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Sample records for bile acids and salts

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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. ...

  7. 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.

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

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    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.

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

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    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

  10. 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,

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

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    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.

  12. Coexpression of bile salt hydrolase gene and catalase gene remarkably improves oxidative stress and bile salt resistance in Lactobacillus casei.

    Science.gov (United States)

    Wang, Guohong; Yin, Sheng; An, Haoran; Chen, Shangwu; Hao, Yanling

    2011-08-01

    Lactic acid bacteria (LAB) encounter various types of stress during industrial processes and gastrointestinal transit. Catalase (CAT) and bile salt hydrolase (BSH) can protect bacteria from oxidative stress or damage caused by bile salts by decomposing hydrogen peroxide (H(2)O(2)) or deconjugating the bile salts, respectively. Lactobacillus casei is a valuable probiotic strain and is often deficient in both CAT and BSH. In order to improve the resistance of L. casei to both oxidative and bile salts stress, the catalase gene katA from L. sakei and the bile salt hydrolase gene bsh1 from L. plantarum were coexpressed in L. casei HX01. The enzyme activities of CAT and BSH were 2.41 μmol H(2)O(2)/min/10(8) colony-forming units (CFU) and 2.11 μmol glycine/min/ml in the recombinant L. casei CB, respectively. After incubation with 8 mM H(2)O(2), survival ratio of L. casei CB was 40-fold higher than that of L. casei CK. Treatment of L. casei CB with various concentrations of sodium glycodeoxycholate (GDCA) showed that ~10(5) CFU/ml cells survived after incubation with 0.5% GDCA, whereas almost all the L. casei CK cells were killed when treaded with 0.4% GDCA. These results indicate that the coexpression of CAT and BSH confers high-level resistance to both oxidative and bile salts stress conditions in L. casei HX01.

  13. Supra-molecular Association and Polymorphic Behaviour In Systems Containing Bile Acid Salts

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    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.

  14. 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.

  15. Gene expression changes associated with Barrett's esophagus and Barrett's-associated adenocarcinoma cell lines after acid or bile salt exposure

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    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.

  16. 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)

  17. Bile salts as semiochemicals in fish

    Science.gov (United States)

    Buchinger, Tyler J.; Li, Weiming; Johnson, Nicholas S.

    2014-01-01

    Bile salts are potent olfactory stimuli in fishes; however the biological functions driving such sensitivity remain poorly understood. We provide an integrative review of bile salts as semiochemicals in fish. First, we present characteristics of bile salt structure, metabolism, and function that are particularly relevant to chemical communication. Bile salts display a systematic pattern of structural variation across taxa, are efficiently synthesized, and are stable in the environment. Bile salts are released into the water via the intestine, urinary tract, or gills, and are highly water soluble. Second, we consider the potential role of bile salts as semiochemicals in the contexts of detecting nearby fish, foraging, assessing risk, migrating, and spawning. Lastly, we suggest future studies on bile salts as semiochemicals further characterize release into the environment, behavioral responses by receivers, and directly test the biological contexts underlying olfactory sensitivity.

  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. Identification of a single sinusoidal bile salt uptake system in skate liver

    International Nuclear Information System (INIS)

    Fricker, G.; Hugentobler, G.; Meier, P.J.; Kurz, G.; Boyer, J.L.

    1987-01-01

    To identify the sinusoidal bile acid uptake system(s) of skate liver, photoaffinity labeling and kinetic transport studies were performed in isolated plasma membranes as well as intact hepatocytes. In both preparations photoaffinity labeling with the photolabile bile salt derivative revealed the presence of a predominant bile salt binding polypeptide with an apparent molecular weight of 54,000. The [ 3 H]-labeling of this polypeptide was inhibited by taurocholate and cholate in a concentration-dependent manner and was virtually abolished by 1 mM of the anion transport inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid. Kinetic studies of hepatic uptake with taurocholate, cholate, and the photoreactive bile salt derivative indicated the involvement of a single transport system, and all three substrates mutually competed with the uptake of each other. Finally, irreversible inhibition of the bile salt uptake system of photoaffinity labeling of hepatocytes with high concentrations of photolabile derivative reduced the V max but the K m of taurocholate uptake. These findings strongly indicate that a single polypeptide with an apparent molecular weight of 54,000 is involved in sinusoidal bile salt uptake into skate hepatocytes. These findings contrast with similar studies in rat liver that implicate both a 54,000- and 48,000-K polypeptide in bile salt uptake and are consistent with a single Na + -independent transport mechanism for hepatic bile salt uptake in this primitive vertebrate

