson, Curt; Ståhle, Lars; Marshall, Guillermo; Nervi, Flavio; Rudling, Mats

    2004-03-01

    Gallstone disease is an important, costly health-care problem in Western societies. It is still unclear whether hepatic lipid regulatory enzymes play primary or secondary roles in gallstone formation. In this study, the aim was to investigate whether the synthesis of bile acids and cholesterol is increased in gallstone disease and to test whether such a metabolic change, if present, might occur before gallstone formation. A total of 125 Chilean Hispanic women (80 without gallstones and 45 with gallstones) matched for age and body mass index were investigated, along with 40 Chilean Mapuche Indian women (20 without gallstones and 20 with gallstones), a population group in which the prevalence for gallstone disease is very high. Fasting blood plasma samples were assayed for 7 alpha-hydroxy-4-cholesten-3-one and lathosterol, 2 strong indicators for hepatic bile acid and body cholesterol synthesis, respectively. Plasma 7 alpha-hydroxy-4-cholesten-3-one levels, corrected for plasma cholesterol, were significantly increased by 50% in Hispanic women with gallstones as compared with gallstone-free Hispanics (P or =100% (P Mapuche Indian women, independently of whether gallstones were present. Plasma lathosterol, corrected for plasma cholesterol, was significantly increased by 22% in Hispanic women with gallstones and in Mapuche Indian women compared with Hispanic women. The results indicate that the synthesis of bile acids and cholesterol is induced in gallstone disease and precedes gallstone development. These inductions presumably occur as a response to an increased intestinal loss of bile acids.

  20. Ursodeoxycholic acid reduces protein levels and nucleation-promoting activity in human gallbladder bile

    NARCIS (Netherlands)

    van Erpecum, K. J.; Portincasa, P.; Eckhardt, E.; Go, P. M.; vanBerge-Henegouwen, G. P.; Groen, A. K.

    1996-01-01

    Background & Aims: Ursodeoxycholic acid prevents gallstone formation in selected patients. The aim of this study was to examine whether decreased concentration and nucleation-promoting activity of various proteins contribute to this beneficial effect. Methods: Gallbladder bile of 13 patients with

  1. Bile Acids Increase Independently From Hypocaloric Restriction After Bariatric Surgery.

    Science.gov (United States)

    Jahansouz, Cyrus; Xu, Hongliang; Hertzel, Ann V; Serrot, Federico J; Kvalheim, Nicholas; Cole, Abigail; Abraham, Anasooya; Luthra, Girish; Ewing, Kristin; Leslie, Daniel B; Bernlohr, David A; Ikramuddin, Sayeed

    2016-12-01

    To measure changes in the composition of serum bile acids (BA) and the expression of Takeda G-protein-coupled receptor 5 (TGR5) acutely after bariatric surgery or caloric restriction. Metabolic improvement after bariatric surgery occurs before substantial weight loss. BA are important metabolic regulators acting through the farnesoid X receptor and TGR5 receptor. The acute effects of surgery on BA and the TGR5 receptor in subcutaneous white adipose tissue (WAT) are unknown. A total of 27 obese patients with type 2 diabetes mellitus were randomized to Roux-en-Y gastric bypass (RYGB) or to hypocaloric diet (HC diet) restriction (NCT 1882036). A cohort of obese patients with and without type 2 diabetes mellitus undergoing vertical sleeve gastrectomy was also recruited (n = 12) as a comparison. After vertical sleeve gastrectomy, the level of BA increased [total: 1.17 ± 1.56 μmol/L to 4.42 ± 3.92 μmol/L (P = 0.005); conjugated BA levels increased from 0.99 ± 1.42 μmol/L to 3.59 ± 3.70 μmol/L (P = 0.01) and unconjugated BA levels increased from 0.18 ± 0.24 μmol/L to 0.83 ± 0.70 μmol/L (P = 0.009)]. With RYGB, there was a trend toward increased BA [total: 1.37 ± 0.97 μmol/L to 3.26 ± 3.01 μmol/L (P = 0.07); conjugated: 1.06 ± 0.81 μmol/L to 2.99 ± 3.02 μmol/L (P = 0.06)]. After HC diet, the level of unconjugated BA decreased [0.92 ± 0.55 μmol/L to 0.32 ± 0.43 μmol/L (P = 0.05)]. The level of WAT TGR5 gene expression decreased after surgery, but not in HC diet. Protein levels did not change. The levels of serum BA increase after bariatric surgery independently from caloric restriction, whereas the level of WAT TGR5 protein is unaffected.

  2. Synthesis of new, UV-photoactive dansyl derivatives for flow cytometric studies on bile acid uptake.

    Science.gov (United States)

    Rohacova, Jana; Marin, M Luisa; Martínez-Romero, Alicia; O'Connor, José-Enrique; Gomez-Lechon, M Jose; Donato, M Teresa; Castell, Jose V; Miranda, Miguel A

    2009-12-07

    Four new fluorescent derivatives of cholic acid have been synthesized; they incorporate a dansyl moiety at 3alpha-, 3beta-, 7alpha- or 7beta- positions. These cholic acid analogs are UV photoactive and also exhibit green fluorescence. In addition, they have been demonstrated to be suitable for studying the kinetics of bile acid transport by flow cytometry.

  3. Gene expression changes associated with Barrett's esophagus and Barrett's-associated adenocarcinoma cell lines after acid or bile salt exposure

    Directory of Open Access Journals (Sweden)

    Sahbaie Peyman

    2007-06-01

    Full Text Available Abstract Background Esophageal reflux and Barrett's esophagus represent two major risk factors for the development of esophageal adenocarcinoma. Previous studies have shown that brief exposure of the Barrett's-associated adenocarcinoma cell line, SEG-1, or primary cultures of Barrett's esophageal tissues to acid or bile results in changes consistent with cell proliferation. In this study, we determined whether similar exposure to acid or bile salts results in gene expression changes that provide insights into malignant transformation. Methods Using previously published methods, Barrett's-associated esophageal adenocarcinoma cell lines and primary cultures of Barrett's esophageal tissue were exposed to short pulses of acid or bile salts followed by incubation in culture media at pH 7.4. A genome-wide assessment of gene expression was then determined for the samples using cDNA microarrays. Subsequent analysis evaluated for statistical differences in gene expression with and without treatment. Results The SEG-1 cell line showed changes in gene expression that was dependent on the length of exposure to pH 3.5. Further analysis using the Gene Ontology, however, showed that representation by genes associated with cell proliferation is not enhanced by acid exposure. The changes in gene expression also did not involve genes known to be differentially expressed in esophageal adenocarcinoma. Similar experiments using short-term primary cultures of Barrett's esophagus also did not result in detectable changes in gene expression with either acid or bile salt exposure. Conclusion Short-term exposure of esophageal adenocarcinoma SEG-1 cells or primary cultures of Barrett's esophagus does not result in gene expression changes that are consistent with enhanced cell proliferation. Thus other model systems are needed that may reflect the impact of acid and bile salt exposure on the esophagus in vivo.

  4. Dynamical Approach to Multiequilibria Problems for Mixtures of Acids and Their Conjugated Bases

    Science.gov (United States)

    Glaser, Rainer E.; Delarosa, Marco A.; Salau, Ahmed Olasunkanmi; Chicone, Carmen

    2014-01-01

    Mathematical methods are described for the determination of steady-state concentrations of all species in multiequilibria systems consisting of several acids and their conjugated bases in aqueous solutions. The main example consists of a mixture of a diprotic acid H[subscript 2]A, a monoprotic acid HB, and their conjugate bases. The reaction…

  5. Enhanced dispersion of boron nitride nanosheets in aqueous media by using bile acid-based surfactants

    Science.gov (United States)

    Chae, Ari; Park, Soo-Jin; Min, Byunggak; In, Insik

    2018-01-01

    Facile noncovalent surface functionalization of hydroxylated boron nitride nanosheet (BNNS-OH) was attempted through the sonication-assisted exfoliation of h-BN in aqueous media in the presence of bile acid-based surfactants such as sodium cholic acid (SC) or sodium deoxycholic acid (SDC), resulting in SC- or SDC-BNNS-OH dispersion with high up to 2 mg ml-1 and enhanced dispersion stability due to the increased negative zeta potential. While prepared SC-BNNS-OH revealed multi-layered BNNS structures, the large lateral sizes of hundreds nanometers and clear h-BN lattice structures are very promising for the preparation and application of water-processable BNNS-based nanomaterials. It is regarded that noncovalent functionalization of BNNS-OH based on σ-π interaction between with σ-rich bile acid-based amphiphiles and π-rich BNNS is very effective to formulate multi-functional BNNS-based nanomaterials or hybrids that can be utilized in various applications where both the pristine properties of BNNS and the extra functions are simultaneously required.

  6. Bile acids and lipids in isolated rat hepatocytes. II. Source of cholesterol used for bile acid formation, estimated by incorporation of tritium from tritiated water, and by the effect of ML-236B

    NARCIS (Netherlands)

    Kempen, H.J.; Vos Van Holstein, M.; Lange, J.de

    1983-01-01

    Chemicals/CAS: cholesterol, 57-88-5; cholic acid, 32500-01-9, 361-09-1, 81-25-4; colestyramine, 11041-12-6, 58391-37-0; compactin, 73573-88-3; lipid, 66455-18-3; tritium oxide, 14940-65-9; Bile Acids and Salts; Cholesterol, 57-88-5; Cholestyramine, 11041-12-6; compactin, 73573-88-3; Lipids;

  7. Functionalization of Fatty Acid Vesicles through Newly Synthesized Bolaamphiphile-DNA Conjugates

    DEFF Research Database (Denmark)

    Wamberg, M. C.; Wieczorek, R.; Brier, S. B.

    2014-01-01

    The surface functionalization of fatty acid vesicles will allow their use as nanoreactors for complex chemistry. In this report, the tethering of several DNA conjugates to decanoic acid vesicles for molecular recognition and synthetic purposes was explored. Due to the highly dynamic nature......), and consists of a single hydrocarbon chain of 20 carbons having on one end a triazole group linked to the S'-phosphate of the nucleic acid and on the other side a hydroxyl-group. Its insertion was so effective that a fluorescent label on the DNA complementary to the conjugate could be used to visualize fatty...... acid structures....

  8. Antitumor activity of newly synthesized oxo and ethylidene derivatives of bile acids and their amides and oxazolines.

    Science.gov (United States)

    Bjedov, Srđan; Jakimov, Dimitar; Pilipović, Ana; Poša, Mihalj; Sakač, Marija

    2017-04-01

    Bile acid derivatives with modifications in side chain and modifications on steroid skeleton were synthetized and their antitumor activity against five human cancer cell lines was investigated. Modifications in side chain include amid group, formed in reaction with 2-amino-2-methylpropanol, and 4,4-dimethyloxazoline group, obtained after cyclization of amides. In the steroid skeleton oxo groups were introduced in position 7 (2, 2a, 2b) and 7,12 (3, 3a, 3b). Ethylidene groups were introduced regio- and stereoselectively on C-7, and/or without stereoselectivity on C-3 by Wittig reaction. By combination of these modifications, a series of 19 bile acid derivatives were synthesized. Compounds containing both C-7 ethylidene and C-12 carbonyl groups (6, 6a, 6b) shown very good antitumor activity with IC 50 amide or oxazoline group has positive effect on cytotoxicity. Different molecular descriptors were determined in silico and after principal component analysis was found that molecular descriptor BLTF96 can be used for fast assessment of experimental cytotoxicity of bile acid derivatives. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Determination and importance of temperature dependence of retention coefficient (RPHPLC) in QSAR model of nitrazepams' partition coefficient in bile acid micelles.

    Science.gov (United States)

    Posa, Mihalj; Pilipović, Ana; Lalić, Mladena; Popović, Jovan

    2011-02-15

    Linear dependence between temperature (t) and retention coefficient (k, reversed phase HPLC) of bile acids is obtained. Parameters (a, intercept and b, slope) of the linear function k=f(t) highly correlate with bile acids' structures. Investigated bile acids form linear congeneric groups on a principal component (calculated from k=f(t)) score plot that are in accordance with conformations of the hydroxyl and oxo groups in a bile acid steroid skeleton. Partition coefficient (K(p)) of nitrazepam in bile acids' micelles is investigated. Nitrazepam molecules incorporated in micelles show modified bioavailability (depo effect, higher permeability, etc.). Using multiple linear regression method QSAR models of nitrazepams' partition coefficient, K(p) are derived on the temperatures of 25°C and 37°C. For deriving linear regression models on both temperatures experimentally obtained lipophilicity parameters are included (PC1 from data k=f(t)) and in silico descriptors of the shape of a molecule while on the higher temperature molecular polarisation is introduced. This indicates the fact that the incorporation mechanism of nitrazepam in BA micelles changes on the higher temperatures. QSAR models are derived using partial least squares method as well. Experimental parameters k=f(t) are shown to be significant predictive variables. Both QSAR models are validated using cross validation and internal validation method. PLS models have slightly higher predictive capability than MLR models. Copyright © 2010 Elsevier B.V. All rights reserved.

  10. Plasma Bile Acids Are Associated with Energy Expenditure and Thyroid Function in Humans

    NARCIS (Netherlands)

    Ockenga, Johann; Valentini, Luzia; Schuetz, Tatjana; Wohlgemuth, Franziska; Glaeser, Silja; Omar, Ajmal; Kasim, Esmatollah; duPlessis, Daniel; Featherstone, Karen; Davis, Julian R.; Tietge, Uwe J. F.; Kroencke, Thomas; Biebermann, Heike; Koehrle, Josef; Brabant, Georg

    Background/Aims: Animal studies implicate a role of bile acids (BA) in thyroid-regulated energy expenditure (EE) via activation of the TGR-5/adenylate cyclase/deiodinase type 2 pathway. Here we investigated these possible associations in humans. Methods: EE, BA, and thyroid hormone status were

  11. Bile acid flux through portal but not peripheral veins inhibits CYP7A1 expression without involvement of ileal FGF19 in rabbits.

    Science.gov (United States)

    Shang, Quan; Guo, Grace L; Honda, Akira; Shi, Daniel; Saumoy, Monica; Salen, Gerald; Xu, Guorong

    2014-08-15

    It was proposed that CYP7A1 expression is suppressed through the gut-hepatic signaling pathway fibroblast growth factor (FGF) 15/19-fibroblast growth factor receptor 4, which is initiated by activation of farnesoid X receptor in the intestine rather than in the liver. The present study tested whether portal bile acid flux alone without ileal FGF19 could downregulate CYP7A1 expression in rabbits. A rabbit model was developed by infusing glycodeoxycholic acid (GDCA) through the splenic vein to bypass ileal FGF19. Study was conducted in four groups of rabbits: control; bile fistula + bovine serum albumin solution perfusion (BF); BF + GDCA (by portal perfusion); and BF + GDCA-f (by femoral perfusion). Compared with only BF, BF + GDCA (6 h portal perfusion) suppressed CYP7A1 mRNA, whereas BF + GDCA-f (via femoral vein) with the same perfusion rate of GDCA did not show inhibitory effects. Meanwhile, there was a decrease in ileal FGF19 expression and portal FGF19 protein levels, but an equivalent increase in biliary bile acid outputs in both GDCA perfusion groups. This study demonstrated that portal bile acid flux alone downregulated CYP7A1 expression with diminished FGF19 expression and protein levels, whereas the same bile acid flux reaching the liver through the hepatic artery via femoral vein had no inhibitory effect on CYP7A1. We propose that bile acid flux through the portal venous system may be a kind of "intestinal factor" that suppresses CYP7A1 expression. Copyright © 2014 the American Physiological Society.

  12. The bile acid deoxycholate elicits defences in Arabidopsis and reduces bacterial infection.

    Science.gov (United States)

    Zarattini, Marco; Launay, Alban; Farjad, Mahsa; Wénès, Estelle; Taconnat, Ludivine; Boutet, Stéphanie; Bernacchia, Giovanni; Fagard, Mathilde

    2017-05-01

    Disease has an effect on crop yields, causing significant losses. As the worldwide demand for agricultural products increases, there is a need to pursue the development of new methods to protect crops from disease. One mechanism of plant protection is through the activation of the plant immune system. By exogenous application, 'plant activator molecules' with elicitor properties can be used to activate the plant immune system. These defence-inducing molecules represent a powerful and often environmentally friendly tool to fight pathogens. We show that the secondary bile acid deoxycholic acid (DCA) induces defence in Arabidopsis and reduces the proliferation of two bacterial phytopathogens: Erwinia amylovora and Pseudomonas syringae pv. tomato. We describe the global defence response triggered by this new plant activator in Arabidopsis at the transcriptional level. Several induced genes were selected for further analysis by quantitative reverse transcription-polymerase chain reaction. We describe the kinetics of their induction and show that abiotic stress, such as moderate drought or nitrogen limitation, does not impede DCA induction of defence. Finally, we investigate the role in the activation of defence by this bile acid of the salicylic acid biosynthesis gene SID2, of the receptor-like kinase family genes WAK1-3 and of the NADPH oxidase-encoding RbohD gene. Altogether, we show that DCA constitutes a promising molecule for plant protection which can induce complementary lines of defence, such as callose deposition, reactive oxygen species accumulation and the jasmonic acid and salicylic acid signalling pathways. © 2016 BSPP AND JOHN WILEY & SONS LTD.

  13. Biotransformation of Flavonoid Conjugates with Fatty Acids and Evaluations of Their Functionalities

    Directory of Open Access Journals (Sweden)

    Cynthia Q. Sun

    2017-11-01

    Full Text Available Enzymatic conjugation with fatty acids including omega-3 polyunsaturated fatty acids (ω-3 PUFAs derived from fish oil to three citrus fruit-derived flavonoids: grapefruit extract, naringin, and neohesperidin dihydrochalcone were investigated. The conversions were achieved over 85% under the catalysis of lipase Novozyme 435 in acetone at 45°C at semi-preparative scale. The conjugates were purified via solvent partition and silica gel chromatography and achieved 90–98% in purity. The NMR analysis of the conjugates confirmed that the fatty acid carbon chain was linked onto the primary –OH group on the glucose moiety of the flavonoids. The purified flavonoid conjugates alongside their original flavonoids were analyzed for antioxidant activities via 2,2-diphenyl-1-picrylhydrazyl scavenging assay, and anti-peroxidation test via peroxide values measured during a 1-week fish oil storage trial. Vascular endothelial growth factor (VEGF assay was conducted with 1, 10, and 100 μM of naringin and grapefruits and their conjugates, respectively, and total VEGF levels were measured at 24 and 48 h, respectively, using ELISA and dot blot analysis. The results from these functionality experiments demonstrated that flavonoid FA conjugates have at least comparable (if not higher antioxidant activity, anti-peroxidation activity, and anti-angiogenic activity.

  14. Insulin suppresses bile acid synthesis in cultured rat hepatocytes by down-regulation of cholesterol 7α-hydroxylase and sterol 27-hydroxylase gene transcription

    NARCIS (Netherlands)

    Twisk, J.; Hoekman, M.F.M.; Lehmann, E.M.; Meijer, P.; Mager, W.H.; Princen, H.M.G.

    1995-01-01

    Evidence from in vivo studies indicates that the bile acid pool and bile acid excretion are increased in humans with diabetes mellitus and in experimental diabetic animals, and that both parameters return to normal levels after administration of insulin. To investigate the biochemical background of

  15. Hepatic disposition of the acyl glucuronide 1-O-gemfibrozil-beta-D-glucuronide: effects of clofibric acid, acetaminophen, and acetaminophen glucuronide.

    Science.gov (United States)

    Sabordo, L; Sallustio, B C; Evans, A M; Nation, R L

    2000-10-01

    Glucuronidation of carboxylic acid compounds results in the formation of electrophilic acyl glucuronides. Because of their polarity, carrier-mediated hepatic transport systems play an important role in determining both intra- and extrahepatic exposure to these reactive conjugates. We have previously shown that the hepatic membrane transport of 1-O-gemfibrozil-beta-D-glucuronide (GG) is carrier-mediated and inhibited by the organic anion dibromosulfophthalein. In this study, we examined the influence of 200 microM acetaminophen, acetaminophen glucuronide, and clofibric acid on the disposition of GG (3 microM) in the recirculating isolated perfused rat liver preparation. GG was taken up by the liver, excreted into bile, and hydrolyzed within the liver to gemfibrozil, which appeared in perfusate but not in bile. Mean +/- S. D. hepatic clearance, apparent intrinsic clearance, hepatic extraction ratio, and biliary excretion half-life of GG were 10.4 +/- 1.4 ml/min, 94.1 +/- 17.9 ml/min, 0.346 +/- 0.046, and 30.9 +/- 4.9 min, respectively, and approximately 73% of GG was excreted into bile. At the termination of the experiment (t = 90 min), the ratio of GG concentrations in perfusate, liver, and bile was 1:35:3136. Acetaminophen and acetaminophen glucuronide had no effect on the hepatic disposition of GG, suggesting relatively low affinities of acetaminophen conjugates for hepatic transport systems or the involvement of multiple transport systems for glucuronide conjugates. In contrast, clofibric acid increased the hepatic clearance, extraction ratio, and apparent intrinsic clearance of GG (P clofibric acid glucuronide at the level of hepatic transport. However, the transporter protein(s) involved remains to be identified.

  16. The effect of conjugated linoleic acid on the fatty acid composition of ...

    African Journals Online (AJOL)

    The effect of conjugated linoleic acid on the fatty acid composition of different tissues and yolk lipids in pigeons. ... South African Journal of Animal Science ... Eight established breeding pairs per group were fed either a commercially pelleted pigeon diet mixed with 0.5% safflower oil (SFO) or 0.5% CLA for 12 weeks. For fatty ...

  17. DIETARY FISH OIL-INDUCED CHANGES IN INTRAHEPATIC CHOLESTEROL TRANSPORT AND BILE-ACID SYNTHESIS IN RATS

    NARCIS (Netherlands)

    SMIT, MJ; TEMMERMAN, AM; WOLTERS, H; KUIPERS, F; BEYNEN, AC; VONK, RJ

    Hepatic cholesterol metabolism was studied in rats fed purified diets supplemented (9% wt/wt) with either fish oil (FO) (n-3 fatty acids) or corn oil (CO) (n-6 fatty acids) for 4 wk. Rats were equipped with permanent catheters in heart, bile duct, and duodenum to allow studies under normal feeding

  18. The effect of BAY o 2752 on bile acid absorption and cholesterol esterification

    International Nuclear Information System (INIS)

    Harnett, K.M.

    1988-01-01

    BAY o 2752 [N,N-(1,11-undecandiyl)bis(2,3-dihydro-2-methyl-1H-indole-1-carboxamide)] has been demonstrated to inhibit intestinal cholesterol absorption in rats. Studies were carried out on male Wistar rats to determine if this drug alters intestinal bile acid absorption or cholesterol esterification by acyl CoA: cholesterol acyltransferase (ACAT) or cholesterol ester hydrolase (CEH). BAY o 2752 did not affect intestinal absorption of taurocholic acid (TC) from ileal segments perfused in vivo with a tragacanth suspension in phosphate buffer containing NaCl, TC, and 24- 14 C-TC as determined by the excretory rate of radioactivity in bile. BAY o 2752 also did not affect the uptake of TC into ileal everted sacs incubated in stirred, gassed Krebs-Ringer bicarbonate buffer with 1 mM TC, 24- 14 C-TC and 3 H-inulin. BAY o 2752 also did not bind TC; TG, in a filtrate of the above solutions remained at 92-98% of control

  19. The effect of BAY o 2752 on bile acid absorption and cholesterol esterification

    Energy Technology Data Exchange (ETDEWEB)

    Harnett, K.M.

    1988-01-01

    BAY o 2752 (N,N-(1,11-undecandiyl)bis(2,3-dihydro-2-methyl-1H-indole-1-carboxamide)) has been demonstrated to inhibit intestinal cholesterol absorption in rats. Studies were carried out on male Wistar rats to determine if this drug alters intestinal bile acid absorption or cholesterol esterification by acyl CoA: cholesterol acyltransferase (ACAT) or cholesterol ester hydrolase (CEH). BAY o 2752 did not affect intestinal absorption of taurocholic acid (TC) from ileal segments perfused in vivo with a tragacanth suspension in phosphate buffer containing NaCl, TC, and 24-{sup 14}C-TC as determined by the excretory rate of radioactivity in bile. BAY o 2752 also did not affect the uptake of TC into ileal everted sacs incubated in stirred, gassed Krebs-Ringer bicarbonate buffer with 1 mM TC, 24-{sup 14}C-TC and {sup 3}H-inulin. BAY o 2752 also did not bind TC; TG, in a filtrate of the above solutions remained at 92-98% of control.

  20. Synthesis of highly stable folic acid conjugated magnetite nanoparticles for targeting cancer cells

    International Nuclear Information System (INIS)

    Mohapatra, S; Mallick, S K; Maiti, T K; Ghosh, S K; Pramanik, P

    2007-01-01

    A new approach towards the design of folic acid conjugated magnetic nanoparticles for enhancing their site specific intracellular uptake against a folate receptor overexpressing cancer cells is reported. Magnetite nanoparticles were prepared by coprecipitation from an Fe 3+ and Fe 2+ solution followed by surface modification with 2-carboxyethyl phosphonic acid to form carboxyl group terminated nanoparticles. Then folic acid and fluorescein isothiocyanate (FITC) were conjugated with carboxylic acid functionalized magnetite nanoparticles using 2,2'-(ethylenedioxy)-bis-ethylamine. These folate-conjugated nanoparticles were characterized in terms of their size by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Surface functional groups and surface composition were analyzed by Fourier transform infrared (FTIR) spectroscopy and x-ray photoelectron spectroscopy (XPS), respectively. Vibration sample magnetometry (VSM) measurements showed the superparamagnetic nature of the particles at room temperature. Folate-conjugated magnetic nanoparticles are noncytotoxic and receptor mediated internalization by HeLa and B16 melanoma F0 cancer cells was confirmed by flow cytometry and confocal microscopy

  1. Hepatocyte MyD88 affects bile acids, gut microbiota and metabolome contributing to regulate glucose and lipid metabolism

    DEFF Research Database (Denmark)

    Duparc, Thibaut; Plovier, Hubert; Marrachelli, Vannina G

    2017-01-01

    performed microarrays and quantitative PCRs in the liver. In addition, we investigated the gut microbiota composition, bile acid profile and both liver and plasma metabolome. We analysed the expression pattern of genes in the liver of obese humans developing non-alcoholic steatohepatitis (NASH). RESULTS...... proliferator activator receptor-α, farnesoid X receptor (FXR), liver X receptors and STAT3) and bile acid profiles involved in glucose, lipid metabolism and inflammation. In addition to these alterations, the genetic deletion of MyD88 in hepatocytes changes the gut microbiota composition and their metabolomes...

  2. Fasting and postprandial serum bile acid concentrations in 10 healthy female red-eared terrapins (Trachemys scripta elegans).

    Science.gov (United States)

    Knotkova, Z; Dorrestein, G M; Jekl, V; Janouskova, J; Knotek, Z

    2008-10-25

    The fasting and postprandial serum concentrations of bile acids and other blood constituents were measured in a group of 10 clinically healthy, female, six-year-old captive red-eared terrapins (Trachemys scripta elegans). The terrapins were housed in a temperate room and maintained in four aquaria in which the water temperature ranged from 24 to 27 degrees C and the temperature above the basking site ranged from 27 to 30 degrees C. The serum concentrations of bile acids were measured four times in a period of five months, and at the second sampling the fasting and two postprandial (after 24 and 48 hours) serum concentrations of total protein, albumin, glucose, uric acid, cholesterol, triglycerides, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and bile acids were determined. Coelioscopy revealed vitellogenic and previtellogenic follicles on the ovaries of all the terrapins, and eggs with calcified shells were detected in two of them. The livers were mostly pink to deep yellow in colour, with sharp edges, a smooth serosal surface, distinct large superficial vessels, and multifocal melanin deposits. Liver biopsies revealed fine, more or less oil red O-positive lipid droplets in all the hepatocytes, but in none of the cases was it considered to be pathological lipidosis. The mean (sd) bile acid concentrations ranged from 7.35 (4.52) to 10.04 (7.40) micromol/l. The fasting and postprandial concentrations were 3.1 (2.3), 4.5 (5.4) (24 hours) and 2.2 (1.5) (48 hours) micromol/l. High concentrations between 27.6 and 66.6 micromol/l were associated with lipaemia. There were no significant differences between the biochemical profiles of the fasting and postprandial serum samples.

  3. Importance of uncharged polar residues and proline in the proximal two-thirds (Pro107–Ser128 of the highly conserved region of mouse ileal Na+-dependent bile acid transporter, Slc10a2, in transport activity and cellular expression

    Directory of Open Access Journals (Sweden)

    Saeki Tohru

    2013-02-01

    Full Text Available Abstract Background SLC10A2-mediated reabsorption of bile acids at the distal end of the ileum is the first step in enterohepatic circulation. Because bile acids act not only as detergents but also as signaling molecules in lipid metabolism and energy production, SLC10A2 is important as the key transporter for understanding the in vivo kinetics of bile acids. SLC10A family members and the homologous genes of various species share a highly conserved region corresponding to Gly104–Pro142 of SLC10A2. The functional importance of this region has not been fully elucidated. Results To elucidate the functional importance of this region, we previously performed mutational analysis of the uncharged polar residues and proline in the distal one-third (Thr130–Pro142 of the highly conserved region in mouse Slc10a2. In this study, proline and uncharged polar residues in the remaining two-thirds of this region in mouse Slc10a2 were subjected to mutational analysis, and taurocholic acid uptake and cell surface localization were examined. Cell surface localization of Slc10a2 is necessary for bile acid absorption. Mutants in which Asp or Leu were substituted for Pro107 (P107N or P107L were abundantly expressed, but their cell surface localization was impaired. The S126A mutant was completely impaired in cellular expression. The T110A and S128A mutants exhibited remarkably enhanced membrane expression. The S112A mutant was properly expressed at the cell surface but transport activity was completely lost. Replacement of Tyr117 with various amino acids resulted in reduced transport activity. The degree of reduction roughly depended on the van der Waals volume of the side chains. Conclusions The functional importance of proline and uncharged polar residues in the highly conserved region of mouse Slc10a2 was determined. This information will contribute to the design of bile acid-conjugated prodrugs for efficient drug delivery or SLC10A2 inhibitors for

  4. Defective canalicular transport and toxicity of dietary ursodeoxycholic acid in the abcb11-/- mouse: transport and gene expression studies.

    Science.gov (United States)

    Wang, Renxue; Liu, Lin; Sheps, Jonathan A; Forrest, Dana; Hofmann, Alan F; Hagey, Lee R; Ling, Victor

    2013-08-15

    The bile salt export pump (BSEP), encoded by the abcb11 gene, is the major canalicular transporter of bile acids from the hepatocyte. BSEP malfunction in humans causes bile acid retention and progressive liver injury, ultimately leading to end-stage liver failure. The natural, hydrophilic, bile acid ursodeoxycholic acid (UDCA) is efficacious in the treatment of cholestatic conditions, such as primary biliary cirrhosis and cholestasis of pregnancy. The beneficial effects of UDCA include promoting bile flow, reducing hepatic inflammation, preventing apoptosis, and maintaining mitochondrial integrity in hepatocytes. However, the role of BSEP in mediating UDCA efficacy is not known. Here, we used abcb11 knockout mice (abcb11-/-) to test the effects of acute and chronic UDCA administration on biliary secretion, bile acid composition, liver histology, and liver gene expression. Acutely infused UDCA, or its taurine conjugate (TUDC), was taken up by the liver but retained, with negligible biliary output, in abcb11-/- mice. Feeding UDCA to abcb11-/- mice led to weight loss, retention of bile acids, elevated liver enzymes, and histological damage to the liver. Semiquantitative RT-PCR showed that genes encoding Mdr1a and Mdr1b (canalicular) as well as Mrp4 (basolateral) transporters were upregulated in abcb11-/- mice. We concluded that infusion of UDCA and TUDC failed to induce bile flow in abcb11-/- mice. UDCA fed to abcb11-/- mice caused liver damage and the appearance of biliary tetra- and penta-hydroxy bile acids. Supplementation with UDCA in the absence of Bsep caused adverse effects in abcb11-/- mice.

  5. Gemfibrozil disrupts lysophosphatidylcholine and bile acid homeostasis via PPARα and its relevance to hepatotoxicity.

    Science.gov (United States)

    Liu, Aiming; Krausz, Kristopher W; Fang, Zhong-Ze; Brocker, Chad; Qu, Aijuan; Gonzalez, Frank J

    2014-04-01

    Gemfibrozil, a ligand of peroxisome proliferator-activated receptor α (PPARα), is one of the most widely prescribed anti-dyslipidemia fibrate drugs. Among the adverse reactions observed with gemfibrozil are alterations in liver function, cholestatic jaundice, and cholelithiasis. However, the mechanisms underlying these toxicities are poorly understood. In this study, wild-type and Ppara-null mice were dosed with a gemfibrozil-containing diet for 14 days. Ultra-performance chromatography electrospray ionization quadrupole time-of-flight mass spectrometry-based metabolomics and traditional approaches were used to assess the mechanism of gemfibrozil-induced hepatotoxicity. Unsupervised multivariate data analysis revealed four lysophosphatidylcholine components in wild-type mice that varied more dramatically than those in Ppara-null mice. Targeted metabolomics revealed taurocholic acid and tauro-α-muricholic acid/tauro-β-muricholic acid were significantly increased in wild-type mice, but not in Ppara-null mice. In addition to the above perturbations in metabolite homeostasis, phenotypic alterations in the liver were identified. Hepatic genes involved in metabolism and transportation of lysophosphatidylcholine and bile acid compounds were differentially regulated between wild-type and Ppara-null mice, in agreement with the observed downstream metabolic alterations. These data suggest that PPARα mediates gemfibrozil-induced hepatotoxicity in part by disrupting phospholipid and bile acid homeostasis.

  6. In Barrett's esophagus patients and Barrett's cell lines, ursodeoxycholic acid increases antioxidant expression and prevents DNA damage by bile acids.

    Science.gov (United States)

    Peng, Sui; Huo, Xiaofang; Rezaei, Davood; Zhang, Qiuyang; Zhang, Xi; Yu, Chunhua; Asanuma, Kiyotaka; Cheng, Edaire; Pham, Thai H; Wang, David H; Chen, Minhu; Souza, Rhonda F; Spechler, Stuart Jon

    2014-07-15

    Hydrophobic bile acids like deoxycholic acid (DCA), which cause oxidative DNA damage and activate NF-κB in Barrett's metaplasia, might contribute to carcinogenesis in Barrett's esophagus. We have explored mechanisms whereby ursodeoxycholic acid (UDCA, a hydrophilic bile acid) protects against DCA-induced injury in vivo in patients and in vitro using nonneoplastic, telomerase-immortalized Barrett's cell lines. We took biopsies of Barrett's esophagus from 21 patients before and after esophageal perfusion with DCA (250 μM) at baseline and after 8 wk of oral UDCA treatment. DNA damage was assessed by phospho-H2AX expression, neutral CometAssay, and phospho-H2AX nuclear foci formation. Quantitative PCR was performed for antioxidants including catalase and GPX1. Nrf2, catalase, and GPX1 were knocked down with siRNAs. Reporter assays were performed using a plasmid construct containing antioxidant responsive element. In patients, baseline esophageal perfusion with DCA significantly increased phospho-H2AX and phospho-p65 in Barrett's metaplasia. Oral UDCA increased GPX1 and catalase levels in Barrett's metaplasia and prevented DCA perfusion from inducing DNA damage and NF-κB activation. In cells, DCA-induced DNA damage and NF-κB activation was prevented by 24-h pretreatment with UDCA, but not by mixing UDCA with DCA. UDCA activated Nrf2 signaling to increase GPX1 and catalase expression, and protective effects of UDCA pretreatment were blocked by siRNA knockdown of these antioxidants. UDCA increases expression of antioxidants that prevent toxic bile acids from causing DNA damage and NF-κB activation in Barrett's metaplasia. Elucidation of this molecular pathway for UDCA protection provides rationale for clinical trials on UDCA for chemoprevention in Barrett's esophagus. Copyright © 2014 the American Physiological Society.

  7. Pluronic®-bile salt mixed micelles.

    Science.gov (United States)

    Patel, Vijay; Ray, Debes; Bahadur, Anita; Ma, Junhe; Aswal, V K; Bahadur, Pratap

    2018-06-01

    The present study was aimed to examine the interaction of two bile salts viz. sodium cholate (NaC) and sodium deoxycholate (NaDC) with three ethylene polyoxide-polypropylene polyoxide (PEO-PPO-PEO) triblock copolymers with similar PPO but varying PEO micelles with a focus on the effect of pH on mixed micelles. Mixed micelles of moderately hydrophobic Pluronic ® P123 were examined in the presence of two bile salts and compared with those from very hydrophobic L121 and very hydrophilic F127. Both the bile salts increase the cloud point (CP) of copolymer solution and decreased apparent micelle hydrodynamic diameter (D h ). SANS study revealed that P123 forms small spherical micelles showing a decrease in size on progressive addition of bile salts. The negatively charged mixed micelles contained fewer P123 molecules but progressively rich in bile salt. NaDC being more hydrophobic displays more pronounced effect than NaC. Interestingly, NaC shows micellar growth in acidic media which has been attributed to the formation of bile acids by protonation of carboxylate ion and subsequent solubilization. In contrast, NaDC showed phase separation at higher concentration. Nuclear Overhauser effect spectroscopy (NOESY) experiments provided information on interaction and location of bile salts in micelles. Results are discussed in terms of hydrophobicity of bile salts and Pluronics ® and the site of bile salt in polymer micelles. Proposed molecular interactions are useful to understand more about bile salts which play important role in physiological processes. Copyright © 2018 Elsevier B.V. All rights reserved.

  8. Nutritional regulation of bile acid metabolism is associated with improved pathological characteristics of the metabolic syndrome

    DEFF Research Database (Denmark)

    Liaset, Bjørn; Hao, Qin; Jørgensen, Henry Johs. Høgh

    2011-01-01

    Bile acids (BAs) are powerful regulators of metabolism, and mice treated orally with cholic acid are protected from diet-induced obesity, hepatic lipid accumulation, and increased plasma triacylglycerol (TAG) and glucose levels. Here, we show that plasma BA concentration in rats was elevated by e...... metabolism can be modulated by diet and that such modulation may prevent/ameliorate the characteristic features of the metabolic syndrome.......Bile acids (BAs) are powerful regulators of metabolism, and mice treated orally with cholic acid are protected from diet-induced obesity, hepatic lipid accumulation, and increased plasma triacylglycerol (TAG) and glucose levels. Here, we show that plasma BA concentration in rats was elevated...... with induction of genes involved in energy metabolism and uncoupling, Dio2, Pgc-1a, and Ucp1, in interscapular brown adipose tissue. Interestingly, the same transcriptional pattern was found in white adipose tissue depots of both abdominal and subcutaneous origin. Accordingly, rats fed SPH-based diet exhibited...

  9. Conjugated Linoleic Acid: good or bad nutrient

    Directory of Open Access Journals (Sweden)

    Gonçalves Daniela C

    2010-10-01

    Full Text Available Abstract Conjugated linoleic acid (CLA is a class of 28 positional and geometric isomers of linoleic acid octadecadienoic.Currently, it has been described many benefits related to the supplementation of CLA in animals and humans, as in the treatment of cancer, oxidative stress, in atherosclerosis, in bone formation and composition in obesity, in diabetes and the immune system. However, our results show that, CLA appears to be not a good supplement in patients with cachexia.

  10. Farnesoid X Receptor Agonist Treatment Alters Bile Acid Metabolism but Exacerbates Liver Damage in a Piglet Model of Short-Bowel Syndrome.

    Science.gov (United States)

    Pereira-Fantini, Prue M; Lapthorne, Susan; Gahan, Cormac G M; Joyce, Susan A; Charles, Jenny; Fuller, Peter J; Bines, Julie E

    2017-07-01

    Options for the prevention of short-bowel syndrome-associated liver disease (SBS-ALDs) are limited and often ineffective. The farnesoid X receptor (FXR) is a newly emerging pharmaceutical target and FXR agonists have been shown to ameliorate cholestasis and metabolic disorders. The aim of this study was to assess the efficacy of obeticholic acid (OCA) treatment in preventing SBS-ALDs. Piglets underwent 75% small-bowel resection (SBS) or sham surgery (sham) and were assigned to either a daily dose of OCA (2.4 mg/kg/day) or were untreated. Clinical measures included weight gain and stool studies. Histologic features were assessed. Ultraperformance liquid chromatography tandem mass spectrometry was used to determine bile acid composition in end point bile and portal serum samples. Gene expression of key FXR targets was assessed in intestinal and hepatic tissues via quantitative polymerase chain reaction. OCA-treated SBS piglets showed decreased stool fat and altered liver histology when compared with nontreated SBS piglets. OCA prevented SBS-associated taurine depletion, however, further analysis of bile and portal serum samples indicated that OCA did not prevent SBS-associated alterations in bile acid composition. The expression of FXR target genes involved in bile acid transport and synthesis increased within the liver of SBS piglets after OCA administration whereas, paradoxically, intestinal expression of FXR target genes were decreased by OCA administration. Administration of OCA in SBS reduced fat malabsorption and altered bile acid composition, but did not prevent the development of SBS-ALDs. We postulate that extensive small resection impacts the ability of the remnant intestine to respond to FXR activation.

  11. Experimental Study of Poly-l-Lactic Acid Biodegradable Stents in Normal Canine Bile Ducts

    International Nuclear Information System (INIS)

    Yamamoto, Kiyosei; Yoshioka, Tetsuya; Furuichi, Kinya; Sakaguchi, Hiroshi; Anai, Hiroshi; Tanaka, Toshihiro; Morimoto, Kengo; Uchida, Hideo; Kichikawa, Kimihiko

    2011-01-01

    Purpose: This study was designed to clarify the advantages of biodegradable stents in terms of mucosal reaction and biodegradation after placement. We designed a biodegradable stent and assessed stent degradation and changes in the normal bile ducts of dogs. Methods: The biodegradable stent is a balloon-expandable Z stent consisting of poly-l-lactic acid (PLLA) with a diameter of 6 mm and a length of 15 mm. We assessed four groups of three beagle dogs each at 1, 3, 6, and 9 months of follow-up. After evaluating stent migration by radiography and stent and bile duct patency by cholangiography, the dogs were sacrificed to remove the bile duct together with the stent. The bile duct lumen was examined macroscopically and histologically, and the stent degradation was examined macroscopically and by scanning electron microscopy (SEM). Results: Bile duct obstruction was absent and none of the stents migrated. Macroscopic evaluation showed moderate endothelial proliferation in the bile ducts at the implant sites at 3 and 6 months and a slight change at 9 months. Slight mononuclear cell infiltration was histologically identified at all time points and epithelial hyperplasia that was moderate at 3 months was reduced to slight at 6 and 9 months. Stent degradation was macroscopically evident in all animals at 9 months and was proven by SEM in two dogs at 6 months and in all of them at 9 months. Conclusions: Our results suggest that PLLA bioabsorbable stents seems to be useful for implantation in the biliary system with further investigation.

  12. Calcium in milk products precipitates intestinal fatty acids and secondary bile acids and thus inhibits colonic cytotoxicity in humans

    NARCIS (Netherlands)

    Govers, MJAP; Termont, DSML; Lapre, JA; Kleibeuker, JH; Vonk, RJ; VanderMeer, R

    1996-01-01

    Dietary calcium may reduce the risk of colon cancer, probably by precipitating cytotoxic surfactants, such as secondary bile acids, in the colonic lumen. We previously showed that milk mineral, an important source of calcium, decreases metabolic risk factors and colonic proliferation in rats, We non

  13. Comparative evaluation of intragastric bile acids and hepatobiliary scintigraphy in the diagnosis of duodenogastric reflux.

    Science.gov (United States)

    Chen, Teng-Fei; Yadav, Praveen K; Wu, Rui-Jin; Yu, Wei-Hua; Liu, Chang-Qin; Lin, Hui; Liu, Zhan-Ju

    2013-01-01

    To assess the diagnostic value of a combination of intragastric bile acids and hepatobiliary scintigraphy in the detection of duodenogastric reflux (DGR). The study contained 99 patients with DGR and 70 healthy volunteers who made up the control group. The diagnosis was based on the combination of several objective arguments: a long history of gastric symptoms (i.e., nausea, epigastric pain, and/or bilious vomiting) poorly responsive to medical treatment, gastroesophageal reflux symptoms unresponsive to proton-pump inhibitors, gastritis on upper gastrointestinal (GI) endoscopy and/or at histology, presence of a bilious gastric lake at > 1 upper GI endoscopy, pathologic 24-h intragastric bile monitoring with the Bilitec device. Gastric juice was aspirated in the GI endoscopy and total bile acid (TBA), total bilirubin (TBIL) and direct bilirubin (DBIL) were tested in the clinical laboratory. Continuous data of gastric juice were compared between each group using the independent-samples Mann-Whitney U-test and their relationship was analysed by Spearman's rank correlation test and Fisher's linear discriminant analysis. Histopathology of DGR patients and 23 patients with chronic atrophic gastritis was compared by clinical pathologists. Using the Independent-samples Mann-Whitney U-test, DGR index (DGRi) was calculated in 28 patients of DGR group and 19 persons of control group who were subjected to hepatobiliary scintigraphy. Receiver operating characteristic curve was made to determine the sensitivity and specificity of these two methods in the diagnosis of DGR. The group of patients with DGR showed a statistically higher prevalence of epigastric pain in comparison with control group. There was no significant difference between the histology of gastric mucosa with atrophic gastritis and duodenogastric reflux. The bile acid levels of DGR patients were significantly higher than the control values (Z: TBA: -8.916, DBIL: -3.914, TBIL: -6.197, all P Reflux: Y = 0.012TBA + 0

  14. Effect of bile acid sequestrants on glycaemic control

    DEFF Research Database (Denmark)

    Hansen, Morten; Sonne, David Peick; Mikkelsen, Kristian Hallundbæk

    2012-01-01

    of hypercholesterolaemia: colestipol, cholestyramine and colesevelam. The BAS colestimide/colestilan is used in Japan. Colesevelam was recently approved by the FDA for the treatment of T2DM. We plan to provide a systematic review with meta-analysis of the glucose-lowering effect of BASs with the aim to evaluate......In addition to the lipid-lowering effect of bile acid sequestrants (BASs), they also lower blood glucose and, therefore, could be beneficial in the treatment of patients with type 2 diabetes mellitus (T2DM). Three oral BASs are approved by the US Food and Drug Administration (FDA) for the treatment...... their potential as glucose-lowering agents in patients with T2DM....

  15. In vitro lipid peroxidation of intestinal bile salt-based nanoemulsions

    DEFF Research Database (Denmark)

    Courraud, J; Charnay, C; Cristol, J P

    2013-01-01

    . Several nanoemulsions were compared in terms of physical characteristics and reactivity to 2,2'-azobis-(2-amidinopropane) hydrochloride (AAPH)-induced oxidation. Formulations included different types of lipids, a detergent (a conjugated bile salt or sodium dodecyl sulfate) and, finally, lipophilic...

  16. Hepatic handling of a synthetic gamma-labeled bile acid (75SeHCAT)

    International Nuclear Information System (INIS)

    Galatola, G.; Jazrawi, R.P.; Bridges, C.; Joseph, A.E.; Northfield, T.C.

    1988-01-01

    75 Se-homocholic acid-taurine ( 75 SeHCAT) is the first available gamma-labeled bile acid, and should therefore be handled more efficiently and specifically by the liver than previous hepatoscintigraphic agents. We have measured serum and hepatic kinetics for 75 SeHCAT, and compared them with those for the conventional hepatobiliary scintigraphic agent 99mTc-hepatoiminodiacetic acid, and with serum kinetics for the corresponding natural bile acid, [ 14 C]cholic acid-taurine. We used a dynamic scintigraphic technique and serial blood sampling in 8 subjects. Initial hepatic uptake rate was identical to initial serum disappearance rate (14% dose/min) for 75 SeHCAT, but significantly lower for 99mTc-hepatoiminodiacetic acid (6% vs. 14% dose/min, p less than 0.001). Hepatic transit time was shorter for 75 SeHCAT (13 min vs. 22 min, p less than 0.02), net hepatic excretory rate was more rapid (1.4% vs. 0.8% dose/min, p less than 0.001), and urinary excretion was lower (1.0% vs. 9.0% dose, p less than 0.001). Initial and late-plasma disappearance rates were significantly lower for 75 SeHCAT (14.3% and 1.5% dose/min) than for [ 14 C]cholic acid-taurine (21.3% and 2.8% dose/min, respectively), and plasma clearance was also lower (2 75 vs. 670 ml/min). In vitro, 75 SeHCAT was bound to serum proteins more completely than [ 14 C]cholic acid-taurine (90.4% vs. 86.5%, p less than 0.005). We conclude that 75 SeHCAT provides a hepatoscintigraphic agent that is handled more efficiently and specifically by the liver than the conventionally used agent 99mTc-hepatoiminodiacetic acid. It is not cleared from the serum as rapidly as [ 14 C]cholic acid-taurine, probably due to its stronger protein binding. The clinical value of 75 SeHCAT in assessing liver disease should be investigated

  17. Structure based classification for bile salt export pump (BSEP) inhibitors using comparative structural modeling of human BSEP

    Science.gov (United States)

    Jain, Sankalp; Grandits, Melanie; Richter, Lars; Ecker, Gerhard F.

    2017-06-01

    The bile salt export pump (BSEP) actively transports conjugated monovalent bile acids from the hepatocytes into the bile. This facilitates the formation of micelles and promotes digestion and absorption of dietary fat. Inhibition of BSEP leads to decreased bile flow and accumulation of cytotoxic bile salts in the liver. A number of compounds have been identified to interact with BSEP, which results in drug-induced cholestasis or liver injury. Therefore, in silico approaches for flagging compounds as potential BSEP inhibitors would be of high value in the early stage of the drug discovery pipeline. Up to now, due to the lack of a high-resolution X-ray structure of BSEP, in silico based identification of BSEP inhibitors focused on ligand-based approaches. In this study, we provide a homology model for BSEP, developed using the corrected mouse P-glycoprotein structure (PDB ID: 4M1M). Subsequently, the model was used for docking-based classification of a set of 1212 compounds (405 BSEP inhibitors, 807 non-inhibitors). Using the scoring function ChemScore, a prediction accuracy of 81% on the training set and 73% on two external test sets could be obtained. In addition, the applicability domain of the models was assessed based on Euclidean distance. Further, analysis of the protein-ligand interaction fingerprints revealed certain functional group-amino acid residue interactions that could play a key role for ligand binding. Though ligand-based models, due to their high speed and accuracy, remain the method of choice for classification of BSEP inhibitors, structure-assisted docking models demonstrate reasonably good prediction accuracies while additionally providing information about putative protein-ligand interactions.

  18. Activation of Constitutive Androstane Receptor (CAR) in Mice Results in Maintained Biliary Excretion of Bile Acids Despite a Marked Decrease of Bile Acids in Liver.

    Science.gov (United States)

    Lickteig, Andrew J; Csanaky, Iván L; Pratt-Hyatt, Matthew; Klaassen, Curtis D

    2016-06-01

    Activation of Constitutive Androstane Receptor (CAR) protects against bile acid (BA)-induced liver injury. This study was performed to determine the effect of CAR activation on bile flow, BA profile, as well as expression of BA synthesis and transport genes. Synthetic CAR ligand 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) was administered to mice for 4 days. BAs were quantified by UPLC-MS/MS (ultraperformance liquid chromatography-tandem mass spectrometry). CAR activation decreases total BAs in livers of male (49%) and female mice (26%), largely attributable to decreases of the 12α-hydroxylated BA taurocholic acid (T-CA) (males (M) 65%, females (F) 45%). Bile flow in both sexes was increased by CAR activation, and the increases were BA-independent. CAR activation did not alter biliary excretion of total BAs, but overall BA composition changed. Excretion of muricholic (6-hydroxylated) BAs was increased in males (101%), and the 12α-OH proportion of biliary BAs was decreased in both males (37%) and females (28%). The decrease of T-CA in livers of males and females correlates with the decreased mRNA of the sterol 12α-hydroxylase Cyp8b1 in males (71%) and females (54%). As a response to restore BAs to physiologic concentrations in liver, mRNA of Cyp7a1 is upregulated following TCPOBOP (males 185%, females 132%). In ilea, mRNA of the negative feedback regulator Fgf15 was unaltered by CAR activation, indicating biliary BA excretion was sufficient to maintain concentrations of total BAs in the small intestine. In summary, the effects of CAR activation on BAs in male and female mice are quite similar, with a marked decrease in the major BA T-CA in the liver. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  19. Bile acid receptor TGR5 overexpression is associated with decreased intestinal mucosal injury and epithelial cell proliferation in obstructive jaundice.