  20. 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).

  1. 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

  2. Bile salts and their importance for drug absorption

    DEFF Research Database (Denmark)

    Holm, René; Müllertz, Anette; Mu, Huiling

    2013-01-01

    Bile salts are present in the intestines of humans as well as the animals used during the development of pharmaceutical products. This review provides a short introduction into the physical chemical properties of bile salts, a description of the bile concentration and composition of bile...... in different animal species and an overview of the literature investigating the influence of bile salts on the in vivo performance of different compounds and drug formulations. Generally, there is a positive effect on bioavailability when bile is present in the gastro-intestinal tract, independent...

  3. 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.

  4. 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

  5. A new insight into the physiological role of bile salt hydrolase among intestinal bacteria from the genus Bifidobacterium.

    Science.gov (United States)

    Jarocki, Piotr; Podleśny, Marcin; Glibowski, Paweł; Targoński, Zdzisław

    2014-01-01

    This study analyzes the occurrence of bile salt hydrolase in fourteen strains belonging to the genus Bifidobacterium. Deconjugation activity was detected using a plate test, two-step enzymatic reaction and activity staining on a native polyacrylamide gel. Subsequently, bile salt hydrolases from B. pseudocatenulatum and B. longum subsp. suis were purified using a two-step chromatographic procedure. Biochemical characterization of the bile salt hydrolases showed that the purified enzymes hydrolyzed all of the six major human bile salts under the pH and temperature conditions commonly found in the human gastrointestinal tract. Next, the dynamic rheometry was applied to monitor the gelation process of deoxycholic acid under different conditions. The results showed that bile acids displayed aqueous media gelating properties. Finally, gel-forming abilities of bifidobacteria exhibiting bile salt hydrolase activity were analyzed. Our investigations have demonstrated that the release of deconjugated bile acids led to the gelation phenomenon of the enzymatic reaction solution containing purified BSH. The presented results suggest that bile salt hydrolase activity commonly found among intestinal microbiota increases hydrogel-forming abilities of certain bile salts. To our knowledge, this is the first report showing that bile salt hydrolase activity among Bifidobacterium is directly connected with the gelation process of bile salts. In our opinion, if such a phenomenon occurs in physiological conditions of human gut, it may improve bacterial ability to colonize the gastrointestinal tract and their survival in this specific ecological niche.

  6. Changes in cholangiocyte bile salt transporter expression and bile duct injury after orthotopic liver transplantation

    NARCIS (Netherlands)

    Hoekstra, H.; Op Den Dries, S.; Buis, C.I.; Khan, A.A.; Gouw, A.S.H.; Groothuis, G.M.M.; Lisman, T.; Porte, R.J.

    2010-01-01

    Background: Bile salts have been shown to contribute to bile duct injury after orthotopic liver transplantation (OLT). Cholangiocytes modify bile composition by reabsorption of bile salts (cholehepatic shunt) and contribute to bile flow by active secretion of sodium and water via cystic fibrosis

  7. Molecular interactions between bile salts, phospholipids and cholesterol : relevance to bile formation, cholesterol crystallization and bile salt toxicity

    NARCIS (Netherlands)

    Moschetta, Antonio

    2001-01-01

    Cholesterol is a nonpolar lipid dietary constituent, absorbed from the small intestine, transported in blood and taken up by the liver. In bile, the sterol is solubilized in mixed micelles by bile salts and phospholipids. In case of supersaturation, cholesterol is kept in vesicles with phospholipid