    Science.gov (United States)

    Ji, Chen-Guang; Xie, Xiao-Li; Yin, Jie; Qi, Wei; Chen, Lei; Bai, Yun; Wang, Na; Zhao, Dong-Qiang; Jiang, Xiao-Yu; Jiang, Hui-Qing

    2017-04-01

    Bile acids stimulate intestinal epithelial proliferation in vitro. We sought to investigate the role of the bile acid receptor TGR5 in the protection of intestinal epithelial proliferation in obstructive jaundice. Intestinal tissues and serum samples were obtained from patients with malignant obstructive jaundice and from bile duct ligation (BDL) rats. Intestinal permeability and morphological changes in the intestinal mucosa were observed. The functions of TGR5 in cell proliferation in intestinal epithelial injury were determined by overexpression or knockdown studies in Caco-2 and FHs 74 Int cells pretreated with lipopolysaccharide (LPS). Internal biliary drainage was superior to external biliary drainage in recovering intestinal permeability and mucosal histology in patients with obstructive jaundice. In BDL rats, feeding of chenodeoxycholic acid (CDCA) decreased intestinal mucosa injury. The levels of PCNA, a marker of proliferation, increased in response to CDCA feeding and were paralleled by elevated TGR5 expression. CDCA upregulated TGR5 expression and promoted proliferation in Caco-2 and FHs 74 Int cells pretreated with LPS. Overexpression of TGR5 resulted in increased PCNA, cell viability, EdU incorporation, and the proportion of cells in S phase, whereas knockdown of TGR5 had the opposite effect. Our data indicate that bile acids promote intestinal epithelial cell proliferation and decrease mucosal injury by upregulating TGR5 expression in obstructive jaundice. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Conjugated Fatty Acid Synthesis

    Science.gov (United States)

    Rawat, Richa; Yu, Xiao-Hong; Sweet, Marie; Shanklin, John

    2012-01-01

    Conjugated linolenic acids (CLNs), 18:3 Δ9,11,13, lack the methylene groups found between the double bonds of linolenic acid (18:3 Δ9,12,15). CLNs are produced by conjugase enzymes that are homologs of the oleate desaturases FAD2. The goal of this study was to map the domain(s) within the Momordica charantia conjugase (FADX) responsible for CLN formation. To achieve this, a series of Momordica FADX-Arabidopsis FAD2 chimeras were expressed in the Arabidopsis fad3fae1 mutant, and the transformed seeds were analyzed for the accumulation of CLN. These experiments identified helix 2 and the first histidine box as a determinant of conjugase product partitioning into punicic acid (18:3 Δ9cis,11trans,13cis) or α-eleostearic acid (18:3 Δ9cis,11trans,13trans). This was confirmed by analysis of a FADX mutant containing six substitutions in which the sequence of helix 2 and first histidine box was converted to that of FAD2. Each of the six FAD2 substitutions was individually converted back to the FADX equivalent identifying residues 111 and 115, adjacent to the first histidine box, as key determinants of conjugase product partitioning. Additionally, expression of FADX G111V and FADX G111V/D115E resulted in an approximate doubling of eleostearic acid accumulation to 20.4% and 21.2%, respectively, compared with 9.9% upon expression of the native Momordica FADX. Like the Momordica conjugase, FADX G111V and FADX D115E produced predominantly α-eleostearic acid and little punicic acid, but the FADX G111V/D115E double mutant produced approximately equal amounts of α-eleostearic acid and its isomer, punicic acid, implicating an interactive effect of residues 111 and 115 in punicic acid formation. PMID:22451660

  1. Voluntary wheel running increases bile acid as well as cholesterol excretion and decreases atherosclerosis in hypercholesterolemic mice.

    Science.gov (United States)

    Meissner, Maxi; Lombardo, Elisa; Havinga, Rick; Tietge, Uwe J F; Kuipers, Folkert; Groen, Albert K

    2011-10-01

    Regular physical activity decreases the risk for atherosclerosis but underlying mechanisms are not fully understood. We questioned whether voluntary wheel running provokes specific modulations in cholesterol turnover that translate into a decreased atherosclerotic burden in hypercholesterolemic mice. Male LDLR-deficient mice (8 weeks old) had either access to a voluntary running wheel for 12 weeks (RUN) or remained sedentary (CONTROL). Both groups were fed a western-type/high cholesterol diet. Running activity and food intake were recorded. At 12 weeks of intervention, feces, bile and plasma were collected to determine fecal, biliary and plasma parameters of cholesterol metabolism and plasma cytokines. Atherosclerotic lesion size was determined in the aortic root. RUN weighed less (∼13%) while food consumption was increased by 17% (p=0.004). Plasma cholesterol levels were decreased by 12% (p=0.035) and plasma levels of pro-atherogenic lipoproteins decreased in RUN compared to control. Running modulated cholesterol catabolism by enhancing cholesterol turnover: RUN displayed an increased biliary bile acid secretion (68%, p=0.007) and increased fecal bile acid (93%, p=0.009) and neutral sterol (33%, p=0.002) outputs compared to control indicating that reverse cholesterol transport was increased in RUN. Importantly, aortic lesion size was decreased by ∼33% in RUN (p=0.033). Voluntary wheel running reduces atherosclerotic burden in hypercholesterolemic mice. An increased cholesterol turnover, specifically its conversion into bile acids, may underlie the beneficial effect of voluntary exercise in mice. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  2. Imaging and retention measurements of selenium 75 homocholic acid conjugated with taurine, and the carbon 14 glycochol breath test to document ileal dysfunction due to late radiation damage

    International Nuclear Information System (INIS)

    Valdes Olmos, R.; Hartog Jager, F. den; Hoefnagel, C.; Taal, B.; Netherlands Cancer Inst., Amsterdam

    1991-01-01

    In order to assess ileal dysfunction in patients with complaints after pelvic radiation therapy, retention measurements and scintigraphic imaging with selenium 75 homocholic acid conjugated with taurine ( 75 Se-HCAT), combined with the carbon 14 clycochol breath test, were evaluated in 39 patients. In 22 patients without ileal resection the results of the 75 Se-HCAT test and the breath test differentiated between a normal functioning ileum (both tests negative) and ileal dysfunction as a cause of complaints (one or both tests positive). Among the patients with ileal dysfunction, the combination of both tests permitted those with bacterial overgrowth (breath test positive, 75 Se-HCAT negative) to be separated from patients with evidence of bile acid malabsorption ( 75 Se-HCAT positive, breath test positive or negative). In 17 patients with small-bowel resection, the 75 Se-HCAT test helped to estimate the severity of bile acid malabsorption with implications for therapy. In this group the breath test was false-negative in 7 cases with abnormal 75 Se-HCAT. Additional systematically performed scintigraphic imaging improved the accuracy of the 75 Se-HCAT test, revealing cases with prolonged colonic accumulation of the radiopharmaceutical, causing spurious retention values. In conclusion, assessment of ileal dysfunction by nuclear medicine techniques in post-irradiation conditions provides information about the aetiology and therefore the possibility of adjustment in the clinical management. (orig.)

  3. Complex interaction between circadian rhythm and diet on bile acid homeostasis in male rats

    NARCIS (Netherlands)

    Eggink, Hannah M; Oosterman, Johanneke E; de Goede, Paul; de Vries, Emmely M; Foppen, Ewout; Koehorst, Martijn; Groen, Albert K; Boelen, Anita; Romijn, Johannes A; la Fleur, Susanne E; Soeters, Maarten R; Kalsbeek, A.

    2017-01-01

    Desynchronization between the master clock in the brain, which is entrained by (day) light, and peripheral organ clocks, which are mainly entrained by food intake, may have negative effects on energy metabolism. Bile acid metabolism follows a clear day/night rhythm. We investigated whether in rats

  4. Feeding of the water extract from Ganoderma lingzhi to rats modulates secondary bile acids, intestinal microflora, mucins, and propionate important to colon cancer.

    Science.gov (United States)

    Yang, Yongshou; Nirmagustina, Dwi Eva; Kumrungsee, Thanutchaporn; Okazaki, Yukako; Tomotake, Hiroyuki; Kato, Norihisa

    2017-09-01

    Consumption of reishi mushroom has been reported to prevent colon carcinogenesis in rodents, although the underlying mechanisms remain unclear. To investigate this effect, rats were fed a high-fat diet supplemented with 5% water extract from either the reishi mushroom (Ganoderma lingzhi) (WGL) or the auto-digested reishi G. lingzhi (AWGL) for three weeks. Both extracts markedly reduced fecal secondary bile acids, such as lithocholic acid and deoxycholic acid (colon carcinogens). These extracts reduced the numbers of Clostridium coccoides and Clostridium leptum (secondary bile acids-producing bacteria) in a per g of cecal digesta. Fecal mucins and cecal propionate were significantly elevated by both extracts, and fecal IgA was significantly elevated by WGL, but not by AWGL. These results suggest that the reishi extracts have an impact on colon luminal health by modulating secondary bile acids, microflora, mucins, and propionate that related to colon cancer.

  5. Kinetic studies of the inhibition of a human liver 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase isozyme by bile acids and anti-inflammatory drugs.

    Science.gov (United States)

    Miyabe, Y; Amano, T; Deyashiki, Y; Hara, A; Tsukada, F

    1995-01-01

    We have investigated the steady-state kinetics for a cytosolic 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase isozyme of human liver and its inhibition by several bile acids and anti-inflammatory drugs such as indomethacin, flufemanic acid and naproxen. Initial velocity and product inhibition studies performed in the NADP(+)-linked (S)-1-indanol oxidation at pH 7.4 were consistent with a sequential ordered mechanism in which NADP+ binds first and leaves last. The bile acids and drugs, competitive inhibitors with respect to the alcohol substrate, exhibited uncompetitive inhibition with respect to the coenzyme, with Ki values less than 1 microM, whereas indomethacin exhibited noncompetitive inhibition (Ki < 24 microM). The kinetics of the inhibition by a mixture of the two inhibitors suggests that bile acids and drugs, except indomethacin, bind to overlapping sites at the active center of the enzyme-coenzyme binary complex.

  6. History of Hepatic Bile Formation: Old Problems, New Approaches

    Science.gov (United States)

    Javitt, Norman B.

    2014-01-01

    Studies of hepatic bile formation reported in 1958 established that it was an osmotically generated water flow. Intravenous infusion of sodium taurocholate established a high correlation between hepatic bile flow and bile acid excretion. Secretin, a hormone that stimulates bicarbonate secretion, was also found to increase hepatic bile flow. The…

  7. Farnesoid X receptor induces Takeda G-protein receptor 5 cross-talk to regulate bile acid synthesis and hepatic metabolism.

    Science.gov (United States)

    Pathak, Preeti; Liu, Hailiang; Boehme, Shannon; Xie, Cen; Krausz, Kristopher W; Gonzalez, Frank; Chiang, John Y L

    2017-06-30

    The bile acid-activated receptors, nuclear farnesoid X receptor (FXR) and the membrane Takeda G-protein receptor 5 (TGR5), are known to improve glucose and insulin sensitivity in obese and diabetic mice. However, the metabolic roles of these two receptors and the underlying mechanisms are incompletely understood. Here, we studied the effects of the dual FXR and TGR5 agonist INT-767 on hepatic bile acid synthesis and intestinal secretion of glucagon-like peptide-1 (GLP-1) in wild-type, Fxr -/- , and Tgr5 -/- mice. INT-767 efficaciously stimulated intracellular Ca 2+ levels, cAMP activity, and GLP-1 secretion and improved glucose and lipid metabolism more than did the FXR-selective obeticholic acid and TGR5-selective INT-777 agonists. Interestingly, INT-767 reduced expression of the genes in the classic bile acid synthesis pathway but induced those in the alternative pathway, which is consistent with decreased taurocholic acid and increased tauromuricholic acids in bile. Furthermore, FXR activation induced expression of FXR target genes, including fibroblast growth factor 15, and unexpectedly Tgr5 and prohormone convertase 1/3 gene expression in the ileum. We identified an FXR-responsive element on the Tgr5 gene promoter. Fxr -/- and Tgr5 -/- mice exhibited reduced GLP-1 secretion, which was stimulated by INT-767 in the Tgr5 -/- mice but not in the Fxr -/- mice. Our findings uncovered a novel mechanism in which INT-767 activation of FXR induces Tgr5 gene expression and increases Ca 2+ levels and cAMP activity to stimulate GLP-1 secretion and improve hepatic glucose and lipid metabolism in high-fat diet-induced obese mice. Activation of both FXR and TGR5 may therefore represent an effective therapy for managing hepatic steatosis, obesity, and diabetes. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  8. Supra-molecular Association and Polymorphic Behaviour In Systems Containing Bile Acid Salts

    Directory of Open Access Journals (Sweden)

    Camillo La Mesa

    2007-08-01

    Full Text Available A wide number of supra-molecular association modes are observed in mixtures containing water and bile salts, BS, (with, eventually, other components. Molecular or micellar solutions transform into hydrated solids, fibres, lyotropic liquid crystals and/or gels by raising the concentration, the temperature, adding electrolytes, surfactants, lipids and proteins. Amorphous or ordered phases may be formed accordingly. The forces responsible for this very rich polymorphism presumably arise from the unusual combination of electrostatic, hydrophobic and hydrogen-bond contributions to the system stability, with subsequent control of the supra-molecular organisation modes. The stabilising effect due to hydrogen bonds does not occur in almost all surfactants or lipids and is peculiar to bile acids and salts. Some supra-molecular organisation modes, supposed to be related to malfunctions and dis-metabolic diseases in vivo, are briefly reported and discussed.

  9. Bile acids are important direct and indirect regulators of the secretion of appetite- and metabolism-regulating hormones from the gut and pancreas

    DEFF Research Database (Denmark)

    Kuhre, Rune Ehrenreich; Albrechtsen, Nicolai Jacob Wewer; Larsen, Olav

    2018-01-01

    OBJECTIVE: Bile acids (BAs) facilitate fat absorption and may play a role in glucose and metabolism regulation, stimulating the secretion of gut hormones. The relative importance and mechanisms involved in BA-stimulated secretion of appetite and metabolism regulating hormones from the gut...... and pancreas is not well described and was the purpose of this study. METHODS: The effects of bile acids on the secretion of gut and pancreatic hormones was studied in rats and compared to the most well described nutritional secretagogue: glucose. The molecular mechanisms that underlie the secretion...... was studied by isolated perfused rat and mouse small intestine and pancreas preparations and supported by immunohistochemistry, expression analysis, and pharmacological studies. RESULTS: Bile acids robustly stimulate secretion of not only the incretin hormones, glucose-dependent insulinotropic peptide (GIP...

  10. Effect of dietary conjugated linoleic acid (CLA) on the growth and ...

    African Journals Online (AJOL)

    p4208528

    Keywords: Conjugated linoleic acid, geese, growth, lipid metabolism, fatty acid composition .... For determination of serum total cholesterol (TC), LDL-C, high density ... separated and quantified by gas–liquid chromatography (Carlo Erba Vega ...

  11. Ursodeoxycholic acid alleviates cholestasis-induced histophysiological alterations in the male reproductive system of bile duct-ligated rats.

    Science.gov (United States)

    Saad, Ramadan A; Mahmoud, Yomna I

    2014-12-01

    Ursodeoxycholic acid is the most widely used drug for treating cholestatic liver diseases. However, its effect on the male reproductive system alterations associated with cholestasis has never been studied. Thus, this study aimed to investigate the effect of ursodeoxycholic acid on cholestasis-induced alterations in the male reproductive system. Cholestasis was induced by bile duct ligation. Bile duct-ligated rats had higher cholestasis biomarkers and lower levels of testosterone, LH and FSH than did the Sham rats. They also had lower reproductive organs weights, and lower sperm motility, density and normal morphology than those of Sham rats. Histologically, these animals suffered from testicular tubular atrophy, interstitial edema, thickening of basement membranes, vacuolation, and depletion of germ cells. After ursodeoxycholic acid administration, cholestasis-induced structural and functional alterations were significantly ameliorated. In conclusion, ursodeoxycholic acid can ameliorate the reproductive complications of chronic cholestasis in male patients, which represents an additional benefit to this drug. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Expression of the bile acid receptor FXR in Barrett's esophagus and enhancement of apoptosis by guggulsterone in vitro

    Directory of Open Access Journals (Sweden)

    Frossard Jean-Louis

    2006-10-01

    Full Text Available Abstract Background Barrett's esophagus, a risk factor for esophageal adenocarcinoma, is associated with reflux disease. The aim of this study was to assess the expression of bile acid receptors in the esophagus (normal, esophagitis, Barrett's esophagus and adenocarcinoma and to investigate their possible function. Results the expression of the bile acid receptors FXR and VDR in esophageal biopsies from patients with a normal mucosa, esophagitis, Barrett's esophagus or adenocarcinoma (n = 6 per group and in cell lines derived from Barrett's esophagus and esophageal adenocarcinoma, was assessed by real time Q-PCR and immunohistochemistry. The effect of guggulsterone, an antagonist of bile acid receptors, on apoptosis of Barrett's esophagus-derived cells was assessed morphologically, by flow cytometry and by measuring caspase 3 activity. The expression of FXR was increased in esophagitis, Barrett's esophagus and adenocarcinoma compared to normal mucosa by a mean of 44, 84 and 16, respectively. Immunohistochemistry showed a weak expression in normal esophagus, a strong focal reactivity in Barrett's esophagus, and was negative in adenocarcinoma. VDR expression did not significantly differ between groups. In cell cultures, the expression of FXR was high in Barrett's esophagus-derived cells and almost undetectable in adenocarcinoma-derived cells, whereas VDR expression in these cell lines was not significantly different. In vitro treatment with guggulsterone was associated with a significant increase in the percentage of apoptotic cells and of the caspase 3 activity. Conclusion the bile acid receptor FXR is significantly overexpressed in Barrett's esophagus compared to normal mucosa, esophagitis and esophageal adenocarcinoma. The induction of apoptosis by guggulsterone in a Barrett's esophagus-derived cell line suggests that FXR may contribute to the regulation of apoptosis.

  13. Retention data of bile acids and their oxo derivatives in characterization of pharmacokinetic properties and in silico ADME modeling.

    Science.gov (United States)

    Trifunović, Jovana; Borčić, Vladan; Vukmirović, Saša; Kon, Svetlana Goločorbin; Mikov, Momir

    2016-09-20

    Information on ADME properties of examined bile acids and their oxo derivatives are scarce, although the interest for bile acids and their use in nanochemistry and macromolecular chemistry is increasing. The purpose of this research was to evaluate the lipophilicity, a crucial physicochemical parameter for describing ADME properties of selected bile acids and their oxo derivatives, and to compare two approaches: experimentally determined hydrophobicity parameters and calculated logP values. Commercially available bile acids - deoxycholic, chenodeoxycholic, hyodeoxycholic and ursodeoxycholic acid were used to synthesize oxo derivatives. Lipophilicity was evaluated in two solvent systems: toluene/ethanol and toluene/butanol. Retention parameters were acquired by normal-phase TLC. The correlations between calculated logP values obtained using five different software and experimentally determined hydrophobicity parameters (RM(0)(tol/eth), RM(0)(tol/but), b(tol/eth) and b(tol/but)) were examined. Correlation analysis confirmed significant dependence between experimental RM(0) values and software calculated parameters. Results suggest satisfactory intestinal absorption after oral administration for all of the examined compounds as well as low volumes of distribution, and high affinity for binding with plasma proteins. Penetration through blood-brain barrier and skin is not satisfactory. All of the examined compounds show high affinity for binding with G-protein coupled receptors and consequently inhibition of ionic channels. Results also suggest possible binding with nuclear receptors. Established lipophilicity testing model of studied compounds showed excellent predictive ability and might represent significant tool in development of relations between chromatographic behavior and ADME properties. Compounds 3α-hydroxy-7,12-dioxo-5β-cholanoic and 12α-hydroxy-3,7-dioxo-5β-cholanoic acid might be the most suitable candidates for further development studies (satisfactory

  14. Bile Acids in the Treatment of Cardiometabolic Diseases.

    Science.gov (United States)

    Vítek, Libor

    2017-11-01

    Bile acids (BA), for decades considered only to have fat-emulsifying functions in the gut lumen, have recently emerged as novel cardio-metabolic modulators. They have real endocrine effects, acting via multiple intracellular receptors in various organs and tissues. BA affect energy homeostasis through the modulation of glucose and lipid metabolism, predominantly by activating the nuclear farnesoid X receptor (FXR), as well as the cytoplasmic membrane G protein-coupled BA receptor TGR5 in a variety of tissues; although numerous other intracellular targets of BA are also in play.The roles of BA in the pathogenesis of diabetes, obesity, metabolic syndrome, and cardiovascular diseases are seriously being considered, and BA and their derivatives seem to represent novel potential therapeutics to treat these diseases of civilization.

  15. Two Major Bile Acids in the Hornbills, (24R,25S)-3α,7α,24-Trihydroxy-5β-cholestan-27-oyl Taurine and Its 12α-Hydroxy Derivative.

    Science.gov (United States)

    Satoh, Rika; Ogata, Hiroaki; Saito, Tetsuya; Zhou, Biao; Omura, Kaoru; Kurabuchi, Satoshi; Mitamura, Kuniko; Ikegawa, Shigeo; Hagey, Lee R; Hofmann, Alan F; Iida, Takashi

    2016-06-01

    Two major bile acids were isolated from the gallbladder bile of two hornbill species from the Bucerotidae family of the avian order Bucerotiformes Buceros bicornis (great hornbill) and Penelopides panini (Visayan tarictic hornbill). Their structures were determined to be 3α,7α,24-dihydroxy-5β-cholestan-27-oic acid and its 12α-hydroxy derivative, 3α,7α,12α,24-tetrahydroxy-5β-cholestan-27-oic acid (varanic acid, VA), both present in bile as their corresponding taurine amidates. The four diastereomers of varanic acid were synthesized and their assigned structures were confirmed by X-ray crystallographic analysis. VA and its 12-deoxy derivative were found to have a (24R,25S)-configuration. 13 additional hornbill species were also analyzed by HPLC and showed similar bile acid patterns to B. bicornis and P. panini. The previous stereochemical assignment for (24R,25S)-VA isolated from the bile of varanid lizards and the Gila monster should now be revised to the (24S,25S)-configuration.

  16. Human bile sorption by cancrinite-type zeolites

    International Nuclear Information System (INIS)

    Linares, Carlos F.; Colmenares, Maryi; Ocanto, Freddy; Valbuena, Oscar

    2009-01-01

    A nitrated cancrinite-type zeolite was synthesized from zeolite X, NaOH and NaNO 3 solutions under autogeneous pressure at 80 deg. C for 48 h. This zeolite was characterized by X-ray diffraction (XRD), FT-IR-spectroscopy, scanning electron microscopy (SEM) and BET surface area. XRD, SEM and FT-IR confirmed the presence of nitrated cancrinite-type zeolite without other collateral phases as sodalite. Then, this sodium zeolite was exchanged with potassium and calcium cations and finally, these modified zeolites were reacted with biliar solutions from human gallbladder. Several factors such as: mass of used cancrinite, nature of the exchanged cation and reaction time of the cancrinite-bile solution interactions were studied. The composition of bile solutions (bile acids, phospholipids and bilirubin) was analyzed before and after the cancrinite-bile solution reaction. Results showed that the components of the bile were notably reduced after the contact with solids. Ca-cancrinite, 120 min of reaction time and 500 mg of solids were the best conditions determined for the bile acid reduction in human bile. When the modified zeolites were compared with the commercial cholestyramine, it was found that zeolites were more active than the latter. These zeolites may be an alternative choice to diminish cholesterol levels in hypercholesterolemic patients

  17. Decreased hepatotoxic bile acid composition and altered synthesis in progressive human nonalcoholic fatty liver disease

    Czech Academy of Sciences Publication Activity Database

    Lake, A.D.; Novák, Petr; Shipkova, P.; Aranibar, N.; Robertson, D.; Reily, M.D.; Lu, Z.; Lehman-McKeeman, L.D.; Cherrington, N.J.

    2013-01-01

    Roč. 268, č. 2 (2013), s. 132-140 ISSN 0041-008X Institutional research plan: CEZ:AV0Z50510513 Institutional support: RVO:60077344 Keywords : Bile Acids * Liver * Metabolomics Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.630, year: 2013

  18. Bile acids induce hepatic stellate cell proliferation via activation of the epidermal growth factor receptor

    NARCIS (Netherlands)

    Svegliati-Baroni, Gianluca; Ridolfi, Francesco; Hannivoort, Rebekka; Saccomanno, Stefania; Homan, Manon; de Minicis, Samuele; Jansen, Peter L. M.; Candelaresi, Cinzia; Benedetti, Antonio; Moshage, Han

    2005-01-01

    BACKGROUND & AIMS: Hepatic stellate cell (HSC) proliferation is a key event in the development of liver fibrosis. In many liver diseases, HSCs are exposed to inflammatory cytokines, reactive oxygen species, and bile acids. Although inflammatory cytokines and reactive oxygen species are known to

  19. Mefenamic acid conjugates based on a hydrophilic biopolymer hydroxypropylcellulose: novel prodrug design, characterization and thermal analysis

    International Nuclear Information System (INIS)

    Hussain, M.A.; Kausar, R.; Amin, M.

    2015-01-01

    Macromolecular prodrugs (MPDs) of mefenamic acid were designed onto a cellulose ether derivative hydroxypropylcellulose (HPC) as ester conjugates. Fabrication of HPC-mefenamic acid conjugates was achieved by using p-toluenesulfonyl chloride as carboxylic acid (a functional group in drug) activator at 80 degree C for 24 h under nitrogen atmosphere. Reaction was preceded under homogeneous reaction conditions as HPC was dissolved before use in DMAc solvent. Imidazole was used as a base. Easy workup reactions resulted in good yields (55-65%) and degree of substitution (DS) of drug (0.37-0.99) onto HPC. The DS was calculated by acid-base titration after saponification and UV/Vis spectrophotometry after hydrolysis. DS by both of the methods was found in good agreement with each other. Aqueous and organic soluble novel prodrugs of mefenamic acid were purified and characterized by different spectroscopic and thermal analysis techniques. The initial, maximum and final degradation temperatures of HPC, mefenamic acid and HPC-mefenamic acid conjugates were drawn from thermogravimetric (TG) and derivative TG curves and compared to access relative thermal stability. The TG analysis has indicated that samples obtained were thermally more stable especially with increased stability of mefenamic acid in HPC-mefenamic acid conjugates. These novel MPDs of mefenamic acid (i.e., HPC-mefenamic acid conjugates) may have potential applications in pharmaceutically viable drug design due to wide range of solubility and extra thermal stability imparted after MPD formation. (author)

  20. Lipoprotein cholesterol uptake mediates upregulation of bile acid synthesis by increasing cholesterol 7a-hydroxylase but not sterol 27- hydroxylase gene expression in cultured rat hepatocytes.

    NARCIS (Netherlands)

    Post, S.M.; Twisk, J.W.R.; van der Fits, L.T.E.; Wit, E.C.M.; Hoekman, M.F.M.; Mager, W.H.; Princen, H.M.G.

    1999-01-01

    Lipoproteins may supply substrate for the formation of bile acids, and the amount of hepatic cholesterol can regulate bile-acid synthesis and increase cholesterol 7α-hydroxylase expression. However, the effect of lipoprotein cholesterol on sterol 27-hydroxylase expression and the role of different

  1. Meat quality and tissue fatty acid profiles in rabbits fed diets supplemented with conjugated linoleic acid

    Czech Academy of Sciences Publication Activity Database

    Marounek, Milan; Skřivanová, V.; Dokoupilová, A.; Czauderna, M.; Berladyn, A.

    2007-01-01

    Roč. 52, č. 12 (2007), s. 552-561 ISSN 0375-8427 Institutional research plan: CEZ:AV0Z50450515 Keywords : rabbits * conjugated linoleic acid * fatty acids Subject RIV: GH - Livestock Nutrition Impact factor: 0.645, year: 2007

  2. Bile acids induce hepatic stellate cell proliferation via activation of the epidermal growth factor receptor

    NARCIS (Netherlands)

    Svegliati-Baroni, G; Ridolfi, F; Hannivoort, R; Saccomanno, S; Homan, M; De Minicis, S; Jansen, PLM; Candelaresi, C; Benedetti, A; Moshage, H

    Background B Aims: Hepatic stellate cell (HSC) proliferation is a key event in the development of liver fibrosis. In many liver diseases, HSCs are exposed to inflammatory cytokines, reactive oxygen species, and bile acids. Although inflammatory cytokines and reactive oxygen species are known to

  3. Early effects of dietary orotic acid upon liver lipid synthesis and bile cholesterol secretion in rats

    International Nuclear Information System (INIS)

    Tokmakjian, S.D.; Haines, D.S.

    1985-01-01

    Dietary orotic acid is known to cause impaired fatty acid synthesis and increased cholesterol synthesis in rats. The authors found that the impaired fatty acid synthesis occurs during the first day of orotic acid feeding and, in studies with albumin-bound [1- 14 C]palmitic acid, an associated decrease in the rate of esterification of this fatty acid into triacylglycerol, phospholipid, and cholesteryl ester was observed. These changes may result from the known decreases in liver levels of adenine nucleotides or, as reported here, from decreased liver CoASH levels in orotic acid-fed rats. The increase in hepatic cholesterol synthesis occurred during the second day of orotic acid feeding. It was detected by increased incorporation of [1,2- 14 C]acetate into cholesterol by liver slices and by a 7-fold increase in HMG-CoA reductase activity. At the same time the biliary output of cholesterol was increased 2-fold and studies using 3 H 2 O revealed that the output of newly synthesized cholesterol in bile was increased 5-fold. The content of cholesteryl ester in hepatic microsomes decreased during orotic acid feeding but free cholesterol was unchanged. The findings are interpreted to suggest that the increased bile cholesterol secretion caused by orotic acid is a result of impaired hepatic cholesterol esterification and that the increase in HMG-CoA reductase activity is a result of diminished negative feedback due to the depleted content of cholesteryl ester in the hepatic microsomes

  4. Characterization of hapten-protein conjugates: antibody generation and immunoassay development for chlorophenoxyacetic acid pesticides.

    Science.gov (United States)

    Boro, Robin C; Singh, K Vikas; Suri, C Raman

    2009-01-01

    The generation of specific and sensitive antibodies against small molecules is greatly dependent upon the characteristics of the hapten-protein conjugates. In this study, we report a new fluorescence-based method for the characterization of hapten-protein conjugates. The method is based on an effect promoted by hapten-protein conjugation density upon the fluorescence intensity of the intrinsic tryptophan chromophore molecules of the protein. The proposed methodology is applied to quantify the hapten-protein conjugation density for two different chlorophenoxyacetic acid pesticides, 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4-dichlorophenoxybutyric acid (2,4-DB), coupled to carrier protein. Highly sensitive anti-2,4-D and anti-2,4-DB antibodies were obtained using these well-characterized hapten-protein conjugates. The generated antibodies were used in an immunoassay format demonstrating inhibitory concentration (IC50) values equal to 30 and 7 ng/mL for 2,4-D and 2,4-DB, respectively. Linearity was observed in the concentration range between 0.1-500 nglmL with LODs around 4 and 3 ng/mL for 2,4-D and 2,4-DB, respectively, in standard water samples. The proposed method was successfully applied for the determination of the extent of hapten-protein conjugation to produce specific antibodies for immunoassay development against pesticides.

  5. Sulindac is excreted into bile by a canalicular bile salt pump and undergoes a cholehepatic circulation in rats

    NARCIS (Netherlands)

    Bolder, U.; Trang, N. V.; Hagey, L. R.; Schteingart, C. D.; Ton-Nu, H. T.; Cerrè, C.; Elferink, R. P.; Hofmann, A. F.

    1999-01-01

    BACKGROUND & AIMS: Dihydroxy bile acids induce a bicarbonate-rich hypercholeresis when secreted into canalicular bile in unconjugated form; the mechanism is cholehepatic shunting. The aim of this study was to identify a xenobiotic that induces hypercholeresis by a similar mechanism. METHODS: Five

  6. Metastable and equilibrium phase diagrams of unconjugated bilirubin IXα as functions of pH in model bile systems: Implications for pigment gallstone formation

    Science.gov (United States)

    Berman, Marvin D.

    2014-01-01

    Metastable and equilibrium phase diagrams for unconjugated bilirubin IXα (UCB) in bile are yet to be determined for understanding the physical chemistry of pigment gallstone formation. Also, UCB is a molecule of considerable biomedical importance because it is a potent antioxidant and an inhibitor of atherogenesis. We employed principally a titrimetric approach to obtain metastable and equilibrium UCB solubilities in model bile systems composed of taurine-conjugated bile salts, egg yolk lecithin (mixed long-chain phosphatidylcholines), and cholesterol as functions of total lipid concentration, biliary pH values, and CaCl2 plus NaCl concentrations. Metastable and equilibrium precipitation pH values were obtained, and average pKa values of the two carboxyl groups of UCB were calculated. Added lecithin and increased temperature decreased UCB solubility markedly, whereas increases in bile salt concentrations and molar levels of urea augmented solubility. A wide range of NaCl and cholesterol concentrations resulted in no specific effects, whereas added CaCl2 produced large decreases in UCB solubilities at alkaline pH values only. UV-visible absorption spectra were consistent with both hydrophobic and hydrophilic interactions between UCB and bile salts that were strongly influenced by pH. Reliable literature values for UCB compositions of native gallbladder biles revealed that biles from hemolytic mice and humans with black pigment gallstones are markedly supersaturated with UCB and exhibit more acidic pH values, whereas biles from nonstone control animals and patients with cholesterol gallstone are unsaturated with UCB. PMID:25359538

  7. Reference standard for serum bile acids in pregnancy.

    LENUS (Irish Health Repository)

    2012-01-31

    Please cite this paper as: Egan N, Bartels A, Khashan A, Broadhurst D, Joyce C, O\\'Mullane J, O\\'Donoghue K. Reference standard for serum bile acids in pregnancy. BJOG 2012;00:000-000. DOI: 10.1111\\/j.1471-0528.2011.03245.x. Objective Obstetric cholestasis (OC) is a liver disorder characterised by pruritus and elevated serum bile acids (SBA) that affects one in 200 pregnant women. It is associated with adverse perinatal outcomes such as premature delivery and stillbirth. Mild OC is defined as SBA levels of 10-39 mumol\\/l, and severe OC is defined by levels >40 mumol\\/l. SBA levels in normal pregnancy have not been investigated. We aimed to establish reference values for SBA in healthy pregnant women across different trimesters of pregnancy. Design Cross-sectional analysis of SBA levels. Setting A large tertiary referral university teaching maternity hospital. Population Healthy pregnant women with a singleton pregnancy and a body mass index (BMI) < 40, excluding women with significant alcohol intake, history of liver disease, prior cholecystectomy and OC. Methods Cross-sectional analysis of SBA levels at 12, 20, 28 and 36 weeks of gestation, and on days 1-3 postpartum. Main outcome measures SBA levels in mumol\\/l. Results A total of 219 women attending for antenatal care were recruited, and SBA levels were assayed at 12, 20, 28 and 36 weeks of gestation, and up to 72 hours postpartum (n = 44-49 cases at each stage). The majority were white European women, with a median age of 30 years (range 17-46 years) and median BMI of 25 (range 18-38). Values of SBA ranged from 0.3 to 9.8 mumol\\/l in 216 women, with only three measurements outside this range. There were no significant changes throughout pregnancy. Conclusions SBA values in uncomplicated pregnancies are consistent, regardless of gestation, and are not elevated in pregnancy. The current reference values for the diagnosis of OC appear to be appropriate.

  8. Synthesis and photophysicochemical studies of a water soluble conjugate between folic acid and zinc tetraaminophthalocyanine

    International Nuclear Information System (INIS)

    Khoza, Phindile; Antunes, Edith; Chen, Ji-Yao; Nyokong, Tebello

    2013-01-01

    This work reports on the synthesis of zinc tetraaminophthalocyanine (ZnTAPc) functionalized with folic acid (FA), forming ZnTAPcFA. The conjugate between FA and ZnTAPc was soluble in water whereas ZnTAPc alone is not. The structure of ZnTAPcFA conjugate was elucidated by 1 H NMR, MALDI-TOF mass and FTIR spectra. Photophysical and photochemical studies of ZnTAPcFA were conducted in DMSO. The increase in fluorescence quantum yield of the conjugate was accompanied by a decrease in the triplet and singlet oxygen quantum yields. The changes in triplet quantum and singlet oxygen quantum yields were marginal when ZnTAPc was simply mixed with FA without a chemical bond. - Highlights: ► A conjugate between folic acid and a zinc tetraaminophthalocyanine was formed. ► The conjugate is water soluble even though the phthalocyanine alone is not. ► The fluorescence quantum yield of the conjugate was enhanced compared to the phthalocyanine alone. ► Triplet quantum yields decreased for the conjugate

  9. Serum bile acids and leptin interact with glucose metabolism in patients with liver cirrhosis

    NARCIS (Netherlands)

    Valentini, Luzia; Glaeser, Silja; Schuetz, Tatjana; Omar, Ajmal; Kasim, Esmatollah; Kroencke, Thomas; Tietge, Uwe J. F.; Lochs, Herbert; Schulzke, Joerg-Dieter; Brabant, Georg; Ockenga, Johann

    Background & aims: We investigated possible involvements of bile acids (BA) and leptin in hepatogenous insulin resistance being present in up to 90% of cirrhotic patients. Methods: Blood was analysed in 10 cirrhotic patients (8m/2f, 48 +/- 10.4 yrs) and 10 controls (8m/2f, 43 +/- 9.3 yrs) after oral

  10. Properties of acid gels made from sodium caseinate-maltodextrin conjugates prepared by a wet heating method.

    Science.gov (United States)

    Zhang, Shuwen; Gong, Yuansheng; Khanal, Som; Lu, Yanjie; Lucey, John A

    2017-11-01

    Covalent attachment of polysaccharides to proteins (conjugation) via the Maillard reaction has been extensively studied. Conjugation can lead to a significant improvement in protein functionality (e.g., solubility, emulsification, and heat stability). Caseins have previously been successfully conjugated with maltodextrin (Md), but the effect on the detailed acid gelation properties has not been examined. We studied the effect of conjugating sodium caseinate (NaCN) with 3 different sized Md samples via the Maillard reaction in aqueous solutions. The Md samples had dextrose equivalents of 4 to 7, 9 to 12, and 20 to 23 for Md40, Md100, and Md200, respectively. The conjugation reaction was performed in mixtures with 5% NaCN and 5% Md, which were heated at 90°C for 10 h. The degree of conjugation was estimated from the reduction in free amino groups as well as color changes. Sodium dodecyl sulfate-PAGE analysis was performed to confirm conjugation by employing staining of both protein and carbohydrate bands. The molar mass of samples was determined by size-exclusion chromatography coupled with multi-angle laser light scattering. After the conjugation reaction, samples were then gelled by the addition of 0.63% (wt/vol) glucono-δ-lactone at 30°C, such that samples reached pH 4.6 after about 13 h. The rheological properties of samples during acidification was monitored by small-strain dynamic oscillatory rheology. The microstructure of acid gels at pH 4.6 was examined by fluorescence microscopy. Conjugation resulted in a loss of 10.8, 8.8, and 11.9% of the available amino groups in the protein for the NaCN-Md40 conjugates (C40), NaCN-Md100 conjugates (C100), and NaCN-Md100 conjugates (C200), respectively. With a decrease in the size of the type of Md, an increase occurred in the molar mass of the resultant conjugate. The weight average molar masses of NaCN-Md samples were 340, 368, and 425 kDa for the conjugates C40, C100, and C200, respectively. Addition of Md to Na

  11. Evolutionary diversity of bile salts in reptiles and mammals, including analysis of ancient human and extinct giant ground sloth coprolites

    Science.gov (United States)

    2010-01-01

    Background Bile salts are the major end-metabolites of cholesterol and are also important in lipid and protein digestion and in influencing the intestinal microflora. We greatly extend prior surveys of bile salt diversity in both reptiles and mammals, including analysis of 8,000 year old human coprolites and coprolites from the extinct Shasta ground sloth (Nothrotherium shastense). Results While there is significant variation of bile salts across species, bile salt profiles are generally stable within families and often within orders of reptiles and mammals, and do not directly correlate with differences in diet. The variation of bile salts generally accords with current molecular phylogenies of reptiles and mammals, including more recent groupings of squamate reptiles. For mammals, the most unusual finding was that the Paenungulates (elephants, manatees, and the rock hyrax) have a very different bile salt profile from the Rufous sengi and South American aardvark, two other mammals classified with Paenungulates in the cohort Afrotheria in molecular phylogenies. Analyses of the approximately 8,000 year old human coprolites yielded a bile salt profile very similar to that found in modern human feces. Analysis of the Shasta ground sloth coprolites (approximately 12,000 years old) showed the predominant presence of glycine-conjugated bile acids, similar to analyses of bile and feces of living sloths, in addition to a complex mixture of plant sterols and stanols expected from an herbivorous diet. Conclusions The bile salt synthetic pathway has become longer and more complex throughout vertebrate evolution, with some bile salt modifications only found within single groups such as marsupials. Analysis of the evolution of bile salt structures in different species provides a potentially rich model system for the evolution of a complex biochemical pathway in vertebrates. Our results also demonstrate the stability of bile salts in coprolites preserved in arid climates

  12. Evolutionary diversity of bile salts in reptiles and mammals, including analysis of ancient human and extinct giant ground sloth coprolites

    Directory of Open Access Journals (Sweden)

    Hofmann Alan F

    2010-05-01

    Full Text Available Abstract Background Bile salts are the major end-metabolites of cholesterol and are also important in lipid and protein digestion and in influencing the intestinal microflora. We greatly extend prior surveys of bile salt diversity in both reptiles and mammals, including analysis of 8,000 year old human coprolites and coprolites from the extinct Shasta ground sloth (Nothrotherium shastense. Results While there is significant variation of bile salts across species, bile salt profiles are generally stable within families and often within orders of reptiles and mammals, and do not directly correlate with differences in diet. The variation of bile salts generally accords with current molecular phylogenies of reptiles and mammals, including more recent groupings of squamate reptiles. For mammals, the most unusual finding was that the Paenungulates (elephants, manatees, and the rock hyrax have a very different bile salt profile from the Rufous sengi and South American aardvark, two other mammals classified with Paenungulates in the cohort Afrotheria in molecular phylogenies. Analyses of the approximately 8,000 year old human coprolites yielded a bile salt profile very similar to that found in modern human feces. Analysis of the Shasta ground sloth coprolites (approximately 12,000 years old showed the predominant presence of glycine-conjugated bile acids, similar to analyses of bile and feces of living sloths, in addition to a complex mixture of plant sterols and stanols expected from an herbivorous diet. Conclusions The bile salt synthetic pathway has become longer and more complex throughout vertebrate evolution, with some bile salt modifications only found within single groups such as marsupials. Analysis of the evolution of bile salt structures in different species provides a potentially rich model system for the evolution of a complex biochemical pathway in vertebrates. Our results also demonstrate the stability of bile salts in coprolites

  13. HPLC and ELISA analyses of larval bile acids from Pacific and western brook lampreys

    Science.gov (United States)

    Yun, S.-S.; Scott, A.P.; Bayer, J.M.; Seelye, J.G.; Close, D.A.; Li, W.

    2003-01-01

    Comparative studies were performed on two native lamprey species, Pacific lamprey (Lampetra tridentata) and western brook lamprey (Lampetra richardsoni) from the Pacific coast along with sea lamprey (Petromyzon marinus) from the Great Lakes, to investigate their bile acid production and release. HPLC and ELISA analyses of the gall bladders and liver extract revealed that the major bile acid compound from Pacific and western brook larval lampreys was petromyzonol sulfate (PZS), previously identified as a migratory pheromone in larval sea lamprey. An ELISA for PZS has been developed in a working range of 20pg-10ng per well. The tissue concentrations of PZS in gall bladder were 127.40, 145.86, and 276.96??g/g body mass in sea lamprey, Pacific lamprey, and western brook lamprey, respectively. Releasing rates for PZS in the three species were measured using ELISA to find that western brook and sea lamprey released PZS 20 times higher than Pacific lamprey did. Further studies are required to determine whether PZS is a chemical cue in Pacific and western brook lampreys. ?? 2003 Elsevier Inc. All rights reserved.

  14. Characterization of Bile Salt Hydrolase from Lactobacillus gasseri FR4 and Demonstration of Its Substrate Specificity and Inhibitory Mechanism Using Molecular Docking Analysis

    Directory of Open Access Journals (Sweden)

    Rizwana Parveen Rani

    2017-05-01

    Full Text Available Probiotic bacteria are beneficial to the health of poultry animals, thus are used as alternative candidates for antibiotics used as growth promoters (AGPs. However, they also reduce the body weight gain due to innate bile salt hydrolase (BSH activity. Hence, the addition of a suitable BSH inhibitor along with the probiotic feed can decrease the BSH activity. In this study, a BSH gene (981 bp encoding 326-amino acids was identified from the genome of Lactobacillus gasseri FR4 (LgBSH. The LgBSH-encoding gene was cloned and purified using an Escherichia coli BL21 (DE3 expression system, and its molecular weight (37 kDa was confirmed by SDS–PAGE and a Western blot analysis. LgBSH exhibited greater hydrolysis toward glyco-conjugated bile salts compared to tauro-conjugated bile salts. LgBSH displayed optimal activity at 52°C at a pH of 5.5, and activity was further increased by several reducing agents (DTT, surfactants (Triton X-100 and Tween 80, and organic solvents (isopropanol, butanol, and acetone. Riboflavin and penicillin V, respectively, inhibited LgBSH activity by 98.31 and 97.84%. A homology model of LgBSH was predicted using EfBSH (4WL3 as a template. Molecular docking analysis revealed that the glycocholic acid had lowest binding energy of -8.46 kcal/mol; on the other hand, inhibitors, i.e., riboflavin and penicillin V, had relatively higher binding energies of -6.25 and -7.38 kcal/mol, respectively. Our results suggest that L. gasseri FR4 along with riboflavin might be a potential alternative to AGPs for poultry animals.

  15. Surface conjugation of poly (dimethyl siloxane) with itaconic acid-based materials for antibacterial effects

    Science.gov (United States)

    Birajdar, Mallinath S.; Cho, Hyunjoo; Seo, Youngmin; Choi, Jonghoon; Park, Hansoo

    2018-04-01

    Poly (dimethyl siloxane) (PDMS) is widely used in various biomedical applications. However, the PDMS surface is known to cause bacterial adhesion and protein absorption issues due to its high hydrophobicity. Therefore, the development of antibacterial and anti-protein products is necessary to prevent these problems. In this study, to improve its antibacterial property and prevent protein adsorption, PDMS surfaces were conjugated with itaconic acid (IA) and poly (itaconic acid) (PIA) via a chemical method. Additionally, IA and PIA were physically blended with PDMS to compare the antibacterial properties of these materials with those of the chemically conjugated PDMS surfaces. The successful synthesis of the PIA polymer structure was confirmed by proton nuclear magnetic resonance (1H NMR) spectroscopy. The successful conjugation of IA and PIA on PDMS was confirmed by attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), water contact angle measurements, and microbicinchoninic acid (BCA) protein assay analyses. The PDMS surfaces functionalized with IA and PIA by the conjugation method better prevented protein adsorption than the bare PDMS. Therefore, these surface-conjugated PDMS can be used in various biomedical applications.

  16. Effects of pelleted or powdered diets containing soy protein or sodium caseinate on lipid concentrations and bile acid excretion in golden Syrian hamsters.

    Science.gov (United States)

    Butteiger, Dustie N; Krul, Elaine S

    2015-08-01

    Custom diets are a convenient vector for oral administration of test articles, but the processing and physical form of a diet can affect its nutritional properties and how it is consumed. Here, the authors evaluated the feeding behavior and physiology of golden Syrian hamsters fed diets of either soy or caseinate protein in pelleted or powdered forms for 28 d to determine whether dietary processing and form mediates the physiological effects of dietary proteins. The authors compared body weight, food consumption, serum cholesterol concentration, serum triglyceride concentration, fecal weight and fecal excretion of bile acids between treatment groups. Hamsters fed powdered diets showed higher food consumption than hamsters fed pelleted diets, regardless of protein source. Hamsters fed soy pelleted diets showed lower serum cholesterol concentration and higher fecal excretion of bile acid than hamsters fed caseinate pelleted diets, and serum cholesterol concentration correlated strongly with fecal excretion of bile acid. This correlation suggests that the physiological effects of soy protein on cholesterol and excretion of bile acid might be related or similarly mediated through diet. The differences observed between hamsters on different diets indicate that dietary form can influence both feeding behavior and the physiological effects of a diet in hamsters.

  17. Relation between bile acid reflux into the stomach and the risk of atrophic gastritis and intestinal metaplasia: a multicenter study of 2283 cases.

    Science.gov (United States)

    Matsuhisa, Takeshi; Arakawa, Tetsuo; Watanabe, Tetsuo; Tokutomi, Tadashi; Sakurai, Kouichi; Okamura, Seisuke; Chono, Shinji; Kamada, Tomoari; Sugiyama, Atsushi; Fujimura, Yoshinori; Matsuzawa, Kenji; Ito, Masanori; Yasuda, Mitsugu; Ota, Hiroyoshi; Haruma, Ken

    2013-09-01

    The relationship between bile acid reflux into the stomach and the risk of atrophic gastritis and intestinal metaplasia is still not well understood. Towards obtaining a better understanding, concentrations of bile acids were measured. This study was carried out with the participation of 14 facilities in Japan, and 2283 samples were collected. The subjects with bile acid concentrations equal to or higher than the limit of detection were divided into four groups of equal size (group A: 0-25%, group B: 26-50%, group C: 51-75%, and group D: 76-100%). Thus, including the control group, there were five groups in total. The odds that the control group would develop atrophic gastritis and intestinal metaplasia was set as 1,and the odds ratios (OR) in groups A, B, C and D were calculated based on the odds in the control group. Regarding the development of atrophic gastritis, no increased risk was observed in either the Helicobacter pylori (H. pylori)-positive or -negative cases. The OR for the development of intestinal metaplasia were significantly higher, for both cases with and without H. pylori infection, in group D. High concentrations of bile acid seem to be associated with an elevated risk of intestinal metaplasia. © 2013 The Authors. Digestive Endoscopy © 2013 Japan Gastroenterological Endoscopy Society.

  18. Potential mechanism of corpus-predominant gastritis after PPI therapy in Helicobacter pylori-positive patients with GERD.

    Science.gov (United States)

    Mukaisho, Ken-ichi; Hagiwara, Tadashi; Nakayama, Takahisa; Hattori, Takanori; Sugihara, Hiroyuki

    2014-09-14

    The long-term use of proton pump inhibitors (PPIs) exacerbates corpus atrophic gastritis in patients with Helicobacter pylori (H. pylori) infection. To identify a potential mechanism for this change, we discuss interactions between pH, bile acids, and H. pylori. Duodenogastric reflux, which includes bile, occurs in healthy individuals, and bile reflux is increased in patients with gastroesophageal reflux disease (GERD). Diluted human plasma and bile acids have been found to be significant chemoattractants and chemorepellents, respectively, for the bacillus H. pylori. Although only taurine conjugates, with a pKa of 1.8-1.9, are soluble in an acidic environment, glycine conjugates, with a pKa of 4.3-5.2, as well as taurine-conjugated bile acids are soluble in the presence of PPI therapy. Thus, the soluble bile acid concentrations in the gastric contents of patients with GERD after continuous PPI therapy are considerably higher than that in those with intact acid production. In the distal stomach, the high concentration of soluble bile acids is likely to act as a bactericide or chemorepellent for H. pylori. In contrast, the mucous layer in the proximal stomach has an optimal bile concentration that forms chemotactic gradients with plasma components required to direct H. pylori to the epithelial surface. H. pylori may then colonize in the stomach body rather than in the pyloric antrum, which may explain the occurrence of corpus-predominant gastritis after PPI therapy in H. pylori-positive patients with GERD.

  19. Recycling rate of bile acids in the enterohepatic recirculation as a major determinant of whole body 75SeHCAT retention.

    Science.gov (United States)

    Peters, A Michael; Walters, Julian R F

    2013-10-01

    Measurement of the whole body retention of orally administered (75)SeHCAT is used to investigate patients with unexplained diarrhoea. Retention values of recycling rate of bile acids. Increased recycling has been largely ignored as a cause of BAD, but, as shown in this study, can readily result in excess bile acids reaching the colon even when ileal absorption efficiency is normal (i.e. 95-97 %). There needs to be a re-evaluation of the causes of BAD in patients without a history of previous intestinal resection or evidence of ileal pathology, such as Crohn's disease.

  20. Dysfunctional families: Clostridium scindens and secondary bile acids inhibit the growth of Clostridium difficile.

    Science.gov (United States)

    Greathouse, K Leigh; Harris, Curtis C; Bultman, Scott J

    2015-01-06

    C. difficile infection is a deadly disease that is influenced by the microbiome. In a recent article in Nature, Buffie et al. (2014) demonstrate that the ability of C. scindens to synthesize secondary bile acids is crucial to providing resistance to C. difficile infection. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Sortilin 1 Loss-of-Function Protects Against Cholestatic Liver Injury by Attenuating Hepatic Bile Acid Accumulation in Bile Duct Ligated Mice.