  8. Deconjugated bile salts produced by extracellular bile-salt hydrolase-like activities from the probiotic Lactobacillus johnsonii La1 inhibit Giardia duodenalis in vitro growth

    Directory of Open Access Journals (Sweden)

    Marie-Agnès Travers

    2016-09-01

    Full Text Available Giardiasis, currently considered a neglected disease, is caused by the intestinal protozoan parasite Giardia duodenalis and is widely spread in human as well as domestic and wild animals. The lack of appropriate medications and the spread of resistant parasite strains urgently call for the development of novel therapeutic strategies. Host microbiota or certain probiotic strains have the capacity to provide some protection against giardiasis. By combining biological and biochemical approaches, we have been able to decipher a molecular mechanism used by the probiotic strain Lactobacillus johnsonii La1 to prevent Giardia growth in vitro. We provide evidence that the supernatant of this strain contains active principle(s not directly toxic to Giardia but able to convert non-toxic components of bile into components highly toxic to Giardia. By using bile acid profiling, these components were identified as deconjugated bile-salts. A bacterial bile-salt-hydrolase of commercial origin was able to mimic the properties of the supernatant. Mass spectrometric analysis of the bacterial supernatant identified two of the three bile-salt-hydrolases encoded in the genome of this probiotic strain. These observations document a possible mechanism by which L. johnsonii La1, by secreting or releasing BSH-like activity(ies in the vicinity of replicating Giardia in an environment where bile is present and abundant, can fight this parasite. This discovery has both fundamental and applied outcomes to fight giardiasis, based on local delivery of deconjugated bile salts, enzyme deconjugation of bile components, or natural or recombinant probiotic strains that secrete or release such deconjugating activities in a compartment where both bile salts and Giardia are present.

  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. Bile duct proliferation associated with bile salt-induced hypercholeresis in Mdr2 P-glycoprotein-deficient mice

    NARCIS (Netherlands)

    Hulzebos, CV; Voshol, PJ; Wolters, H; Kruit, JK; Ottenhof, R; Groen, AK; Stellaard, F; Verkade, HJ; Kuipers, F

    Baekground/Aims: Bile flow consists of bile salt-dependent bile flow (BSDF), generated by canalicular secretion of bile salts, and bile salt-independent flow (BSIF), probably of combined canalicular and ductular origin. Bile salt transport proteins have been identified in cholangiocytes suggesting a

  11. [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.

  12. Bile salts stimulate mucin secretion by cultured dog gallbladder epithelial cells independent of their detergent effect.

    OpenAIRE

    Klinkspoor, J H; Yoshida, T; Lee, S P

    1998-01-01

    1. Bile salts stimulate mucin secretion by the gallbladder epithelium. We have investigated whether this stimulatory effect is due to a detergent effect of bile salts. 2. The bile salts taurocholic acid (TC) and tauroursodeoxycholic acid (TUDC) and the detergents Triton X-100 (12.5-400 microM) and Tween-20 (0.1-3.2 mM) were applied to monolayers of cultured dog gallbladder epithelial cells. Mucin secretion was studied by measuring the secretion of [3H]N-acetyl-d-glucosamine-labelled glycoprot...

  13. Isolation, Identification and Partial Characterization of a Lactobacillus casei Strain with Bile Salt Hydrolase Activity from Pulque.

    Science.gov (United States)

    González-Vázquez, R; Azaola-Espinosa, A; Mayorga-Reyes, L; Reyes-Nava, L A; Shah, N P; Rivera-Espinoza, Y