    Science.gov (United States)

    Li, Jibiao; Woolbright, Benjamin L; Zhao, Wen; Wang, Yifeng; Matye, David; Hagenbuch, Bruno; Jaeschke, Hartmut; Li, Tiangang

    2018-01-01

    Sortilin 1 (Sort1) is an intracellular trafficking receptor that mediates protein sorting in the endocytic or secretory pathways. Recent studies revealed a role of Sort1 in the regulation of cholesterol and bile acid (BA) metabolism. This study further investigated the role of Sort1 in modulating BA detoxification and cholestatic liver injury in bile duct ligated mice. We found that Sort1 knockout (KO) mice had attenuated liver injury 24 h after bile duct ligation (BDL), which was mainly attributed to less bile infarct formation. Sham-operated Sort1 KO mice had about 20% larger BA pool size than sham-operated wildtype (WT) mice, but 24 h after BDL Sort1 KO mice had significantly attenuated hepatic BA accumulation and smaller BA pool size. After 14 days BDL, Sort1 KO mice showed significantly lower hepatic BA concentration and reduced expression of inflammatory and fibrotic marker genes, but similar degree of liver fibrosis compared with WT mice. Unbiased quantitative proteomics revealed that Sort1 KO mice had increased hepatic BA sulfotransferase 2A1, but unaltered phase-I BA metabolizing cytochrome P450s or phase-III BA efflux transporters. Consistently, Sort1 KO mice showed elevated plasma sulfated taurocholate after BDL. Finally, we found that liver Sort1 was repressed after BDL, which may be due to BA activation of farnesoid x receptor. In conclusion, we report a role of Sort1 in the regulation of hepatic BA detoxification and cholestatic liver injury in mice. The mechanisms underlying increased hepatic BA elimination in Sort1 KO mice after BDL require further investigation. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  2. Fish protein hydrolysate elevates plasma bile acids and reduces visceral adipose tissue mass in rats

    DEFF Research Database (Denmark)

    Liaset, Bjørn; Madsen, Lise; Hao, Qin

    2009-01-01

    levels relative to rats fed soy protein or casein. Concomitantly, the saithe FPH fed rats had reduced liver lipids and fasting plasma TAG levels. Furthermore, visceral adipose tissue mass was reduced and expression of genes involved in fatty acid oxidation and energy expenditure was induced in perirenal....../retroperitoneal adipose tissues of rats fed saithe FPH. Our results provide the first evidence that dietary protein sources with different amino acid compositions can modulate the level of plasma bile acids and our data suggest potential novel mechanisms by which dietary protein sources can affect energy metabolism....

  3. 5α-Bile alcohols function as farnesoid X receptor antagonists

    International Nuclear Information System (INIS)

    Nishimaki-Mogami, Tomoko; Kawahara, Yosuke; Tamehiro, Norimasa; Yoshida, Takemi; Inoue, Kazuhide; Ohno, Yasuo; Nagao, Taku; Une, Mizuho

    2006-01-01

    The farnesoid X receptor (FXR) is a bile acid/alcohol-activated nuclear receptor that regulates lipid homeostasis. Unlike other steroid receptors, FXR binds bile acids in an orientation that allows the steroid nucleus A to face helix 12 in the receptor, a crucial domain for coactivator-recruitment. Because most naturally occurring bile acids and alcohols contain a cis-oriented A, which is distinct from that of other steroids and cholesterol metabolites, we investigated the role of this 5β-configuration in FXR activation. The results showed that the 5β-(A/B cis) bile alcohols 5β-cyprinol and bufol are potent FXR agonists, whereas their 5α-(A/B trans) counterparts antagonize FXR transactivation and target gene expression. Both isomers bound to FXR, but their ability to induce coactivator-recruitment and thereby induce transactivation differed. These findings suggest a critical role for the A orientation of bile salts in agonist/antagonist function

  4. An improved method of microencapsulation of probiotic bacteria for their stability in acidic and bile conditions during storage.

    Science.gov (United States)

    Ding, W K; Shah, N P

    2009-03-01

    The purpose of this study was to develop a method for applying an extra coating of palm oil and poly-L-lysine (POPL) to alginate (ALG) microcapsules to enhance the survival of probiotic bacteria. Eight strains of probiotic bacteria including Lactobacillus rhamnosus, Bifidobacterium longum, L. salivarius, L. plantarum, L. acidophilus, L. paracasei, B. lactis type Bl-O4, and B. lactis type Bi-07 were encapsulated using alginate alone or alginate with POPL. Electron microscopy was used to measure the size of the microcapsules and to determine their surface texture. To assess if the addition of POPL improved the viability of probiotic bacteria in acidic conditions, both ALG and POPL microcapsules were inoculated into pH 2.0 MRS broths and their viability was assessed over a 2-h incubation period. Two bile salts including oxgall bile salt and taurocholic acid were used to test the bile tolerance of probiotic bacteria entrapped in ALG and POPL microcapsules. To assess the porosity and the ability of the microcapsule to hold small molecules in an aqueous environment a water-soluble fluorescent dye, 6-carboxyflourescin (6 FAM), was encapsulated and its release was monitored using a UV spectrophotometer. The results indicated that coating the microcapsules with POPL increased the overall size of the capsules by an average of 3 microm +/- 0.67. However, microcapsules with added POPL had a much smoother surface texture when examined under an electron microscope. The results also indicated that the addition of POPL to microcapsules improved the average viability of probiotic bacteria by > 1 log CFU/mL when compared to ALG microcapsules at 2 h of exposure to acidic conditions. However, similar plate counts were observed between ALG and POPL microcapsules when exposed to bile salts. This suggests that an extra coating of POPL could be readily broken down by bile salts that are commonly found in the lower gastrointestinal tract (GIT). Upon testing the porosity of the

  5. Bile acids, neutral steroids, and bacteria in feces as affected by a mixed, a lacto-ovovegetarian, and a vegan diet.

    Science.gov (United States)

    van Faassen, A; Bol, J; van Dokkum, W; Pikaar, N A; Ockhuizen, T; Hermus, R J

    1987-12-01

    In a metabolic ward 12 healthy male subjects consumed mixed Western (M), lacto-ovovegetarian (L), and vegan (V) diets in a randomized order for 20 d each. The concentrations of deoxycholic acid, isolithocholic acid, and total bile acids in 4-d composites of feces on the L and V diets were significantly lower than on the M diet. The chenodeoxycholic-to-isolithocholic plus lithocholic acid ratio was significantly higher on the V diet. The concentrations of coprostanol and of coprostanol plus cholesterol were highest on M diet and lowest on V diet. The number of fecal lactobacilli and enterococci on the V diet was significantly lower than on the M or the L diets. This study showed a decrease in the concentration of fecal (secondary) bile acids by the L and the V diets and an alteration of the fecal flora composition by the V diet.

  6. High expression of L-type amino acid transporter 1 as a prognostic marker in bile duct adenocarcinomas

    International Nuclear Information System (INIS)

    Yanagisawa, Nobuyuki; Hana, Kiyomi; Nakada, Norihiro; Ichinoe, Masaaki; Koizumi, Wasaburo; Endou, Hitoshi; Okayasu, Isao; Murakumo, Yoshiki

    2014-01-01

    Oncocytic L-type amino acid transporter (LAT) 1 may be a prognostic indicator and target of new molecular therapeutic agents against malignancies. To investigate whether LAT1 expression influence the outcomes of patients with bile duct cancer, the expression of LAT1, LAT2, CD98, and Ki-67 was investigated immunohistochemically in 134 surgically resected bile duct adenocarcinomas, including 84 distal extrahepatic bile duct adenocarcinomas, 21 hilar cholangiocarcinomas, 15 intrahepatic cholangiocarcinomas, and 14 ampullary adenocarcinomas. LAT1 expression was weakly correlated with CD98 expression and Ki-67 labeling index (LI). Kaplan–Meier analysis showed a significant difference in prognosis between patients with bile duct adenocarcinomas having LAT1-high and -low scores, whereas LAT2 and CD98 expression and Ki-67 LI were not predictive of poor prognosis. Prognosis tended to be worse in patients having tumors with LAT1-high/LAT2-low than LAT1-low/LAT2-high scores (P = 0.0686). Multivariable analyses revealed that LAT1 expression, surgical margin, pT stage were independent prognostic factors. In conclusion, aberrant overexpression of LAT1 in bile duct adenocarcinoma predicts poor prognosis, suggesting that LAT1 may be a potential target of anticancer therapy

  7. Urinary Elimination of Bile Acid Glucuronides under Severe Cholestatic Situations: Contribution of Hepatic and Renal Glucuronidation Reactions

    Directory of Open Access Journals (Sweden)

    Martin Perreault

    2018-01-01

    Full Text Available Biliary obstruction, a severe cholestatic complication, causes accumulation of toxic bile acids (BAs in liver cells. Glucuronidation, catalyzed by UDP-glucuronosyltransferase (UGT enzymes, detoxifies cholestatic BAs. Using liquid chromatography coupled to tandem mass spectrometry, 11 BA glucuronide (-G species were quantified in prebiliary and postbiliary stenting serum and urine samples from 17 patients with biliary obstruction. Stenting caused glucuronide- and fluid-specific changes in BA-G levels and BA-G/BA metabolic ratios. In vitro glucuronidation assays with human liver and kidney microsomes revealed that even if renal enzymes generally displayed lower KM values, the two tissues shared similar glucuronidation capacities for BAs. By contrast, major differences between the two tissues were observed when four human BA-conjugating UGTs 1A3, 1A4, 2B4, and 2B7 were analyzed for mRNA and protein levels. Notably, the BA-24G producing UGT1A3 enzyme, abundant in the liver, was not detected in kidney microsomes. In conclusion, the circulating and urinary BA-G profiles are hugely impacted under severe cholestasis. The similar BA-glucuronidating abilities of hepatic and renal extracts suggest that both the liver and kidney may contribute to the urine BA-G pool.

  8. Radioimmunoassay for the determination of free and conjugated abscisic acid

    International Nuclear Information System (INIS)

    Weiler, E.W.

    1979-01-01

    The characterization and application of a radioimmunoassay specific for free and conjugated abscisic acid (ABA) is reported, The antibodies produced against a bovine serum albumin-(+-)-ABA conjugate have a high affinity for ABA (Ka= 1.3 x 10 9 l mol -1 ). Trans, trans-ABA and related compounds, such as xanthoxin, phaseic acid, dihydrophaseic acid, vomifoliol or violaxanthin do not interfere with the assay. The detection limit of this method is 0.25 x 10 -12 mol ABA, the measuring range extends to 20 x 10 -12 mol, and average recoveries are 103%. Because of the high specificity of this immunoassay, no extract purification steps are required prior to analysis. Several hundred plants can be analyzed per day in a semi-automatic assay performance. ABA has been detected in all higher plant families examined, but was absent in the blue-green alga, Spirulina platensis, the liverwort Marchantia polymorpha, and two species of fungi. (orig.) [de

  9. Effect of dietary conjugated linoleic acid (CLA) on the growth and ...

    African Journals Online (AJOL)

    Effect of dietary conjugated linoleic acid (CLA) on the growth and lipid metabolism of geese and fatty acid composition of their tissues. ... Dietary CLA altered serum lipid concentrations by decreasing total cholesterol, triglyceride and low density lipoprotein-cholesterol concentrations, the atherogenic index and activity of ...

  10. Synthesis and photophysicochemical studies of a water soluble conjugate between folic acid and zinc tetraaminophthalocyanine

    Energy Technology Data Exchange (ETDEWEB)

    Khoza, Phindile; Antunes, Edith [Department of Chemistry, Rhodes University, PO Box 94, Grahamstown (South Africa); Chen, Ji-Yao [State Key Laboratory of Surface Physics and Department of Physics, Fudan University, Shanghai 200433 (China); Nyokong, Tebello, E-mail: t.nyokong@ru.ac.za [Department of Chemistry, Rhodes University, PO Box 94, Grahamstown (South Africa)

    2013-02-15

    This work reports on the synthesis of zinc tetraaminophthalocyanine (ZnTAPc) functionalized with folic acid (FA), forming ZnTAPcFA. The conjugate between FA and ZnTAPc was soluble in water whereas ZnTAPc alone is not. The structure of ZnTAPcFA conjugate was elucidated by {sup 1}H NMR, MALDI-TOF mass and FTIR spectra. Photophysical and photochemical studies of ZnTAPcFA were conducted in DMSO. The increase in fluorescence quantum yield of the conjugate was accompanied by a decrease in the triplet and singlet oxygen quantum yields. The changes in triplet quantum and singlet oxygen quantum yields were marginal when ZnTAPc was simply mixed with FA without a chemical bond. - Highlights: Black-Right-Pointing-Pointer A conjugate between folic acid and a zinc tetraaminophthalocyanine was formed. Black-Right-Pointing-Pointer The conjugate is water soluble even though the phthalocyanine alone is not. Black-Right-Pointing-Pointer The fluorescence quantum yield of the conjugate was enhanced compared to the phthalocyanine alone. Black-Right-Pointing-Pointer Triplet quantum yields decreased for the conjugate.

  11. Organic Solute Transporter α-β Protects Ileal Enterocytes From Bile Acid–Induced InjurySummary

    Directory of Open Access Journals (Sweden)

    Courtney B. Ferrebee

    Full Text Available Background & Aims: Ileal bile acid absorption is mediated by uptake via the apical sodium-dependent bile acid transporter (ASBT, and export via the basolateral heteromeric organic solute transporter α-β (OSTα-OSTβ. In this study, we investigated the cytotoxic effects of enterocyte bile acid stasis in Ostα-/- mice, including the temporal relationship between intestinal injury and initiation of the enterohepatic circulation of bile acids. Methods: Ileal tissue morphometry, histology, markers of cell proliferation, gene, and protein expression were analyzed in male and female wild-type and Ostα-/- mice at postnatal days 5, 10, 15, 20, and 30. Ostα-/-Asbt-/- mice were generated and analyzed. Bile acid activation of intestinal Nrf2-activated pathways was investigated in Drosophila. Results: As early as day 5, Ostα-/- mice showed significantly increased ileal weight per length, decreased villus height, and increased epithelial cell proliferation. This correlated with premature expression of the Asbt and induction of bile acid–activated farnesoid X receptor target genes in neonatal Ostα-/- mice. Expression of reduced nicotinamide adenine dinucleotide phosphate oxidase-1 and Nrf2–anti-oxidant responsive genes were increased significantly in neonatal Ostα-/- mice at these postnatal time points. Bile acids also activated Nrf2 in Drosophila enterocytes and enterocyte-specific knockdown of Nrf2 increased sensitivity of flies to bile acid–induced toxicity. Inactivation of the Asbt prevented the changes in ileal morphology and induction of anti-oxidant response genes in Ostα-/- mice. Conclusions: Early in postnatal development, loss of Ostα leads to bile acid accumulation, oxidative stress, and a restitution response in ileum. In addition to its essential role in maintaining bile acid homeostasis, Ostα-Ostβ functions to protect the ileal epithelium against bile acid–induced injury. NCBI Gene Expression Omnibus: GSE99579. Keywords: Ileum

  12. Postprandial Plasma Concentrations of Individual Bile Acids and FGF-19 in Patients With Type 2 Diabetes

    NARCIS (Netherlands)

    Sonne, David P.; van Nierop, F. Samuel; Kulik, Willem; Soeters, Maarten R.; Vilsbøll, Tina; Knop, Filip K.

    2016-01-01

    Bile acids regulate lipid and carbohydrate metabolism by interaction with membrane or intracellular proteins including the nuclear farnesoid X receptor (FXR). Postprandial activation of ileal FXR leads to secretion of fibroblast growth factor 19 (FGF-19), a gut hormone that may be implicated in

  13. Bile acid synthesis in man. In vivo activity of the 25-hydroxylation pathway

    International Nuclear Information System (INIS)

    Duane, W.C.; Pooler, P.A.; Hamilton, J.N.

    1988-01-01

    During biosynthesis of bile acid, carbons 25-26-27 are removed from the cholesterol side-chain. Side-chain oxidation begins either with hydroxylation at the 26-position, in which case the three-carbon fragment is released as propionic acid, or with hydroxylation at the 25-position, in which case the three-carbon fragment is released as acetone. We have previously shown in the rat that the contribution of the 25-hydroxylation pathway can be quantitated in vivo by measuring production of [ 14 C]acetone from [ 14 C]26-cholesterol. In the present study, we adapted this method to human subjects. 4 d after oral administration of 100 microCi of [ 14 C]26-cholesterol and 1 d after beginning a constant infusion of 16.6 mumol/min unlabeled acetone, three men and two women underwent breath collections. Expired acetone was trapped and purified as the 2,4 dinitrophenylhydrazine derivative. 14 CO 2 was trapped quantitatively using phenethylamine. Specific activity of breath acetone was multiplied by the acetone infusion rate to calculate production of [ 14 C]acetone. [ 14 C]Acetone production averaged 4.9% of total release of 14 C from [ 14 C]26-cholesterol, estimated by 14 CO2 output. The method was validated by showing that [ 14 C]acetone production from [ 14 C]isopropanol averaged 86.9% of the [ 14 C]-isopropanol infusion rate. We conclude that in man, as in the rat, the 25-hydroxylation pathway accounts for less than 5% of bile acid synthesis

  14. Polymeric bile acid sequestrants: review of design, in vitro binding activities, and hypocholesterolemic effects

    Czech Academy of Sciences Publication Activity Database

    Heřmánková, Eva; Žák, A.; Poláková, Lenka; Hobzová, Radka; Hromádka, R.; Širc, Jakub

    2018-01-01

    Roč. 144, 20 January (2018), s. 300-317 ISSN 0223-5234 R&D Projects: GA MPO(CZ) FV10380; GA MŠk(CZ) LQ1604; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:61389013 Keywords : review * bile acid sequestrant * pleiotropic effect Subject RIV: CD - Macromolecular Chemistry OBOR OECD: Medicinal chemistry Impact factor: 4.519, year: 2016

  15. Explanation of colon cancer pathophysiology through analyzing the ...

    African Journals Online (AJOL)

    Abstract. Background: The colon plays a key role in regulating the homeostasis of bile acids. Aim: The present study aims to evaluate the influence of colon cancer towards the homeostasis of bile acids. Methods: The free and conjugated bile acids were determined using ultraperformance LC (UPLC) coupled with ABI 4000.

  16. Explanation of colon cancer pathophysiology through analyzing the ...

    African Journals Online (AJOL)

    Background: The colon plays a key role in regulating the homeostasis of bile acids. Aim: The present study aims to evaluate the influence of colon cancer towards the homeostasis of bile acids. Methods: The free and conjugated bile acids were determined using ultraperformance LC (UPLC) coupled with ABI 4000 QTRAP ...

  17. Pd(II)/Bipyridine-Catalyzed Conjugate Addition of Arylboronic Acids to α,β-Unsaturated Carboxylic Acids. Synthesis of β-Quaternary Carbons Substituted Carboxylic Acids.

    Science.gov (United States)

    Liu, Rui; Yang, Zhenyu; Ni, Yuxin; Song, Kaixuan; Shen, Kai; Lin, Shaohui; Pan, Qinmin

    2017-08-04

    Pd(II)/bipyridine-catalyzed conjugate addition of arylboronic acids to α,β-unsaturated carboxylic acids (including β,β-disubstituted acrylic acids) was developed and optimized, which provided a mild and convenient method for the highly challenging synthesis of β-quaternary carbons substituted carboxylic acids.

  18. Presence of bile acids in human follicular fluid and their relation with embryo development in modified natural cycle IVF

    NARCIS (Netherlands)

    Nagy, R. A.; van Montfoort, A. P. A.; Dikkers, A.; van Echten-Arends, J.; Homminga, I.; Land, J. A.; Hoek, A.; Tietge, U. J. F.

    STUDY QUESTION: Are bile acids (BA) and their respective subspecies present in human follicular fluid (FF) and do they relate to embryo quality in modified natural cycle IVF (MNC-IVF)? SUMMARY ANSWER: BAconcentrations are 2-fold higher in follicular fluid than in serum and ursodeoxycholic acid

  19. Raw milk traditional Italian ewe cheeses as a source of Lactobacillus casei strains with acid-bile resistance and antigenotoxic properties.

    Science.gov (United States)

    Corsetti, Aldo; Caldini, Giovanna; Mastrangelo, Mario; Trotta, Francesca; Valmorri, Sara; Cenci, Giovanni

    2008-07-31

    Twenty-five Lactobacillus casei group strains isolated from ewe cheeses from Abruzzo region, central Italy, were identified by 16S rRNA gene sequencing, differentiated by RAPD-PCR analysis and characterized as in vitro for acid-bile tolerance and antigenotoxic properties. All the strains were very susceptible to simulated gastric fluid (pH 2.0) but most of them recovered viability (ca. 2-3 log-units) when transferred and maintained in simulated intestinal fluid (0.5% w/v bovine bile) for 3 h. Some strains showed potential for deactivating representative genotoxins as highlighted by the SOS-Chromotest. Twelve were active and nine moderately active against 4-nitroquinoline-1-oxide, and one active and only one moderately active against N-methyl-N'-nitro-N-nitrosoguanidine. The active strains produced evident spectroscopic modification of genotoxins after co-incubation. Most isolates with antigenotoxic activity resulted as acid-bile tolerant demonstrating that cheese autochthonous lactobacilli may reach the gut as a viable form and prevent genotoxin DNA damage.

  20. Metastable and equilibrium phase diagrams of unconjugated bilirubin IXα as functions of pH in model bile systems: Implications for pigment gallstone formation.

    Science.gov (United States)

    Berman, Marvin D; Carey, Martin C

    2015-01-01

    Metastable and equilibrium phase diagrams for unconjugated bilirubin IXα (UCB) in bile are yet to be determined for understanding the physical chemistry of pigment gallstone formation. Also, UCB is a molecule of considerable biomedical importance because it is a potent antioxidant and an inhibitor of atherogenesis. We employed principally a titrimetric approach to obtain metastable and equilibrium UCB solubilities in model bile systems composed of taurine-conjugated bile salts, egg yolk lecithin (mixed long-chain phosphatidylcholines), and cholesterol as functions of total lipid concentration, biliary pH values, and CaCl2 plus NaCl concentrations. Metastable and equilibrium precipitation pH values were obtained, and average pKa values of the two carboxyl groups of UCB were calculated. Added lecithin and increased temperature decreased UCB solubility markedly, whereas increases in bile salt concentrations and molar levels of urea augmented solubility. A wide range of NaCl and cholesterol concentrations resulted in no specific effects, whereas added CaCl2 produced large decreases in UCB solubilities at alkaline pH values only. UV-visible absorption spectra were consistent with both hydrophobic and hydrophilic interactions between UCB and bile salts that were strongly influenced by pH. Reliable literature values for UCB compositions of native gallbladder biles revealed that biles from hemolytic mice and humans with black pigment gallstones are markedly supersaturated with UCB and exhibit more acidic pH values, whereas biles from nonstone control animals and patients with cholesterol gallstone are unsaturated with UCB. Copyright © 2015 the American Physiological Society.

  1. Limitations in the use of 14C-glycocholate breath and stool bile acid determinations in patients with chronic diarrhea

    International Nuclear Information System (INIS)

    Ferguson, J.; Walker, K.; Thomson, A.B.

    1986-01-01

    Analysis of a modified 14 C-glycocholate breath test on 165 consecutive in-patients being investigated for chronic diarrhea showed that the measurement of 14 CO 2 between 3 and 6 h after oral dosing of 5 microCi of 14 C-glycocholic acid was of only limited use to distinguish between patients with Crohn's disease (CD), idiopathic bile salt wastage (IBW), or ileal resection (IR) from those with the irritable bowel syndrome (IBS). Continuing 14 CO 2 collections for up to 24 h was of little more help in establishing the presence of bacterial overgrowth syndrome (BOS) and in distinguishing between BOS and CD. Stool bile acid measurements were of use in differentiating between IBW and IBS, but did not distinguish between CD and BOS or between CD and IR. Since the range of normal values was defined by measurements in the IBS group, a positive test was specific for an organic cause of chronic diarrhea. Even so, the sensitivity of the test was relatively low: CD, 53%; IR, 23%; IBW, 14 %; and BOS, 10%. We believe that the 24-h 14 C-glycocholic breath test combined with the measurement of stool bile acids represents a screening test of only limited use for the identification of organic causes of chronic diarrhea

  2. Prospective evaluation of ursodeoxycholic acid withdrawal in patients with primary sclerosing cholangitis.

    Science.gov (United States)

    Wunsch, Ewa; Trottier, Jocelyn; Milkiewicz, Malgorzata; Raszeja-Wyszomirska, Joanna; Hirschfield, Gideon M; Barbier, Olivier; Milkiewicz, Piotr

    2014-09-01

    Ursodeoxycholic acid (UDCA) is no longer recommended for management of adult patients with primary sclerosing cholangitis (PSC). We undertook a prospective evaluation of UDCA withdrawal in a group of consecutive patients with PSC. Twenty six patients, all treated with UDCA (dose range: 10-15 mg/kg/day) were included. Paired blood samples for liver biochemistry, bile acids, and fibroblast growth factor 19 (FGF19) were collected before UDCA withdrawal and 3 months later. Liquid chromatography/tandem mass spectrometry was used for quantification of 29 plasma bile acid metabolites. Pruritus and health-related quality of life (HRQoL) were assessed with a 10-point numeric rating scale, the Medical Outcomes Study Short Form-36 (SF-36), and PBC-40 questionnaires. UDCA withdrawal resulted in a significant deterioration in liver biochemistry (increase of alkaline phosphatase of 75.6%; Pacid analysis revealed a significant decrease in lithocholic acid and its derivatives after UDCA withdrawal, but no effect on concentrations of primary bile acids aside from an increased accumulation of their taurine conjugates. After UDCA removal cholestatic parameters, taurine species of cholic acid and chenodeoxycholic acid correlated with serum FGF19 levels. No significant effect on HRQoL after UDCA withdrawal was observed; however, 42% of patients reported a deterioration in their pruritus. At 3 months, discontinuation of UDCA in patients with PSC causes significant deterioration in liver biochemistry and influences concentrations of bile acid metabolites. A proportion of patients report increased pruritus, but other short-term markers of quality of life are unaffected. © 2014 by the American Association for the Study of Liver Diseases.

  3. Fatty acid profiles in tissues of mice fed conjugated linoleic acid

    DEFF Research Database (Denmark)

    Gøttsche, Jesper; Straarup, Ellen Marie

    2006-01-01

    The incorporation of vaccenic acid (VA, 0.5 and 1.2%), conjugated linoleic acid (CLA, mixture of primarily c9,t11- and t10,c12-CLA, 1.2%), linoleic acid (LA, 1.2%) and oleic acid (OA, 1.2%) into different tissues of mice was examined. The effects on the fatty acid composition of triacylglycerols...... (TAG) and phospholipids (PL) in kidney, spleen, liver and adipose tissue were investigated. VA and CLA (c9,t11- and t10,c12-CLA) were primarily found in TAG, especially in kidney and adipose tissue, respectively. Conversion of VA to c9,t11-CLA was indicated by our results, as both fatty acids were...... incorporated into all the analyzed tissues when a diet containing VA but not c9,t11-CLA was fed. Most of the observed effects on the fatty acid profiles were seen in the CLA group, whereas only minor effects were observed in the VA groups compared with the CA group. Thus, CLA increased n-3 polyunsaturated...