    2015-12-01

    The aim of this study was to isolate, from pulque, Lactobacillus spp. capable of survival in simulated gastrointestinal stress conditions. Nine Gram-positive rods were isolated; however, only one strain (J57) shared identity with Lactobacillus and was registered as Lactobacillus casei J57 (GenBank accession: JN182264). The other strains were identified as Bacillus spp. The most significant observation during the test of tolerance to simulated gastrointestinal conditions (acidity, gastric juice and bile salts) was that L. casei J57 showed a rapid decrease (p ≤ 0.05) in the viable population at 0 h. Bile salts were the stress condition that most affected its survival, from which deoxycholic acid and the mix of bile salts (oxgall) were the most toxic. L. casei J57 showed bile salt hydrolase activity over primary and secondary bile salts as follows: 44.91, 671.72, 45.27 and 61.57 U/mg to glycocholate, taurocholate, glycodeoxycholate and taurodeoxycholate. In contrast, the control strain (L. casei Shirota) only showed activity over tauroconjugates. These results suggest that L. casei J57 shows potential for probiotic applications.

  14. 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.

  15. Interactions between Bacteria and Bile Salts in the Gastrointestinal and Hepatobiliary Tracts

    Directory of Open Access Journals (Sweden)

    Verónica Urdaneta

    2017-10-01

    Full Text Available Bile salts and bacteria have intricate relationships. The composition of the intestinal pool of bile salts is shaped by bacterial metabolism. In turn, bile salts play a role in intestinal homeostasis by controlling the size and the composition of the intestinal microbiota. As a consequence, alteration of the microbiome–bile salt homeostasis can play a role in hepatic and gastrointestinal pathological conditions. Intestinal bacteria use bile salts as environmental signals and in certain cases as nutrients and electron acceptors. However, bile salts are antibacterial compounds that disrupt bacterial membranes, denature proteins, chelate iron and calcium, cause oxidative damage to DNA, and control the expression of eukaryotic genes involved in host defense and immunity. Bacterial species adapted to the mammalian gut are able to endure the antibacterial activities of bile salts by multiple physiological adjustments that include remodeling of the cell envelope and activation of efflux systems and stress responses. Resistance to bile salts permits that certain bile-resistant pathogens can colonize the hepatobiliary tract, and an outstanding example is the chronic infection of the gall bladder by Salmonella enterica. A better understanding of the interactions between bacteria and bile salts may inspire novel therapeutic strategies for gastrointestinal and hepatobiliary diseases that involve microbiome alteration, as well as novel schemes against bacterial infections.

  16. 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.

  17. 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.

  18. 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.

  19. Displacement of Drugs From Cyclodextrin Complexes by Bile Salts

    DEFF Research Database (Denmark)

    Olesen, Niels Erik; Westh, Peter; Holm, Rene

    2016-01-01

    of drug from the cyclodextrin cavity by bile salts present in the small intestine. As bile salts in the intestine are present at concentrations above the critical micelle concentration, an understanding of the interaction between cyclodextrins and bile salts at such supramicellar concentrations (SMC......) is required for a better biopharmaceutical understanding of the release mechanism from orally dosed cyclodextrin complexes. To address this, experiments were conducted by isothermal titration calorimetry to determine how various b-cyclodextrins and bile salt interacts at SMC. Combined analysis of the current...... results and earlier data demonstrated that direct interactions between bile salt micelles and cyclodextrin were negligible. From this knowledge, an extended form of the UCD was suggested to describe the concentration of cyclodextrins to achieve full drug solubilization in the intestine where bile salts...

  20. 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

  1. 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.

  2. Effects of bile salt flux variations on the expression of hepatic bile salt transporters in vivo in mice

    NARCIS (Netherlands)

    Wolters, H; Elzinga, BM; Baller, JFW; Boverhof, R; Schwarz, M; Stieger, B; Verkade, HJ; Kuipers, F

    2002-01-01

    Background/Aims: Expression of hepatic bile salt transporters is partly regulated by bile salts via activation of nuclear farnesoid X-activated receptor (Fxr). We investigated the physiological relevance of this regulation by evaluating transporter expression in mice experiencing different

  3. Effects of bile salt flux variations on the expression of hepatic bile salt transporters in vivo in mice

    NARCIS (Netherlands)

    Wolters, H; Elzinga, BM; Baller, JFW; Boverhof, R; Schwarz, M; Stieger, B; Verkade, HJ; Kuipers, F

    Background/Aims: Expression of hepatic bile salt transporters is partly regulated by bile salts via activation of nuclear farnesoid X-activated receptor (Fxr). We investigated the physiological relevance of this regulation by evaluating transporter expression in mice experiencing different

  4. Supramolecular Complexes Formed in Systems Bile Salt-Bilirubin-Silica

    Science.gov (United States)

    Vlasova, N. N.; Severinovskaya, O. V.; Golovkova, L. P.