  4. Effect of ursodeoxycholic acid on bile secretion after endoscopic nasobiliary drainage in patients with cholestatic liver disease of various causes

    Directory of Open Access Journals (Sweden)

    LI Lei

    2016-03-01

    Full Text Available ObjectiveTo observe the effect of ursodeoxycholic acid (UDCA on bile secretion in patients with cholestatic liver disease of various causes. MethodsA total of 48 patients who underwent endoscopic nasobiliary drainage (ENBD in Beijing You′an Hospital Affiliated to Capital Medical University from July 2013 to May 2014 were enrolled and divided into UDCA treatment group (n=36 and control group (n=12. The patients in the UDCA group were further divided into common bile duct stone group (n=9, cholangiocarcinoma group (n=7, sclerosing cholangitis group (n=7, and post-liver transplantation group (n=13. The patients in the UDCA treatment group received oral UDCA capsules (250 mg, 3 times/day since the second day after surgery, and the daily volume of bile drainage was recorded for 7 days after surgery. Serum levels of total bilirubin (TBil, total bile acid (TBA, gamma-glutamyl transpeptidase (GGT, and alkaline phosphatase (ALP were measured on the day before surgery and the 7th day after surgery, and the effects of UDCA on volume of bile drainage, TBil, TBA, GGT, and ALP were compared between groups. The t-test was applied for comparison between groups, comparison of continuous data between these groups was made by analysis of variance; the chi-square test was applied for comparison of categorical data between groups. ResultsCompared with the control group, the UDCA treatment group had a significantly increased volume of bile drainage on the 3rd, 4th, and 5th days after surgery (t=2.461, 3.896, and 2.760; P=0.048, 0.021, and 0.034, and the increase in volume of bile drainage was more significant in the common bile duct stone group, the cholangiocarcinoma group, and the post-liver transplantation group, with peak values appearing on the 4th day after surgery. The patients in the common bile duct stone group and the post-liver transplantation group had significantly lower serum levels of TBil, GGT, and ALP on the 7th day after surgery (t=3.340, 2

  5. The hypocholesterolemic and antiatherogenic effects of Cholazol H, a chemically functionalized insoluble fiber with bile acid sequestrant properties in hamsters.

    Science.gov (United States)

    Wilson, T A; Romano, C; Liang, J; Nicolosi, R J

    1998-08-01

    Cholazol H (Alpha-Beta Technology, Worcester, MA), a chemically functionalized, insoluble dietary fiber with bile acid sequestrant properties, was studied in 30 male F1 B Golden Syrian hamsters for its effect on plasma lipid concentrations and early atherogenesis in experiment 1. In experiment 2, 30 male Golden Syrian hamsters were studied for the effects on plasma lipids and fecal excretion of bile acids. In experiment 1, three groups of 10 hamsters each were fed a chow-based hypercholesterolemic diet supplemented with 5% coconut oil and 0.1% cholesterol for 6 weeks. After 6 weeks, hamsters were continued on the diet with either 0% drug (hypercholesterolemic diet [HCD]), 0.5% cholestyramine (CSTY), or 0.5% Cholazol H for 8 weeks. Fasting plasma lipids were measured at weeks 6, 10, and 14, and early atherosclerosis (fatty streak formation) was measured at week 14. Relative to HCD, CSTY and Cholazol H significantly lowered plasma total cholesterol (TC) (-37%, P coconut oil and 0.05% cholesterol and either 0% drug HCD, 0.5% CSTY, or 0.5% Cholazol H for 4 weeks. Fasting plasma lipids were measured at weeks 2 and 4, and fecal bile acids were measured at week 4. Both Cholazol H and CSTY were equally effective in significantly lowering plasma TC (-16%, P < .003, and -13%, P < .01, respectively) and nonHDL-C (-22%, P < .004, and -18%, P < .02, respectively), with no significant effect on HDL-C and TG relative to HCD. Cholazol H and CSTY produced a significantly greater concentration of fecal total bile acids (39%, P < .001, and 28%, P < .002, respectively) relative to HCD. Also, there was a 48% (P < .002) and 65% (P < .001) greater fecal concentration of cholic acid (CA) for Cholazol H-treated hamsters compared with HCD- and CSTY-treated hamsters, respectively. Cholazol H also significantly increased fecal concentration of deoxycholic acid (DCA; 56%, P < .02) compared with HCD. In summary, Cholazol H is as effective as CSTY for prevention of diet

  6. Activation of transmembrane bile acid receptor TGR5 stimulates insulin secretion in pancreatic {beta} cells

    Energy Technology Data Exchange (ETDEWEB)

    Kumar, Divya P.; Rajagopal, Senthilkumar; Mahavadi, Sunila [Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA (United States); Mirshahi, Faridoddin [Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA (United States); Grider, John R. [Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA (United States); Murthy, Karnam S., E-mail: skarnam@vcu.edu [Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA (United States); Sanyal, Arun J., E-mail: asanyal@mcvh-vcu.edu [Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA (United States)

    2012-10-26

    Highlights: Black-Right-Pointing-Pointer G protein coupled receptor TGR5 is expressed in mouse and human islets. Black-Right-Pointing-Pointer TGR5 is coupled to activation of Gs and Ca{sup 2+} release via cAMP/Epac/PLC-{epsilon} pathway. Black-Right-Pointing-Pointer Activation of TGR5 by bile salts and selective ligands causes insulin secretion. Black-Right-Pointing-Pointer TGR5 could be a potential therapeutic target to treat diabetes. -- Abstract: Bile acids act as signaling molecules and stimulate the G protein coupled receptor, TGR5, in addition to nuclear farnesoid X receptor to regulate lipid, glucose and energy metabolism. Bile acid induced activation of TGR5 in the enteroendocrine cells promotes glucagon like peptide-1 (GLP-1) release, which has insulinotropic effect in the pancreatic {beta} cells. In the present study, we have identified the expression of TGR5 in pancreatic {beta} cell line MIN6 and also in mouse and human pancreatic islets. TGR5 selective ligands, oleanolic acid (OA) and INT-777 selectively activated G{alpha}{sub s} and caused an increase in intracellular cAMP and Ca{sup 2+}. OA and INT-777 also increased phosphoinositide (PI) hydrolysis and the increase was blocked by NF449 (a selective G{alpha}{sub s} inhibitor) or (U73122) (PI hydrolysis inhibitor). OA, INT-777 and lithocholic acid increased insulin release in MIN6 and human islets and the increase was inhibited by treatment with NF449, (U73122) or BAPTA-AM (chelator of calcium), but not with myristoylated PKI (PKA inhibitor), suggesting that the release is dependent on G{sub s}/cAMP/Ca{sup 2+} pathway. 8-pCPT-2 Prime -O-Me-cAMP, a cAMP analog, which activates Epac, but not PKA also stimulated PI hydrolysis. In conclusion, our study demonstrates that the TGR5 expressed in the pancreatic {beta} cells regulates insulin secretion and highlights the importance of ongoing therapeutic strategies targeting TGR5 in the control of glucose homeostasis.

  7. Activation of transmembrane bile acid receptor TGR5 stimulates insulin secretion in pancreatic β cells

    International Nuclear Information System (INIS)

    Kumar, Divya P.; Rajagopal, Senthilkumar; Mahavadi, Sunila; Mirshahi, Faridoddin; Grider, John R.; Murthy, Karnam S.; Sanyal, Arun J.

    2012-01-01

    Highlights: ► G protein coupled receptor TGR5 is expressed in mouse and human islets. ► TGR5 is coupled to activation of Gs and Ca 2+ release via cAMP/Epac/PLC-ε pathway. ► Activation of TGR5 by bile salts and selective ligands causes insulin secretion. ► TGR5 could be a potential therapeutic target to treat diabetes. -- Abstract: Bile acids act as signaling molecules and stimulate the G protein coupled receptor, TGR5, in addition to nuclear farnesoid X receptor to regulate lipid, glucose and energy metabolism. Bile acid induced activation of TGR5 in the enteroendocrine cells promotes glucagon like peptide-1 (GLP-1) release, which has insulinotropic effect in the pancreatic β cells. In the present study, we have identified the expression of TGR5 in pancreatic β cell line MIN6 and also in mouse and human pancreatic islets. TGR5 selective ligands, oleanolic acid (OA) and INT-777 selectively activated Gα s and caused an increase in intracellular cAMP and Ca 2+ . OA and INT-777 also increased phosphoinositide (PI) hydrolysis and the increase was blocked by NF449 (a selective Gα s inhibitor) or (U73122) (PI hydrolysis inhibitor). OA, INT-777 and lithocholic acid increased insulin release in MIN6 and human islets and the increase was inhibited by treatment with NF449, (U73122) or BAPTA-AM (chelator of calcium), but not with myristoylated PKI (PKA inhibitor), suggesting that the release is dependent on G s /cAMP/Ca 2+ pathway. 8-pCPT-2′-O-Me-cAMP, a cAMP analog, which activates Epac, but not PKA also stimulated PI hydrolysis. In conclusion, our study demonstrates that the TGR5 expressed in the pancreatic β cells regulates insulin secretion and highlights the importance of ongoing therapeutic strategies targeting TGR5 in the control of glucose homeostasis.

  8. Reversal of metabolic disorders by pharmacological activation of bile acid receptors TGR5 and FXR

    Directory of Open Access Journals (Sweden)

    Kavita Jadhav

    2018-03-01

    Full Text Available Objectives: Activation of the bile acid (BA receptors farnesoid X receptor (FXR or G protein-coupled bile acid receptor (GPBAR1; TGR5 improves metabolic homeostasis. In this study, we aim to determine the impact of pharmacological activation of bile acid receptors by INT-767 on reversal of diet-induced metabolic disorders, and the relative contribution of FXR vs. TGR5 to INT-767's effects on metabolic parameters. Methods: Wild-type (WT, Tgr5−/−, Fxr−/−, Apoe−/− and Shp−/− mice were used to investigate whether and how BA receptor activation by INT-767, a semisynthetic agonist for both FXR and TGR5, could reverse diet-induced metabolic disorders. Results: INT-767 reversed HFD-induced obesity dependent on activation of both TGR5 and FXR and also reversed the development of atherosclerosis and non-alcoholic fatty liver disease (NAFLD. Mechanistically, INT-767 improved hypercholesterolemia by activation of FXR and induced thermogenic genes via activation of TGR5 and/or FXR. Furthermore, INT-767 inhibited several lipogenic genes and de novo lipogenesis in the liver via activation of FXR. We identified peroxisome proliferation-activated receptor γ (PPARγ and CCAAT/enhancer-binding protein α (CEBPα as novel FXR-regulated genes. FXR inhibited PPARγ expression by inducing small heterodimer partner (SHP whereas the inhibition of CEBPα by FXR was SHP-independent. Conclusions: BA receptor activation can reverse obesity, NAFLD, and atherosclerosis by specific activation of FXR or TGR5. Our data suggest that, compared to activation of FXR or TGR5 only, dual activation of both FXR and TGR5 is a more attractive strategy for treatment of common metabolic disorders. Keywords: Farnesoid X receptor, TGR5, Atherosclerosis, Obesity, NAFLD

  9. Thyroid hormone reduces PCSK9 and stimulates bile acid synthesis in humans[S

    OpenAIRE

    Bonde, Ylva; Breuer, Olof; L?tjohann, Dieter; Sj?berg, Stefan; Angelin, Bo; Rudling, Mats

    2014-01-01

    Reduced plasma LDL-cholesterol is a hallmark of hyperthyroidism and is caused by transcriptional stimulation of LDL receptors in the liver. Here, we investigated whether thyroid hormone (TH) actions involve other mechanisms that may also account for the reduction in LDL-cholesterol, including effects on proprotein convertase subtilisin/kexin type 9 (PCSK9) and bile acid synthesis. Twenty hyperthyroid patients were studied before and after clinical normalization, and the responses to hyperthyr...

  10. Resveratrol-loaded glycyrrhizic acid-conjugated human serum albumin nanoparticles wrapping resveratrol nanoparticles: Preparation, characterization, and targeting effect on liver tumors.

    Science.gov (United States)

    Wu, Mingfang; Lian, Bolin; Deng, Yiping; Feng, Ziqi; Zhong, Chen; Wu, Weiwei; Huang, Yannian; Wang, Lingling; Zu, Chang; Zhao, Xiuhua

    2017-08-01

    In this study, glycyrrhizic acid-conjugated human serum albumin nanoparticles wrapping resveratrol nanoparticles were prepared to establish a tumor targeting nano-sized drug delivery system. Glycyrrhizic acid was coupled to human serum albumin, and resveratrol was encapsulated in glycyrrhizic acid-conjugated human serum albumin by high-pressure homogenization emulsification. The average particle size of sample nanoparticles prepared under the optimal conditions was 108.1 ± 5.3 nm with a polydispersity index (PDI) of 0.001, and the amount of glycyrrhizic acid coupled with human serum albumin was 112.56 µg/mg. The drug encapsulation efficiency and drug loading efficiency were 83.6 and 11.5%, respectively. The glycyrrhizic acid-conjugated human serum albumin nanoparticles wrapping resveratrol nanoparticles were characterized through laser light scattering, scanning electron microscopy, Fourier-transform infrared spectroscopy, X-ray diffraction, differential scanning calorimetry, thermogravimetric analyses, and gas chromatography. The characterization results showed that resveratrol in glycyrrhizic acid-conjugated human serum albumin nanoparticles wrapping resveratrol nanoparticles existed in amorphous state and the residual amounts of chloroform and methanol in nanoparticles were separately less than the international conference on harmonization (ICH) limit. The in vitro drug-release study showed that the nanoparticles released the drug slowly and continuously. The inhibitory rate of glycyrrhizic acid-conjugated human serum albumin nanoparticles wrapping resveratrol nanoparticles was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2 H-tetrazolium bromide method. The IC50 values of glycyrrhizic acid-conjugated human serum albumin nanoparticles wrapping resveratrol nanoparticles and resveratrol were 62.5 and 95.5 µg/ml, respectively. The target ability of glycyrrhizic acid-conjugated human serum albumin nanoparticles wrapping resveratrol nanoparticles

  11. Combined quantification of faecal sterols, stanols, stanones and bile acids in soils and terrestrial sediments by gas chromatography-mass spectrometry.

    Science.gov (United States)

    Birk, Jago Jonathan; Dippold, Michaela; Wiesenberg, Guido L B; Glaser, Bruno

    2012-06-15

    Faeces incorporation can alter the concentration patterns of stanols, stanones, Δ(5)-sterols and bile acids in soils and terrestrial sediments. A joint quantification of these substances would give robust and specific information about the faecal input. Therefore, a method was developed for their purification and determination via gas chromatography-mass spectrometry (GC-MS) based on a total lipid extract (TLE) of soils and terrestrial sediments. Stanols, stanones, Δ(5)-steroles and bile acids were extracted by a single Soxhlet extraction yielding a TLE. The TLE was saponified with KOH in methanol. Sequential liquid-liquid extraction was applied to recover the biomarkers from the saponified extract and to separate the bile acids from the neutral stanoles, stanones and Δ(5)-steroles. The neutral fraction was directly purified using solid phase extraction (SPE) columns packed with 5% deactivated silica gel. The bile acids were methylated in dry HCl in methanol and purified on SPE columns packed with activated silica gel. A mixture of hexamethyldisilazane (HMDS), trimethylchlorosilane (TMCS) and pyridine was used to silylate the hydroxyl groups of the stanols and Δ(5)-sterols avoiding a silylation of the keto groups of the stanones in their enol-form. Silylation of the bile acids was carried out with N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) containing N-trimethylsilylimidazole (TSIM). TLEs from a set of soils with different physico-chemical properties were used for method evaluation and for comparison of amounts of faecal biomarkers analysed with saponification and without saponification of the TLE. Therefore, a Regosol, a Podzol and a Ferralsol were sampled. To proof the applicability of the method for faecal biomarker analyses in archaeological soils and sediments, additional samples were taken from pre-Columbian Anthrosols in Amazonia and an Anthrosol from a site in central Europe settled since the Neolithic. The comparison of the amounts of steroids

  12. Comparative studies of bile salts. A new type of bile salt from Arapaima gigas (Cuvier) (family Osteoglossidae).

    Science.gov (United States)

    Haslewood, G A; Tökés, L

    1972-03-01

    1. Arapaima gigas bile salts were hydrolysed by alkali or cleaved with dioxan-trichloroacetic acid to give cholic acid, arapaimic acid, arapaimol-A and arapaimol-B. 2. I.r., n.m.r. and mass spectroscopy and [alpha](D) measurements indicated that arapaimic acid and arapaimol-A and -B are respectively 2alpha,3alpha,7alpha,12alpha-tetrahydroxy-5beta,25in-cholestan-26-oic acid, 5beta,25R-cholestane-2beta,3alpha,7alpha,12alpha,26-pentol and 5beta-cholestane-2beta,3alpha,7alpha,12alpha,26,27-hexol. 3. Partial synthesis of 2beta,3alpha,7alpha,12alpha-tetrahydroxy-5alpha- and -5beta-cholan-24-oic acid and their spectral examination fully confirmed these conclusions. 4. A. gigas bile salts show primitive features in that they comprise alcohol sulphates and a C(27) acid; they are also specialized in showing 2beta-hydroxylation.

  13. Preparation, isolation and identification of non-conjugated C18:2 fatty acid isomers.

    Science.gov (United States)

    Fardin-Kia, Ali Reza

    2016-12-01

    Non-conjugated geometric/positional isomers of linoleic acid (c9,c12-18:2) are often present in processed foods and oils. The following work presents a simple addition/elimination reaction for preparation of non-conjugated 18:2 fatty acid isomers. A mixture containing positional and geometric isomers of C18:2 fatty acids was produced by addition of hydrobromic acid to the fatty acid double bonds, followed by its elimination with a strong sterically hindered base. Pure 8,12-, 8,13-, 9,12-, and 9,13-18:2 fatty acid methyl esters were isolated from the synthetic mixture by a combination of sub-ambient RP-HPLC and Ag + -HPLC. The determination of the double bond position was achieved by GC-MS using picolinyl esters derivatives. The determination of the fatty acid double bond geometric configuration was obtained by partial hydrogenation of the isolated isomer with hydrazine, followed by the GC-FID analysis. Published by Elsevier Ireland Ltd.

  14. Boldine enhances bile production in rats via osmotic and Farnesoid X receptor dependent mechanisms

    International Nuclear Information System (INIS)

    Cermanova, Jolana; Kadova, Zuzana; Zagorova, Marie; Hroch, Milos; Tomsik, Pavel; Nachtigal, Petr; Kudlackova, Zdenka; Pavek, Petr; Dubecka, Michaela; Ceckova, Martina; Staud, Frantisek; Laho, Tomas; Micuda, Stanislav

    2015-01-01

    Boldine, the major alkaloid from the Chilean Boldo tree, is used in traditional medicine to support bile production, but evidence to support this function is controversial. We analyzed the choleretic potential of boldine, including its molecular background. The acute- and long-term effects of boldine were evaluated in rats either during intravenous infusion or after 28-day oral treatment. Infusion of boldine instantly increased the bile flow 1.4-fold in healthy rats as well as in animals with Mrp2 deficiency or ethinylestradiol induced cholestasis. This effect was not associated with a corresponding increase in bile acid or glutathione biliary excretion, indicating that the effect is not related to stimulation of either bile acid dependent or independent mechanisms of bile formation and points to the osmotic activity of boldine itself. We subsequently analyzed bile production under conditions of changing biliary excretion of boldine after bolus intravenous administration and found strong correlations between both parameters. HPLC analysis showed that bile concentrations of boldine above 10 μM were required for induction of choleresis. Importantly, long-term pretreatment, when the bile collection study was performed 24-h after the last administration of boldine, also accelerated bile formation despite undetectable levels of the compound in bile. The effect paralleled upregulation of the Bsep transporter and increased biliary clearance of its substrates, bile acids. We consequently confirmed the ability of boldine to stimulate the Bsep transcriptional regulator, FXR receptor. In conclusion, our study clarified the mechanisms and circumstances surrounding the choleretic activity of boldine. - Highlights: • Boldine may increase bile production by direct as well as indirect mechanisms. • Biliary concentrations of boldine above 10 μM directly stimulate bile production. • Long-term oral boldine administration increases bile acid (BA) biliary secretion. • Boldine

  15. Boldine enhances bile production in rats via osmotic and Farnesoid X receptor dependent mechanisms

    Energy Technology Data Exchange (ETDEWEB)

    Cermanova, Jolana [Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove (Czech Republic); Kadova, Zuzana [Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove (Czech Republic); Deparment of Pharmacology and Toxicology, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove (Czech Republic); Zagorova, Marie [Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove (Czech Republic); Hroch, Milos [Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove (Czech Republic); Department of Medical Biochemistry, Charles University in Prague, Faculty of Medicine in Hradec Kralove (Czech Republic); Tomsik, Pavel [Department of Medical Biochemistry, Charles University in Prague, Faculty of Medicine in Hradec Kralove (Czech Republic); Nachtigal, Petr; Kudlackova, Zdenka [Department of Biological and Medical Sciences, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove (Czech Republic); Pavek, Petr; Dubecka, Michaela; Ceckova, Martina; Staud, Frantisek [Deparment of Pharmacology and Toxicology, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove (Czech Republic); Laho, Tomas [Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove (Czech Republic); Micuda, Stanislav, E-mail: micuda@lfhk.cuni.cz [Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove (Czech Republic)

    2015-05-15

    Boldine, the major alkaloid from the Chilean Boldo tree, is used in traditional medicine to support bile production, but evidence to support this function is controversial. We analyzed the choleretic potential of boldine, including its molecular background. The acute- and long-term effects of boldine were evaluated in rats either during intravenous infusion or after 28-day oral treatment. Infusion of boldine instantly increased the bile flow 1.4-fold in healthy rats as well as in animals with Mrp2 deficiency or ethinylestradiol induced cholestasis. This effect was not associated with a corresponding increase in bile acid or glutathione biliary excretion, indicating that the effect is not related to stimulation of either bile acid dependent or independent mechanisms of bile formation and points to the osmotic activity of boldine itself. We subsequently analyzed bile production under conditions of changing biliary excretion of boldine after bolus intravenous administration and found strong correlations between both parameters. HPLC analysis showed that bile concentrations of boldine above 10 μM were required for induction of choleresis. Importantly, long-term pretreatment, when the bile collection study was performed 24-h after the last administration of boldine, also accelerated bile formation despite undetectable levels of the compound in bile. The effect paralleled upregulation of the Bsep transporter and increased biliary clearance of its substrates, bile acids. We consequently confirmed the ability of boldine to stimulate the Bsep transcriptional regulator, FXR receptor. In conclusion, our study clarified the mechanisms and circumstances surrounding the choleretic activity of boldine. - Highlights: • Boldine may increase bile production by direct as well as indirect mechanisms. • Biliary concentrations of boldine above 10 μM directly stimulate bile production. • Long-term oral boldine administration increases bile acid (BA) biliary secretion. • Boldine

  16. Bile Acid Sequestration Reduces Plasma Glucose Levels in db/db Mice by Increasing Its Metabolic Clearance Rate

    NARCIS (Netherlands)

    Meissner, M.; Herrema, H.J.; Dijk, van Th.; Gerding, A.; Havinga, R.; Boer, T.; Müller, M.R.; Reijngoud, D.J.; Groen, A.K.; Kuipers, F.

    2011-01-01

    Aims/Hypothesis: Bile acid sequestrants (BAS) reduce plasma glucose levels in type II diabetics and in murine models of diabetes but the mechanism herein is unknown. We hypothesized that sequestrant-induced changes in hepatic glucose metabolism would underlie reduced plasma glucose levels.

  17. Improved cellular activity of antisense peptide nucleic acids by conjugation to a cationic peptide-lipid (CatLip) domain

    DEFF Research Database (Denmark)

    Koppelhus, Uffe; Shiraishi, Takehiko; Zachar, Vladimir

    2008-01-01

    Conjugation to cationic cell penetrating peptides (such as Tat, Penetratin, or oligo arginines) efficiently improves the cellular uptake of large hydrophilic molecules such as oligonucleotides and peptide nucleic acids, but the cellular uptake is predominantly via an unproductive endosomal pathway...... for future in vivo applications. We find that simply conjugating a lipid domain (fatty acid) to the cationic peptide (a CatLip conjugate) increases the biological effect of the corresponding PNA (CatLip) conjugates in a luciferase cellular antisense assay up to 2 orders of magnitude. The effect increases...... with increasing length of the fatty acid (C8-C16) but in parallel also results in increased cellular toxicity, with decanoic acid being optimal. Furthermore, the relative enhancement is significantly higher for Tat peptide compared to oligoarginine. Confocal microscopy and chloroquine enhancement indicates...

  18. In vivo multiphoton imaging of bile duct ligation

    Science.gov (United States)

    Liu, Yuan; Li, Feng-Chieh; Chen, Hsiao-Chin; Chang, Po-shou; Yang, Shu-Mei; Lee, Hsuan-Shu; Dong, Chen-Yuan

    2008-02-01

    Bile is the exocrine secretion of liver and synthesized by hepatocytes. It is drained into duodenum for the function of digestion or drained into gallbladder for of storage. Bile duct obstruction is a blockage in the tubes that carry bile to the gallbladder and small intestine. However, Bile duct ligation results in the changes of bile acids in serum, liver, urine, and feces1, 2. In this work, we demonstrate a novel technique to image this pathological condition by using a newly developed in vivo imaging system, which includes multiphoton microscopy and intravital hepatic imaging chamber. The images we acquired demonstrate the uptake, processing of 6-CFDA in hepatocytes and excretion of CF in the bile canaliculi. In addition to imaging, we can also measure kinetics of the green fluorescence intensity.