    The formation of supramolecular complexes between bilirubin and primary micelles of bile salts has been studied. The association constants of bile salts and binding of bilirubin with these associates have been determined. The adsorption of bilirubin and bile salts from individual and mixed aqueous solutions onto hydrophobic silica surfaces has been investigated. The interaction of bilirubin with primary bile salt micelles and the strong retention in mixed micelles, which are supramolecular complexes, result in the adsorption of bilirubin in free state only.

  5. Defective bile salt biosynthesis and hydroxylation in mice with reduced cytochrome P450 activity

    NARCIS (Netherlands)

    Kunne, Cindy; Acco, Alexandra; Hohenester, Simon; Duijst, Suzanne; de Waart, Dirk R.; Zamanbin, Alaleh; Oude Elferink, Ronald P. J.

    2013-01-01

    The difference in bile salt (BS) composition between rodents and humans is mainly caused by formation of muricholate in rodents as well as by efficient rehydroxylation of deoxycholic acid. The aim of this study was to characterize bile formation in a mouse model (Hrn mice) with hepatic disruption of

  6. 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

  7. 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

  8. The influence of bile salts on the distribution of simvastatin in the octanol/buffer system.

    Science.gov (United States)

    Đanić, Maja; Pavlović, Nebojša; Stanimirov, Bojan; Vukmirović, Saša; Nikolić, Katarina; Agbaba, Danica; Mikov, Momir

    2016-01-01

    Distribution coefficient (D) is useful parameter for evaluating drugs permeability properties across biological membranes, which are of importance for drugs bioavailability. Given that bile acids are intensively studied as drug permeation-modifying and -solubilizing agents, the aim of this study was to estimate the influence of sodium salts of cholic (CA), deoxycholic (DCA) and 12-monoketocholic acids (MKC) on distribution coefficient of simvastatin (SV) (lactone [SVL] and acid form [SVA]) which is a highly lipophilic compound with extremely low water solubility and bioavailability. LogD values of SVA and SVL with or without bile salts were measured by liquid-liquid extraction in n-octanol/buffer systems at pH 5 and 7.4. SV concentrations in aqueous phase were determined by HPLC-DAD. Chem3D Ultra program was applied for computation of physico-chemical properties of analyzed compounds and their complexes. Statistically significant decrease in both SVA and SVL logD was observed for all three studied bile salts at both selected pH. MKC exerted the most pronounced effect in the case of SVA while there were no statistically significant differences between observed bile salts for SVL. The calculated physico-chemical properties of analyzed compounds and their complexes supported experimental results. Our data indicate that the addition of bile salts into the n-octanol/buffer system decreases the values of SV distribution coefficient at both studied pH values. This may be the result of the formation of hydrophilic complexes increasing the solubility of SV that could consequently impact the pharmacokinetic parameters of SV and the final drug response in patients.

  9. Effects of heat, cold, acid and bile salt adaptations on the stress tolerance and protein expression of kefir-isolated probiotic Lactobacillus kefiranofaciens M1.