  19. Plasma bile acids are not associated with energy metabolism in humans

    Directory of Open Access Journals (Sweden)

    Brufau Gemma

    2010-09-01

    Full Text Available Abstract Bile acids (BA have recently been shown to increase energy expenditure in mice, but this concept has not been tested in humans. Therefore, we investigated the relationship between plasma BA levels and energy expenditure in humans. Type 2 diabetic (T2DM patients (n = 12 and gender, age and BMI-matched healthy controls (n = 12 were studied before and after 8 weeks of treatment with a BA sequestrant. In addition, patients with liver cirrhosis (n = 46 were investigated, since these display elevated plasma BA together with increased energy expenditure. This group was compared to gender-, age- and BMI-matched healthy controls (n = 20. Fasting plasma levels of total BA and individual BA species as well as resting energy expenditure were determined. In response to treatment with the BA sequestrant, plasma deoxycholic acid (DCA levels decreased in controls (-60%, p

  20. Digestion of phospholipids after secretion of bile into the duodenum changes the phase behavior of bile components.

    Science.gov (United States)

    Birru, Woldeamanuel A; Warren, Dallas B; Ibrahim, Ahmed; Williams, Hywel D; Benameur, Hassan; Porter, Christopher J H; Chalmers, David K; Pouton, Colin W

    2014-08-04

    Bile components play a significant role in the absorption of dietary fat, by solubilizing the products of fat digestion. The absorption of poorly water-soluble drugs from the gastrointestinal tract is often enhanced by interaction with the pathways of fat digestion and absorption. These processes can enhance drug absorption. Thus, the phase behavior of bile components and digested lipids is of great interest to pharmaceutical scientists who seek to optimize drug solubilization in the gut lumen. This can be achieved by dosing drugs after food or preferably by formulating the drug in a lipid-based delivery system. Phase diagrams of bile salts, lecithin, and water have been available for many years, but here we investigate the association structures that occur in dilute aqueous solution, in concentrations that are present in the gut lumen. More importantly, we have compared these structures with those that would be expected to be present in the intestine soon after secretion of bile. Phosphatidylcholines are rapidly hydrolyzed by pancreatic enzymes to yield equimolar mixtures of their monoacyl equivalents and fatty acids. We constructed phase diagrams that model the association structures formed by the products of digestion of biliary phospholipids. The micelle-vesicle phase boundary was clearly identifiable by dynamic light scattering and nephelometry. These data indicate that a significantly higher molar ratio of lipid to bile salt is required to cause a transition to lamellar phase (i.e., liposomes in dilute solution). Mixed micelles of digested bile have a higher capacity for solubilization of lipids and fat digestion products and can be expected to have a different capacity to solubilize lipophilic drugs. We suggest that mixtures of lysolecithin, fatty acid, and bile salts are a better model of molecular associations in the gut lumen, and such mixtures could be used to better understand the interaction of drugs with the fat digestion and absorption pathway.

  1. Crystal structure of axolotl (Ambystoma mexicanum) liver bile acid-binding protein bound to cholic and oleic acid.

    Science.gov (United States)

    Capaldi, Stefano; Guariento, Mara; Perduca, Massimiliano; Di Pietro, Santiago M; Santomé, José A; Monaco, Hugo L

    2006-07-01

    The family of the liver bile acid-binding proteins (L-BABPs), formerly called liver basic fatty acid-binding proteins (Lb-FABPs) shares fold and sequence similarity with the paralogous liver fatty acid-binding proteins (L-FABPs) but has a different stoichiometry and specificity of ligand binding. This article describes the first X-ray structure of a member of the L-BABP family, axolotl (Ambystoma mexicanum) L-BABP, bound to two different ligands: cholic and oleic acid. The protein binds one molecule of oleic acid in a position that is significantly different from that of either of the two molecules that bind to rat liver FABP. The stoichiometry of binding of cholate is of two ligands per protein molecule, as observed in chicken L-BABP. The cholate molecule that binds buried most deeply into the internal cavity overlaps well with the analogous bound to chicken L-BABP, whereas the second molecule, which interacts with the first only through hydrophobic contacts, is more external and exposed to the solvent. (c) 2006 Wiley-Liss, Inc.

  2. Investigating the chemical changes of chlorogenic acids during coffee brewing: conjugate addition of water to the olefinic moiety of chlorogenic acids and their quinides.

    Science.gov (United States)

    Matei, Marius Febi; Jaiswal, Rakesh; Kuhnert, Nikolai

    2012-12-12

    Coffee is one of the most popular and consumed beverages in the world and is associated with a series of benefits for human health. In this study we focus on the reactivity of chlorogenic acids, the most abundant secondary metabolites in coffee, during the coffee brewing process. We report on the hydroxylation of the chlorogenic acid cinnamoyl substituent by conjugate addition of water to form 3-hydroxydihydrocaffeic acid derivatives using a series of model compounds including monocaffeoyl and dicaffeoylquinic acids and quinic acid lactones. The regiochemistry of conjugate addition was established based on targeted tandem MS experiments. Following conjugate addition of water a reversible water elimination yielding cis-cinnamoyl derivatives accompanied by acyl migration products was observed in model systems. We also report the formation of all of these derivatives during the coffee brewing process.

  3. Retention of bile salts in micellar electrokinetic chromatography: relation of capacity factor to octanol-water partition coefficient and critical micellar concentration.

    Science.gov (United States)

    Lucangioli, S E; Carducci, C N; Tripodi, V P; Kenndler, E

    2001-12-25

    The capacity factors of 16 anionic cholates (from six bile salts, including their glyco- and tauro-conjugates) were determined in a micellar electrokinetic chromatography (MEKC) system consisting of buffer, pH 7.5 (phosphate-boric acid; 20 mmol/l) with 50 mmol/l sodium dodecyl sulfate (SDS) as micelle former and 10% acetonitrile as organic modifier. The capacity factors of the fully dissociated, negatively charged analytes (ranging between 0.2 and 60) were calculated from their mobilities, with a reference background electrolyte (BGE) without SDS representing "free" solution. For comparison, the capacity factors were derived for a second reference BGE where the SDS concentration (5 mmol/l) is close to the critical micellar concentration (CMC). The capacity factors are compared with the logarithm of the octanol-water partition coefficient, log Pow, as measure for lipophilicity. Clear disagreement between these two parameters is found especially for epimeric cholates with the hydroxy group in position 7. In contrast, fair relation between the capacity factor of the analytes and their CMC is observed both depending strongly on the orientation of the OH groups, and tauro-conjugation as well. In this respect the retention behaviour of the bile salts in MEKC seems to reflect their role as detergents in living systems, and might serve as model parameter beyond lipophilicity.

  4. Preparation and Characterization of Self-Assembled Nanoparticles of Hyaluronic Acid-Deoxycholic Acid Conjugates

    Directory of Open Access Journals (Sweden)

    Xuemeng Dong

    2010-01-01

    Full Text Available Novel amphiphilic biopolymers were synthesized using hyaluronic acid (HA as a hydrophilic segment and deoxycholic acid (DOCA as a hydrophobic segment by a 1-ethyl-3-(3-dimethylaminopropyl carbodiimide mediated coupling reaction. The structural characteristics of the HA-DOCA conjugates were investigated using H1 NMR. Self-assembled nanoparticles were prepared based on HA-DOCA conjugates, and its characteristics were investigated using dynamic laser light scattering, transmission electron microscopy (TEM, and fluorescence spectroscopy. The mean diameter was about 293.5 nm with unimodal size distribution in distilled water. The TEM images revealed that the shape of HA-DOCA self-aggregates was spherical. The critical aggregation concentration (CAC was in the range of 0.025–0.056 mg/mL. The partition equilibrium constant (Kv of pyrene in self-aggregates solution was from 1.45×104 to 3.64×104. The aggregation number of DOCA groups per hydrophobic microdomain, estimated by the fluorescence quenching method using cetylpyridinium chloride, increased with increasing degree of substitution.

  5. Conjugated linoleic acid in ewe milk fat.

    Science.gov (United States)

    Luna, Pilar; Fontecha, Javier; Juárez, Manuela; de la Fuente, Miguel Angel

    2005-11-01

    Ewe milk fat from five different herds was studied to determine the content of conjugated linoleic acid (CLA) isomers. Research was carried out by combining gas chromatography-mass spectrometry (GC-MS) of fatty acid methyl esters (FAME) and 4,4-dimethyloxazolyne derivatives (DMOX) with silver ion-high performance liquid chromatography (Ag+-HPLC). Reconstructed mass spectral profiles of CLA characteristic ions from DMOX were used to identify positional isomers and Ag+-HPLC to quantify them. Total CLA content varied from 0.57 to 0.97 g/100 g of total fatty acids. FAME and DMOX were separated into a complex mixture of minor isomers and major rumenic acid (9-cis 11-trans C18:2) by GC-MS using a 100-m polar capillary column. Rumenic acid would represent more than 75% of total CLA. 11-trans 13-trans, 11-13 cis/trans plus trans/cis and 7-9 cis/trans plus trans/cis were the main CLA isomers after rumenic acid. Minor amounts of 8-10 and 10-12 C18:2 isomers were also found. Although most of the isomers were present in each herd's milk, differences in content were observed for some CLA species.

  6. Conjugated linoleic acid as a potential protective factor in prevention of breast cancer 

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    Agnieszka Białek

    2013-01-01

    Full Text Available Cancers are the second leading cause of deaths in Poland, among both women and men. Breast cancer is the malignancy most frequently diagnosed in women. In 2008 mammary cancer was diagnosed in up to 14 500 patients. It is also the second most common cause of cancer deaths among women in our country. Although the etiology of most cases of this disease is not known, risk factors include a variety of nutritional factors. The amount of fat consumed in the diet and the quantity and quality of fatty acids are especially crucial. Among fatty acids to which great importance in modification of cancer risk is attributed are conjugated linoleic acid. Conjugated linoleic acids (CLA are a group of positional and geometric isomers of linoleic acid, with a conjugated double bond system in the carbon chain. The main natural source of them is milk and dairy products and meat of different species of ruminants, in which cis-9, trans-11 octadecadienoic acid (rumenic acid occurs in the largest quantities, constituting over 90�0of the total pool of CLA. Another important isomer is trans-10, cis-12 octadecadienoic acid, which occurs with rumenic acid in dietary supplements, usually in the ratio 1:1. Surveys conducted show their possible health promoting effects in obesity, atherosclerosis, cardiovascular diseases, osteoporosis, diabetes, insulin resistance, inflammation, and various types of cancer, especially breast cancer. 

  7. Acidic bile salts induces mucosal barrier dysfunction through let-7a reduction during gastric carcinogenesis after Helicobacter pylori eradication

    Science.gov (United States)

    Takahashi, Yasushi; Uno, Kaname; Iijima, Katsunori; Abe, Yasuhiko; Koike, Tomoyuki; Asano, Naoki; Asanuma, Kiyotaka; Shimosegawa, Tooru

    2018-01-01

    Gastric cancer (GC) after eradication for Helicobacter pylori (H.pylori) increases, but its carcinogenesis is not elucidated. It is mainly found in acid non-secretion areas (ANA), as mucosal regeneration in acid secretory areas (AA) after eradication changes the acidity and bile toxicity of gastric juice. We aimed to clarify the role of barrier dysfunction of ANA by the stimulation of pH3 bile acid cocktail (ABC) during carcinogenesis. We collected 18 patients after curative endoscopic resection for GC, identified later than 24 months after eradication, and took biopsies by Congo-red chromoendoscopy to distinguish AA and ANA (UMIN00018967). The mucosal barrier function was investigated using a mini-Ussing chamber system and molecular biological methods. The reduction in mucosal impedance in ANA after stimulation was significantly larger than that in AA, 79.6% vs. 87.9%, respectively. The decrease of zonula occludens-1 (ZO-1) and let-7a and the increase of snail in ANA were significant compared to those in AA. In an in vitro study, the restoration of ZO-1 and let-7a as well as the induction of snail were observed after stimulation. High mobility group A2 (HMGA2)-snail activation, MTT proliferation, and cellular infiltration capacity were significantly increased in AGS transfected with let-7a inhibitor, and vice versa. Accordingly, using a mini-Ussing chamber system for human biopsy specimens followed by an in vitro study, we demonstrated for the first time that the exposure of acidic bile salts to ANA might cause serious barrier dysfunction through the let-7a reduction, promoting epithelial-mesenchymal transition during inflammation-associated carcinogenesis even after eradication. PMID:29719591

  8. Cholesterol-lowering effects and mechanisms in view of bile acid pathway of resveratrol and resveratrol-glucuronides

    Science.gov (United States)

    Resveratrol (Res) was previously reported to be capable of lowering plasma TC and LDL-C. The mechanism behind Res is not clearly understood, although it is presumed to have an effect on bile acid metabolism in the liver: a significant way in eliminating cholesterol from the body. As one of the major...

  9. Effect of Safflower Oil on Concentration of Conjugated Linoleic Acid of Kefir Prepared by Low-fat Milk.

    Science.gov (United States)

    Farsad-Naeimi, Alireza; Imani, Saeid; Arefhosseini, Seyed R; Alizadeh, Mohammad

    2015-01-01

    Conjugated linoleic acid (CLA) is a special fatty acid in dairy products with unique antioxidant and anti-cancerous effects. Kefir, a milk product, comprises normalized homogenized cow's milk, the fructose and lactulose syrup as well as a symbiotic starter which has improved probiotic characteristics. The study was aimed to discuss patents and to examine the effect of different safflower oil concentrations on CLA content of the kefir drink prepared by low-fat milk. Safflower oil was added at 0.1, 0.3 and 0.5% (V/V) to low-fat cow's milk and six formulations of kefir samples were prepared. The CLA content of the kefir products was measured at pH=6.0 and pH=6.8 by gas chromatography. Acid and bile tolerance of bacterial microenvironment in the products were also determined. Substitution of natural fat content of milk with safflower oil resulted in proportional increase in the CLA contents of kefir in a dose dependent manner. The highest concentration of CLA was found under 0.5% (V/V) of safflower oil at pH 6.0 and temperature of 37 °C. Adding the Safflower oil into milk used for kefir production, increased CLA content from 0.123 (g/100 g) in pure safflower free samples to 0.322 (g/100 g) in samples with 0.5% (V/V) of safflower oil. The current study revealed that substitution of safflower oil with natural fat of cow's milk may help the production of kefir samples with remarkable increase in CLA content of final product.

  10. REV-ERBalpha participates in circadian SREBP signaling and bile acid homeostasis.

    Directory of Open Access Journals (Sweden)

    Gwendal Le Martelot

    2009-09-01

    Full Text Available In mammals, many aspects of behavior and physiology, and in particular cellular metabolism, are coordinated by the circadian timing system. Molecular clocks are thought to rely on negative feedback loops in clock gene expression that engender oscillations in the accumulation of transcriptional regulatory proteins, such as the orphan receptor REV-ERBalpha. Circadian transcription factors then drive daily rhythms in the expression of clock-controlled output genes, for example genes encoding enzymes and regulators of cellular metabolism. To gain insight into clock output functions of REV-ERBalpha, we carried out genome-wide transcriptome profiling experiments with liver RNA from wild-type mice, Rev-erbalpha knock-out mice, or REV-ERBalpha overexpressing mice. On the basis of these genetic loss- and gain-of-function experiments, we concluded that REV-ERBalpha participates in the circadian modulation of sterol regulatory element-binding protein (SREBP activity, and thereby in the daily expression of SREBP target genes involved in cholesterol and lipid metabolism. This control is exerted via the cyclic transcription of Insig2, encoding a trans-membrane protein that sequesters SREBP proteins to the endoplasmic reticulum membranes and thereby interferes with the proteolytic activation of SREBPs in Golgi membranes. REV-ERBalpha also participates in the cyclic expression of cholesterol-7alpha-hydroxylase (CYP7A1, the rate-limiting enzyme in converting cholesterol to bile acids. Our findings suggest that this control acts via the stimulation of LXR nuclear receptors by cyclically produced oxysterols. In conclusion, our study suggests that rhythmic cholesterol and bile acid metabolism is not just driven by alternating feeding-fasting cycles, but also by REV-ERBalpha, a component of the circadian clockwork circuitry.

  11. Effect of 6-8 weeks of oral ursodeoxycholic acid administration on serum concentrations of fasting and postprandial bile acids and biochemical analytes in healthy dogs.

    Science.gov (United States)

    Deitz, Krysta L; Makielski, Kelly M; Williams, Jackie M; Lin, Hui; Morrison, Jo Ann

    2015-09-01

    Ursodeoxycholic acid (UDCA) is commonly used for the treatment of hepatobiliary disease. UDCA is a bile acid that can be detected in the bile acid assay. Its effect on biochemical analytes is unknown. The aim of this study was to determine the effect of 6-8 weeks of UDCA administration on fasting and postprandial concentrations of serum bile acids (SBA), cholesterol, triglycerides, bilirubin, and liver enzyme activities in healthy dogs. Twenty healthy dogs received UDCA for 6-8 weeks. CBC, biochemistry profile, urinalysis, fasting and postprandial SBA, and hepatobiliary ultrasound examination were performed prior to starting UDCA (timepoint 0) and after 6-8 weeks of therapy, while animals were still receiving UDCA (timepoint 1). Timepoint 0 and timepoint 1 values were compared with a paired t-test. SBA were remeasured 72 hours after UDCA discontinuation. Only mean fasting SBA at timepoint 1 increased significantly (P = .03) from timepoint 0 (2.26 μmol/L at time 0 and 3.81 μmol/L at time 1) but were not elevated above the normal reference interval (0-9 μmol/L). Two dogs had timepoint 1 fasting SBA above the reference interval (10 and 11.7 μmol/L). One dog had timepoint 1 postprandial SBA above the reference interval at 20.1 μmol/L (reference interval 0-17 μmol/L). Repeat SBA 72 hours after UDCA discontinuation were normal. Long-term administration of UDCA to healthy dogs may increase fasting SBA above pretreatment values (typically within the reference interval). Long-term administration of UDCA to healthy dogs does not alter liver enzyme activities, and bilirubin, cholesterol, or triglyceride concentrations. © 2015 American Society for Veterinary Clinical Pathology.

  12. Conjugated linolenic acid (CLnA), conjugated linoleic acid (CLA) and other biohydrogenation intermediates in plasma and milk fat of cows fed raw or extruded linseed.

    Science.gov (United States)

    Akraim, F; Nicot, M C; Juaneda, P; Enjalbert, F

    2007-07-01

    Thirty lactating dairy cows were used in a 3 × 3 Latin-square design to investigate the effects of a raw or extruded blend of linseed and wheat bran (70:30) on plasma and milk fatty-acids (FA). Linseed diets, containing 16.6% linseed blend on a dry-matter basis, decreased milk yield and protein percentage. They decreased the proportions of FA with less than 18 carbons in plasma and milk and resulted in cis-9, cis-12, cis-15 18:3 proportions that were more than three and four times higher in plasma and milk, respectively, whereas cis-9, cis-12 18:2 proportions were decreased by 10-15%. The cis-9, trans-11, cis-15 18:3 isomer of conjugated linolenic acid was not detected in the milk of control cows, but was over 0.15% of total FA in the milk fat of linseed-supplemented cows. Similarly, linseed increased plasma and milk proportions of all biohydrogenation (BH) intermediates in plasma and milk, including the main isomer of conjugated linoleic acid cis-9, trans-11 18:2, except trans-4 18:1 and cis-11, trans-15 18:2 in plasma lipids. In milk fat, compared with raw linseed, extruded linseed further reduced 6:0-16:0 even-chain FA, did not significantly affect the proportions of 18:0, cis-9 18:1 and cis-9, cis-12 18:2, tended to increase cis-9, cis-12, cis-15 18:3, and resulted in an additional increase in the proportions of most BH intermediates. It was concluded that linseed addition can improve the proportion of conjugated linoleic and linolenic acids, and that extrusion further increases the proportions of intermediates of ruminal BH in milk fat.

  13. Liver ischemia and ischemia-reperfusion induces and trafficks the multi-specific metal transporter Atp7b to bile duct canaliculi: possible preferential transport of iron into bile.

    Science.gov (United States)

    Goss, John A; Barshes, Neal R; Karpen, Saul J; Gao, Feng-Qin; Wyllie, Samuel

    2008-04-01

    Both Atp7b (Wilson disease gene) and Atp7a (Menkes disease gene) have been reported to be trafficked by copper. Atp7b is trafficked to the bile duct canaliculi and Atp7a to the plasma membrane. Whether or not liver ischemia or ischemia-reperfusion modulates Atp7b expression and trafficking has not been reported. In this study, we report for the first time that the multi-specific metal transporter Atp7b is significantly induced and trafficked by both liver ischemia alone and liver ischemia-reperfusion, as judged by immunohistochemistry and Western blot analyses. Although hepatocytes also stained for Atp7b, localized intense staining of Atp7b was found on bile duct canaliculi. Inductive coupled plasma-mass spectrometry analysis of bile copper, iron, zinc, and manganese found a corresponding significant increase in biliary iron. In our attempt to determine if the increased biliary iron transport observed may be a result of altered bile flow, lysosomal trafficking, or glutathione biliary transport, we measured bile flow, bile acid phosphatase activity, and glutathione content. No significant difference was found in bile flow, bile acid phosphatase activity, and glutathione, between control livers and livers subjected to ischemia-reperfusion. Thus, we conclude that liver ischemia and ischemia-reperfusion induction and trafficking Atp7b to the bile duct canaliculi may contribute to preferential iron transport into bile.

  14. Scintigraphic diagnosis of bile leakage after laparoscopic cholecystectomy. A prospective study

    NARCIS (Netherlands)

    Pasmans, H. L.; Go, P. M.; Gouma, D. J.; Heidendal, G. A.; van Engelshoven, J. M.; van Kroonenburgh, M. J.

    1992-01-01

    To assess the role of Tc-99m IDA cholescintigraphy in diagnosing bile leakage and bile obstruction after laparoscopic cholecystectomy, 51 studies were performed in 51 patients on the first postoperative day. Two different radioactive bile acid analogs were used, Tc-99m HIDA and Tc-99m trimethylbromo

  15. Proinflammatory cytokines and bile acids upregulate ΔNp73 protein, an inhibitor of p53 and p73 tumor suppressors.

    Directory of Open Access Journals (Sweden)

    Elena Zaika

    Full Text Available Gastroesophageal reflux disease (GERD is the main etiological factor behind the recent rapid increase in the incidence of esophageal adenocarcinoma. During reflux, esophageal cells are exposed to bile at low pH resulting in cellular damage and inflammation, which are known to facilitate cancer development. In this study, we investigated the regulation of p73 isoform, ΔNp73α, in the reflux condition. Previous studies have reported that ΔNp73 exhibits anti-apoptotic and oncogenic properties through inhibition of p53 and p73 proteins. We found that direct exposure of esophageal cells to bile acids in an acidic environment alters the phosphorylation of ΔNp73, its subcellular localization and increases ΔNp73 protein levels. Upregulation of ΔNp73 was also observed in esophageal tissues collected from patients with GERD and Barrett's metaplasia, a precancerous lesion in the esophagus associated with gastric reflux. c-Abl, p38 MAPK, and IKK protein kinases were identified to interact in the regulation of ΔNp73. Their inhibition with chemotherapeutic agents and siRNA suppresses ΔNp73. We also found that pro-inflammatory cytokines, IL-1β and TNFα, are potent inducers of ΔNp73α, which further enhance the bile acids/acid effect. Combined, our studies provide evidence that gastroesophageal reflux alters the regulation of oncogenic ΔNp73 isoform that may facilitate tumorigenic transformation of esophageal metaplastic epithelium.

  16. The effect of dietary prebiotics and probiotics on body weight, large intestine indices, and fecal bile acid profile in wild type and IL10-/- mice.

    Directory of Open Access Journals (Sweden)

    Shiu-Ming Kuo

    Full Text Available Previous studies have suggested roles of probiotics and prebiotics on body weight management and intestinal function. Here, the effects of a dietary prebiotic, inulin (50 mg/g diet, and probiotic, Bfidobacterium animalis subsp. lactis (Bb12 (final dose verified at 10(5 colony forming unit (cfu/g diet, comparable to human consumption, were determined separately and in combination in mice using cellulose-based AIN-93G diets under conditions allowed for the growth of commensal bacteria. Continuous consumption of Bb12 and/or inulin did not affect food intake or body, liver, and spleen weights of young and adult mice. Fecal bile acid profiles were determined by nanoESI-MS/MS tandem mass spectrometry. In the presence of inulin, more bacterial deconjugation of taurine from primary bile acids was observed along with an increased cecal weight. Consumption of inulin in the absence or presence of Bb12 also increased the villus cell height in the proximal colon along with a trend of higher bile acid sulfation by intestinal cells. Feeding Bb12 alone at the physiological dose did not affect bile acid deconjugation and had little effect on other intestinal indices. Although interleukin (IL10-null mice are susceptible to enterocolitis, they maintained the same body weight as the wild type mice under our specific pathogen-free housing condition and showed no signs of inflammation. Nevertheless, they had smaller cecum suggesting a mildly compromised intestinal development even before the disease manifestation. Our results are consistent with the notion that dietary factors such as prebiotics play important roles in the growth of intestinal microbiota and may impact on the intestinal health. In addition, fecal bile acid profiling could potentially be a non-invasive tool in monitoring the intestinal environment.

  17. Conjugated Linoleic Acid (CLA) content in different tissues of ruminants fed with CLA supplementation

    OpenAIRE

    Pellattiero, Erika

    2014-01-01

    Conjugated Linoleic Acid (CLA) are a group of positional and geometric isomers of Linoleic Acid characterized by a carbon chain containing 18 carbon atoms and two double bonds, not in the classic position (cis), but conjugated from the carbons atoms 9, 10 or 11. Double bonds have different position in the carbon chain ([7,9], [8,10], [9,11], [10,12], [11,13] and [12,14]) and four different geometric distribution (cis/trans, trans/cis, cis/cis and trans/trans). In total 24 possible isomers are...

  18. Viability, Acid and Bile Tolerance of Spray Dried Probiotic Bacteria and Some Commercial Probiotic Supplement Products Kept at Room Temperature.

    Science.gov (United States)

    Dianawati, Dianawati; Mishra, Vijay; Shah, Nagendra P

    2016-06-01

    Production of probiotic food supplements that are shelf-stable at room temperature has been developed for consumer's convenience, but information on the stability in acid and bile environment is still scarce. Viability and acid and bile tolerance of microencapsulated Bifidobacterium spp. and Lactobacillus acidophilus and 4 commercial probiotic supplements were evaluated. Bifidobacterium and L. acidophilus were encapsulated with casein-based emulsion using spray drying. Water activity (aw ) of the microspheres containing Bifidobacterium or L. acidophilus (SD GM product) was adjusted to 0.07 followed by storage at 25 °C for 10 wk. Encapsulated Bifidobacterium spp. and Lactobacillus acidophilus and 4 commercial probiotic supplement products (AL, GH, RE, and BM) were tested. Since commercial probiotic products contained mixed bacteria, selective media MRS-LP (containing L-cysteine and Na-propionate) and MRS-clindamycin agar were used to grow Bifidobacterium spp. or L. acidophilus, respectively, and to inhibit the growth of other strains. The results showed that aw had a strong negative correlation with the viability of dehydrated probiotics of the 6 products. Viable counts of Bifidobacterium spp. and L. acidophilus of SD GM, AL, and GH were between 8.3 and 9.2 log CFU/g, whereas that of BM and RE were between 6.7 and 7.3 log CFU/g. Bifidobacterium in SD GM, in AL, and in GH products and L. acidophilus in SD GM, in AL, and in BM products demonstrated high tolerance to acid. Most of dehydrated probiotic bacteria were able to survive in bile environment except L. acidophilus in RE product. Exposure to gastric juice influenced bacterial survivability in subsequent bile environment. © 2016 Institute of Food Technologists®

  19. Recirculation and reutilization of micellar bile lecithin.

    Science.gov (United States)

    Robins, S J

    1975-09-01

    Bile lecithins, solubilized in micellar bile salt and radiolabeled in the 1-acyl fatty acid, phosphorus, and choline positions, were infused in the small bowel of fasted rats. Absorption of each label was virtually complete after 24 h. However, these lecithins were extensively hydrolyzed in the bowel lumen as well as after absorption, and neither the fatty acid nor phosphorus was significantly retained in the enterohepatic circulation or reutilized for biliary lecithin synthesis. In contrast, while choline was also dissociated from absorbed lecithin, choline was instead retained in the liver, reincorporated into newly synthesized hepatic lecithin, and sercreted in biliary lecithin in 10-fold greater amounts than either the fatty acid or phosphorus. However, the extent of choline incorporation into bile lecithin was limited and was not further increased when free choline was directly injected into the portal vein. The data therefore suggest that although only choline of absorbed lecithin is retained in the enterohepatic circulation and preserved for new biliary lecithin synthesis, exogenous choline utilization is regulated by the size of the available hepatic pool.

  20. Analysis of Peptides and Conjugates by Amino Acid Analysis

    DEFF Research Database (Denmark)

    Højrup, Peter

    2015-01-01

    Amino acid analysis is a highly accurate method for characterization of the composition of synthetic peptides. Together with mass spectrometry, it gives a reliable control of peptide quality and quantity before conjugation and immunization.Peptides are hydrolyzed, preferably in gas phase, with 6 M...... HCl at 110 °C for 20-24 h and the resulting amino acids analyzed by ion-exchange chromatography with post-column ninhydrin derivatization. Depending on the hydrolysis conditions, tryptophan is destroyed, and cysteine also, unless derivatized, and the amides, glutamine and asparagine, are deamidated...... to glutamic acid and aspartic acid, respectively. Three different ways of calculating results are suggested, and taking the above limitations into account, a quantitation better than 5 % can usually be obtained....

  1. Dansyl-labeled cholic acid as a tool to build speciation diagrams for the aggregation of bile acids.

    Science.gov (United States)

    Gomez-Mendoza, Miguel; Marin, M Luisa; Miranda, Miguel A

    2012-12-27

    Bile acids (BAs) are a family of natural steroids biosynthesized from cholesterol in the liver that tend to form aggregates in solution. A fluorescent derivative of cholic acid, namely 3α-Dns-ChA, was employed as a reporter to establish the speciation diagrams of the most abundant BAs that can be found mainly in three microenvironments, solution, and primary and secondary aggregates. The developed methodology is based on the analysis of the combined steady-state and time-resolved experiments performed on 3α-Dns-ChA whose emission behavior was found to be strongly medium dependent. In particular, speciation diagrams of sodium glycocholate (NaGCh), sodium taurocholate (NaTCh), sodium chenodeoxycholate (NaCDCh), sodium glycochenodeoxycholate (NaGCDCh), sodium deoxycholate (NaDCh), and sodium ursodeoxycholate (NaUDCh) were successfully built up.

  2. A technique for extraction and Thin Layer Chromatography visualization of fecal bile acids applied to neotropical felid scats

    Directory of Open Access Journals (Sweden)

    Ada Virginia Cazón Narvaez

    1999-06-01

    Full Text Available Fecal bile acid patterns have been used successfully to identify scats. Neotropical felid scats are capable of this biochemical identification because they present low concentrations of plant pigments that would interfere in fecal bile acids detection. However, neotropical felid scats have poor quantities of bile acids, so we developed in this work a proper technique for their extraction, visualization and determination. Twenty eighth feces of seven different felid species, collected from Zoological and Wildlife Parks, were dried and pulverized. The procedure for analyzing feces is : Take one g of pulverized feces and shake for 3 hr at room temperature in 20 ml benzene : methanol; filter and evaporate to 5 ml. Spot on TLC plate and develop in toluene :acetic acid:water. Dry and visualize with anisaldehyde. Field collected scats could be identified by the bile acids pattern revealed by this specific technique and ,then, used as a source of information for distribution, density and food habits studies.Los patrones de ácidos biliares fecales han sido utilizados satisfactoriamente para identificar heces. Las heces de félidos neotropicales son propicias para ser identificadas bioquímicamente, ya que contienen baja concentración de pigmentos vegetales que pudieran interferir en la detección de ácidos biliares. Sin embargo los ácidos biliares se encuentran en bajas concentraciones en las heces, por lo cual desarrollamos en este trabajo una técnica apropiada para su extracción, visualización y determinación. Veintiocho heces de diferentes félidos recolectadas de Zoológicos y Estaciones de Fauna Silvestre fueron secadas y pulverizadas. El procedimiento para analizar las heces es : Tomar un gramo de feca pulverizada y agitar en 20 ml de benceno :metanol a temperatura ambiente durante 3 hr ; luego filtrar y evaporar hasta 5 ml. Sembrar en placa de TLC y desarrollar en tolueno :ác. acético :agua. Secar y revelar con anisaldehído. Las heces

  3. Thermodynamics of the interaction of γ-cyclodextrin and tauro- and glyco-conjugated bile salts

    DEFF Research Database (Denmark)

    Schönbeck, Jens Christian Sidney; Westh, Peter; Holm, René

    2013-01-01

    The structural differences in the interaction between natural γ-cyclodextrin and bile salts common in rat, dog and man was were investigated by 1H-ROESY and 13C NMR and molecular modeling and the thermodynamic parameters of the reaction by isothermal titration calorimetry. The γ-cyclodextrin was ......The structural differences in the interaction between natural γ-cyclodextrin and bile salts common in rat, dog and man was were investigated by 1H-ROESY and 13C NMR and molecular modeling and the thermodynamic parameters of the reaction by isothermal titration calorimetry. The γ...

  4. Colesevelam attenuates cholestatic liver and bile duct injury in Mdr2-/- mice by modulating composition, signalling and excretion of faecal bile acids.

    Science.gov (United States)

    Fuchs, Claudia Daniela; Paumgartner, Gustav; Mlitz, Veronika; Kunczer, Victoria; Halilbasic, Emina; Leditznig, Nadja; Wahlström, Annika; Ståhlman, Marcus; Thüringer, Andrea; Kashofer, Karl; Stojakovic, Tatjana; Marschall, Hanns-Ulrich; Trauner, Michael

    2018-04-10

    Interruption of the enterohepatic circulation of bile acids (BAs) may protect against BA-mediated cholestatic liver and bile duct injury. BA sequestrants are established to treat cholestatic pruritus, but their impact on the underlying cholestasis is still unclear. We aimed to explore the therapeutic effects and mechanisms of the BA sequestrant colesevelam in a mouse model of sclerosing cholangitis. Mdr2 -/- mice received colesevelam for 8 weeks. Gene expression profiles of BA homeostasis, inflammation and fibrosis were explored in liver, intestine and colon. Hepatic and faecal BA profiles and gut microbiome were analysed. Glucagon-like peptide 1 (GLP-1) levels in portal blood were measured by ELISA. Furthermore, Mdr2 -/- mice as well as wild-type 3,5-diethoxy-carbonyl-1,4-dihydrocollidine-fed mice were treated with GLP-1-receptor agonist exendin-4 for 2 weeks prior to analysis. Colesevelam reduced serum liver enzymes, BAs and expression of proinflammatory and profibrogenic markers. Faecal BA profiling revealed increased levels of secondary BAs after resin treatment, while hepatic and biliary BA composition showed a shift towards more hydrophilic BAs. Colonic GLP-1 secretion, portal venous GLP-1 levels and intestinal messenger RNA expression of gut hormone Proglucagon were increased, while ileal Fgf15 expression was abolished by colesevelam. Exendin-4 treatment increased bile duct mass without promoting a reactive cholangiocyte phenotype in mouse models of sclerosing cholangitis. Microbiota analysis showed an increase of the phylum δ-Proteobacteria after colesevelam treatment and a shift within the phyla Firmicutes from Clostridiales to Lactobacillus . Colesevelam increases faecal BA excretion and enhances BA conversion towards secondary BAs, thereby stimulating secretion of GLP-1 from enteroendocrine L-cells and attenuates liver and bile duct injury in Mdr2 -/- mice. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article

  5. Activation of CFTR by ASBT-mediated bile salt absorption

    NARCIS (Netherlands)

    Bijvelds, MJC; Jorna, H; Verkade, HJ; Bot, AGM; Hofmann, F; Agellon, LB; Sinaasappel, M; de Jonge, HR

    2005-01-01

    In cholangiocytes, bile salt (BS) uptake via the apical sodium-dependent bile acid transporter (ASBT) may evoke ductular flow by enhancing cAMP-mediated signaling to the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. We considered that ASBT-mediated BS uptake in the distal

  6. Bile acid sequestration normalizes plasma cholesterol and reduces atherosclerosis in hypercholesterolemic mice. No additional effect of physical activity

    NARCIS (Netherlands)

    Meissner, Maxi; Wolters, Henk; de Boer, Rudolf A.; Havinga, Rick; Boverhof, Renze; Bloks, Vincent W.; Kuipers, Folkert; Groen, Albert K.

    Aims: Bile acid sequestrants (BAS) and physical activity (RUN) decrease incidence of cardiovascular events. Both treatments are often prescribed, yet it is not known whether their beneficial effects are additive. We assessed the effects of BAS treatment alone and in combination with RUN on

  7. An optimized probucol microencapsulated formulation integrating a secondary bile acid (deoxycholic acid as a permeation enhancer

    Directory of Open Access Journals (Sweden)

    Mooranian A

    2014-09-01

    Full Text Available Armin Mooranian,1 Rebecca Negrulj,1 Nigel Chen-Tan,2 Gerald F Watts,3 Frank Arfuso,4 Hani Al-Salami11Biotechnology and Drug Development Research Laboratory, School of Pharmacy, Curtin Health Innovation Research Institute, Biosciences Research Precinct, Curtin University, 2Faculty of Science and Engineering, Curtin University, 3School of Medicine and Pharmacology, Royal Perth Hospital, University of Western Australia, 4School of Biomedical Science, Curtin Health Innovation Research Institute, Biosciences Research Precinct, Curtin University, Perth, AustraliaAbstract: The authors have previously designed, developed, and characterized a novel microencapsulated formulation as a platform for the targeted delivery of therapeutics in an animal model of type 2 diabetes, using the drug probucol (PB. The aim of this study was to optimize PB microcapsules by incorporating the bile acid deoxycholic acid (DCA, which has good permeation-enhancing properties, and to examine its effect on microcapsules’ morphology, rheology, structural and surface characteristics, and excipients’ chemical and thermal compatibilities. Microencapsulation was carried out using a BÜCHI-based microencapsulating system established in the authors’ laboratory. Using the polymer sodium alginate (SA, two microencapsulated formulations were prepared: PB-SA (control and PB-DCA-SA (test at a constant ratio (1:30 and 1:3:30, respectively. Complete characterization of the microcapsules was carried out. The incorporation of DCA resulted in better structural and surface characteristics, uniform morphology, and stable chemical and thermal profiles, while size and rheological parameters remained similar to control. In addition, PB-DCA-SA microcapsules showed good excipients’ compatibilities, which were supported by data from differential scanning calorimetry, Fourier transform infrared spectroscopy, scanning electron microscopy, and energy dispersive X-ray studies, suggesting

  8. Determination of conjugated linoleic acid (CLA) concentrations in milk chocolate.

    Science.gov (United States)

    Hurst, W J; Tarka, S M; Dobson, G; Reid, C M

    2001-03-01

    The fatty acids from a series of milk-chocolate-based confectionery samples were analyzed as methyl esters by GC to determine the presence and amount of conjugated linoleic acid (CLA). A single peak corresponding to the 9-cis,11-trans isomer and ranging from less than 0.1% to nearly 0.2% of the total fatty acids, corresponding to up to 0.3 mg per g of chocolate, was observed. One of the chocolate extracts and a milk extract were subjected to silver ion HPLC and GC-MS in order to confirm the identity of the major isomer and tentatively identity minor isomers.

  9. A study of the relationship between serum bile acids and propranolol pharmacokinetics and pharmacodynamics in patients with liver cirrhosis and in healthy controls.

    Directory of Open Access Journals (Sweden)

    Anne B Taegtmeyer

    Full Text Available The main objectives of the study were to determine the exposure and bioavailability of oral propranolol and to investigate their associations with serum bile acid concentration in patients with liver cirrhosis and in healthy controls. A further objective was to study the pharmacodynamics of propranolol. An open-label crossover study was performed to determine the pharmacokinetics and pharmacodynamics of propranolol after oral (40 mg and intravenous (1 mg administration as well as the concentration of total and individual fasting serum bile acids in 15 patients with liver cirrhosis and 5 healthy controls. After intravenous propranolol, patients showed a 1.8-fold increase in the area under the plasma concentration-time curve (AUC0-∞, a 1.8-fold increase in volume of distribution and a 3-fold increase in the elimination half-life (mean ± SEM: 641±100 vs. 205±43 minutes compared to controls. After oral application, AUC0-∞ and elimination half-life of propranolol were increased 6- and 4-fold, respectively, and bioavailability 3-fold (83±8 vs. 27±9.2%. Maximal effects on blood pressure and heart rate occurred during the first 4 and first 2 hours, respectively, after intravenous and oral application in both patients and controls. Total serum bile acid concentrations were higher in patients than controls (42±11 vs. 2.7±0.3 µmol/L and were linearly correlated with the serum chenodeoxycholic acid concentration. There was a linear correlation between the SBA concentration and propranolol oral AUC0-∞ in subjects not receiving interacting drugs (r2 = 0.73, n = 18. The bioavailability of and exposure to oral propranolol are increased in patients with cirrhosis. Fasting serum bile acid concentration may be helpful in predicting the exposure to oral propranolol in these patients.

  10. The effects of conjugated linoleic acid (CLA) and canola oil on the ...

    African Journals Online (AJOL)

    Dietary conjugated linoleic acid (CLA) causes adverse effects on quality of eggs by modifying the fatty acid composition of the yolk. Supplementing oils prevent CLA-induced changes, but cause a decrease in the level of egg CLA. The objective of the study was to investigate the incorporation of CLA into the egg and its effect ...

  11. Boldine enhances bile production in rats via osmotic and farnesoid X receptor dependent mechanisms.

    Science.gov (United States)

    Cermanova, Jolana; Kadova, Zuzana; Zagorova, Marie; Hroch, Milos; Tomsik, Pavel; Nachtigal, Petr; Kudlackova, Zdenka; Pavek, Petr; Dubecka, Michaela; Ceckova, Martina; Staud, Frantisek; Laho, Tomas; Micuda, Stanislav

    2015-05-15

    Boldine, the major alkaloid from the Chilean Boldo tree, is used in traditional medicine to support bile production, but evidence to support this function is controversial. We analyzed the choleretic potential of boldine, including its molecular background. The acute- and long-term effects of boldine were evaluated in rats either during intravenous infusion or after 28-day oral treatment. Infusion of boldine instantly increased the bile flow 1.4-fold in healthy rats as well as in animals with Mrp2 deficiency or ethinylestradiol induced cholestasis. This effect was not associated with a corresponding increase in bile acid or glutathione biliary excretion, indicating that the effect is not related to stimulation of either bile acid dependent or independent mechanisms of bile formation and points to the osmotic activity of boldine itself. We subsequently analyzed bile production under conditions of changing biliary excretion of boldine after bolus intravenous administration and found strong correlations between both parameters. HPLC analysis showed that bile concentrations of boldine above 10 μM were required for induction of choleresis. Importantly, long-term pretreatment, when the bile collection study was performed 24-h after the last administration of boldine, also accelerated bile formation despite undetectable levels of the compound in bile. The effect paralleled upregulation of the Bsep transporter and increased biliary clearance of its substrates, bile acids. We consequently confirmed the ability of boldine to stimulate the Bsep transcriptional regulator, FXR receptor. In conclusion, our study clarified the mechanisms and circumstances surrounding the choleretic activity of boldine. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Bile pigments in pulmonary and vascular disease

    Directory of Open Access Journals (Sweden)

    Stefan W. Ryter

    2012-03-01

    Full Text Available The bile pigments, biliverdin and bilirubin, are endogenously-derived substances generated during enzymatic heme degradation. These compounds have been shown to act as chemical antioxidants in vitro. Bilirubin formed in tissues circulates in the serum, prior to undergoing hepatic conjugation and biliary excretion. The excess production of bilirubin has been associated with neurotoxicity, in particular to the newborn. Nevertheless, clinical evidence suggests that mild states of hyperbilirubinemia may be beneficial in protecting against cardiovascular disease in adults. Pharmacological application of either bilirubin and/or its biological precursor biliverdin, can provide therapeutic benefit in several animal models of cardiovascular and pulmonary disease. Furthermore, biliverdin and bilirubin can confer protection against ischemia/reperfusion injury and graft rejection secondary to organ transplantation in animal models. Several possible mechanisms for these effects have been proposed, including direct antioxidant and scavenging effects, and modulation of signaling pathways regulating inflammation, apoptosis, cell proliferation, and immune responses. The practicality and therapeutic-effectiveness of bile pigment application to humans remains unclear.

  13. Bile Acids, FXR, and Metabolic Effects of Bariatric Surgery

    Directory of Open Access Journals (Sweden)

    Olivier F. Noel

    2016-01-01

    Full Text Available Overweight and obesity represent major risk factors for diabetes and related metabolic diseases. Obesity is associated with a chronic and progressive inflammatory response leading to the development of insulin resistance and type 2 diabetes (T2D mellitus, although the precise mechanism mediating this inflammatory process remains poorly understood. The most effective intervention for the treatment of obesity, bariatric surgery, leads to glucose normalization and remission of T2D. Recent work in both clinical studies and animal models supports bile acids (BAs as key mediators of these effects. BAs are involved in lipid and glucose homeostasis primarily via the farnesoid X receptor (FXR transcription factor. BAs are also involved in regulating genes involved in inflammation, obesity, and lipid metabolism. Here, we review the novel role of BAs in bariatric surgery and the intersection between BAs and immune, obesity, weight loss, and lipid metabolism genes.

  14. EXOCRINE FUNCTION OF THE LIVER IN RATS WITH EXPOSURE TO CОRVITIN.

    Science.gov (United States)

    Vovkun, T V; Yanchuk, P I; Shtanova, L Y; Vesеlskyу, S P; Shalamaу, A S

    In acute experiments on rats with cannulated bile duct we studied the effect of Corvitin, water-soluble analogue of quercetin, on secretion of bile. Intraportal administration of the test compound at doses of 2,5; 5 and 10 mg/kg resulted in a significant increase in the volume of secreted bile by 20,9, 31,2 and 20,4%, respectively, as compared with the control. Using the method of thin layer chromatography it was established the mild stimulating effect of Corvitin on the processes of bile acids conjugation with taurine and glycine, especially when administered at a dose of 5 mg/kg. This flavonoid did not affect the concentration of glycocholic acid, however increased the content of glycochenodeoxycholic and glycodeoxycholic acids in the mixture between 15 to 35,1%. Regarding free bile acids, the concentration of cholic acid, chenodeoxycholic and deoxycholic acids in the mixture was increased significantly relative to control only after Corvitin application at dose 10 mg/ kg. In the first case – from 17,9 to 29,8%, in the second – from 25 to 65,4%. At the dose of 5 mg/kg, Corvitin significantly increased the ratio of bile cholates conjugation (maximum by 23,2%), whereas 10 mg/kg of the drug decreased this index by 27,0%. After administration of Corvitin, the hydroxylation ratio in all experimental groups differed little from the control: at the dose of 5 and 10 mg/kg this parameter decreased by 14%. Thus, Corvitin modulates exocrine function of the liver, causing an increase in bile secretion and concentration of different cholates, dose-dependently increasing or decreasing the effectiveness of multienzyme systems providing processes of bile acids conjugation in rats.

  15. In Vitro Antioxidant-Activity Evaluation of Gallic-Acid-Grafted Chitosan Conjugate Synthesized by Free-Radical-Induced Grafting Method.

    Science.gov (United States)

    Hu, Qiaobin; Wang, Taoran; Zhou, Mingyong; Xue, Jingyi; Luo, Yangchao

    2016-07-27

    The major objective of this work was to develop a green and facile process to prepare gallic acid-chitosan conjugate and comprehensively evaluate the physicochemical properties and biological activities of an as-prepared water-soluble chitosan derivative. A free-radical-induced grafting approach using an ascorbic acid-hydrogen peroxide redox pair was adopted. The obtained conjugate was characterized by Fourier transform infrared spectroscopy, UV-vis, X-ray diffraction, and pKa analysis. The antioxidant activities were evaluated by 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6)-sulphonic acid (ABTS), reducing power, and oxygen-radical antioxidant-capacity assays. The results showed that the mass ratio of gallic acid to chitosan played a vital role in determining the grafting degree and ζ potential of the conjugates, with the ratio of 0.5:1 being the optimal ratio that resulted in the highest grafting degree. The antioxidant assays demonstrated that conjugation significantly improved the antioxidant activities, being dramatically higher than that of free chitosan. It was notable that the DPPH- and ABTS-scavenging activities of conjugate at 0.4 mg/mL reached the same level as the free gallic acid at the equivalent concentration. Our study demonstrated a green and facile synthesis approach to preparing a novel water-soluble chitosan derivative that may have promising potentials in the food industry.

  16. Amplified spontaneous emission from the exciplex state of a conjugated polymer "PFO" in oleic acid

    Science.gov (United States)

    Idriss, Hajo; Taha, Kamal K.; Aldaghri, O.; Alhathlool, R.; AlSalhi, M. S.; Ibnaouf, K. H.

    2016-09-01

    The amplified spontaneous emission (ASE) characteristics of a conjugated polymer poly (9, 9-dioctylfluorenyl-2, 7-diyl) (PFO) in oleic acid have been studied under different concentrations and temperatures. Here, the ASE spectra of PFO in oleic acid have been obtained using a transverse cavity configuration where the conjugated PFO was pumped by laser pulses from the third harmonic of Nd: YAG laser (355 nm). The PFO in oleic acid produces ASE from an exciplex state - a new molecular species. The obtained results were compared with the PFO in benzene. Such ASE spectra from the exciplex state have not been observed for the PFO in benzene.

  17. The role of an alginate suspension on pepsin and bile acids - key aggressors in the gastric refluxate. Does this have implications for the treatment of gastro-oesophageal reflux disease?

    Science.gov (United States)

    Strugala, Vicki; Avis, Jeanine; Jolliffe, Ian G; Johnstone, Lesley M; Dettmar, Peter W

    2009-08-01

    During a reflux event the oesophagus is exposed to a heterogeneous mixture of gastric juice components. The role of non-acid components of the refluxate in causing damage to the oesophagus is now well established but no therapeutic option exists to address this. The role of Gaviscon Advance (GA), a raft-forming alginate suspension, in protecting the oesophagus from damage by pepsin and bile acids (aggressors) was investigated using a series of in-vitro models. GA was able to dose-dependently inhibit pepsin activity over and above the neutralisation effect of the formulation. This was evident against both protein and collagen substrates using two distinct colorimetric assays. GA was able to retard the diffusion of pepsin and multiple bile acids using a Franz cell model. Using the raft-forming mode of action GA was able to remove both pepsin and multiple bile acids from a simulated reflux event. There was capacity in the GA raft to accommodate aggressors from multiple reflux events. GA can specifically remove both pepsin and bile acids from the refluxate, limit their diffusion and affect enzymatic activity of pepsin. There is a role for GA to reduce the damaging potential of the refluxate and thus protect the oesophagus.

  18. Preparation of chitosan-ferulic acid conjugate: Structure characterization and in the application of pharmaceuticals.

    Science.gov (United States)

    Li, Chen; Li, Jian-Bin

    2017-12-01

    A novel drug delivery system based on chitosan derivatives was prepared by introducting ferulic acid to chitosan adopting a free radical-induced grafting procedure. This paper used an ascorbic acid/hydrogen peroxide redox pair as radical initiator. The chitosan derivative was characterized by Fourier transformed infrared (FTIR), Ultraviolet-visible spectrum (UV), Differential scanning calorimetry (DSC), X-ray diffraction (XRD) and Electron microscopic scanning (SEM). What is more, preparing microcapsules with the chitosan conjugate as wall material, the drug release propertie of chitosan conjugates were compared with that of a blank chitosan, which treated in the same conditions but in the absence of ferulic acid. The study clearly demonstrates that free radical-induced grafting procedure was an effective reaction methods and chitosan-ferulic acid is a potential functionalized carrier material for drug delivery. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Attenuated Effects of Bile Acids on Glucose Metabolism and Insulin Sensitivity in a Male Mouse Model of Prenatal Undernutrition

    NARCIS (Netherlands)

    Ma, Huijuan; Sales, Vicencia M.; Wolf, Ashley R.; Subramanian, Sathish; Matthews, Tucker J.; Chen, Michael; Sharma, Aparna; Gall, Walt; Kulik, Wim; Cohen, David E.; Adachi, Yusuke; Griffin, Nicholas W.; Gordon, Jeffrey I.; Patti, Mary-Elizabeth; Isganaitis, Elvira

    2017-01-01

    Prenatal undernutrition and low birth weight are associated with risk of type 2 diabetes and obesity. Prenatal caloric restriction results in low birth weight, glucose intolerance, obesity, and reduced plasma bile acids (BAs) in offspring mice. Because BAs can regulate systemic metabolism and

  20. Bile-induced secretion of glucagon-like peptide-1: pathophysiological implications in type 2 diabetes?

    DEFF Research Database (Denmark)

    Knop, Filip Krag

    2010-01-01

    During the last decades it has become clear that bile acids not only act as simple fat solubilizers, but additionally represent complex hormonal metabolic integrators. Bile acids activate both nuclear receptors (controlling transcription of genes involved in for example bile acid, cholesterol......, and glucose metabolism) and the cell surface G protein-coupled receptor TGR5 (modulating energy expenditure in brown fat and muscle cells). It has been shown that TGR5 is expressed in enteroendocrine L cells, which secrete the potent glucose-lowering incretin hormone glucagon-like peptide-1 (GLP-1). Recently...