    Science.gov (United States)

    Chen, Ming-Ju; Tang, Hsin-Yu; Chiang, Ming-Lun

    2017-09-01

    Lactobacillus kefiranofaciens M1 is a probiotic strain isolated from Taiwanese kefir grains. The present study evaluated the effects of heat, cold, acid and bile salt adaptations on the stress tolerance of L. kefiranofaciens M1. The regulation of protein expression of L. kefiranofaciens M1 under these adaptation conditions was also investigated. The results showed that adaptation of L. kefiranofaciens M1 to heat, cold, acid and bile salts induced homologous tolerance and cross-protection against heterologous challenge. The extent of induced tolerance varied depending on the type and condition of stress. Proteomic analysis revealed that 27 proteins exhibited differences in expression between non-adapted and stress-adapted L. kefiranofaciens M1 cells. Among these proteins, three proteins involved in carbohydrate metabolism (triosephosphate isomerase, enolase and NAD-dependent glycerol-3-phosphate dehydrogenase), two proteins involved in pH homeostasis (ATP synthase subunits AtpA and AtpB), two stress response proteins (chaperones DnaK and GroEL) and one translation-related protein (30S ribosomal protein S2) were up-regulated by three of the four adaptation treatments examined. The increased synthesis of these stress proteins might play a critical protective role in the cellular defense against heat, cold, acid and bile salt stresses. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Solubilization and Interaction Studies of Bile Salts with Surfactants and Drugs: a Review.

    Science.gov (United States)

    Malik, Nisar Ahmad

    2016-05-01

    In this review, bile salt, bile salt-surfactant, and bile salt-drug interactions and their solubilization studies are mainly focused. Usefulness of bile salts in digestion, absorption, and excretion of various compounds and their rare properties in ordering the shape and size of the micelles owing to the presence of hydrophobic and hydrophilic faces are taken into consideration while compiling this review. Bile salts as potential bio-surfactants to solubilize drugs of interest are also highlighted. This review will give an insight into the selection of drugs in different applications as their properties get modified by interaction with bile salts, thus influencing their solution behavior which, in turn, modifies the phase-forming behavior, microemulsion, and clouding phenomenon, besides solubilization. Finally, their future perspectives are taken into consideration to assess their possible uses as bio-surfactants without side effects to human beings.

  11. 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.

  12. 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

  13. Cytoprotection by fructose and other ketohexoses during bile salt-induced apoptosis of hepatocytes.

    Science.gov (United States)

    Zeid, I M; Bronk, S F; Fesmier, P J; Gores, G J

    1997-01-01

    Toxic bile salts cause hepatocyte necrosis at high concentrations and apoptosis at lower concentrations. Although fructose prevents bile salt-induced necrosis, the effect of fructose on bile salt-induced apoptosis is unclear. Our aim was to determine if fructose also protects against bile salt-induced apoptosis. Fructose inhibited glycochenodeoxycholate (GCDC)-induced apoptosis in a concentration-dependent manner with a maximum inhibition of 72% +/- 10% at 10 mmol/L. First, we determined if fructose inhibited apoptosis by decreasing adenosine triphosphate (ATP) and intracellular pH (pHi). Although fructose decreased ATP to effects, alterations in the expression of bcl-2, or metal chelation, we next determined if the poorly metabolized ketohexoses, tagatose and sorbose, also inhibited apoptosis; unexpectedly, both ketohexoses inhibited apoptosis. Because bile salt-induced apoptosis and necrosis are inhibited by fructose, these data suggest that similar processes initiate bile salt-induced hepatocyte necrosis and apoptosis. In contrast, acidosis, which inhibits necrosis, potentiates apoptosis. Thus, ketohexose-sensitive pathways appear to initiate both bile salt-induced cell apoptosis and necrosis, whereas dissimilar, pH-sensitive, effector mechanisms execute these two different cell death processes.

  14. Bile salts stimulate mucin secretion by cultured dog gallbladder epithelial cells independent of their detergent effect.

    Science.gov (United States)

    Klinkspoor, J H; Yoshida, T; Lee, S P

    1998-05-15

    1. Bile salts stimulate mucin secretion by the gallbladder epithelium. We have investigated whether this stimulatory effect is due to a detergent effect of bile salts. 2. The bile salts taurocholic acid (TC) and tauroursodeoxycholic acid (TUDC) and the detergents Triton X-100 (12.5-400 microM) and Tween-20 (0.1-3.2 mM) were applied to monolayers of cultured dog gallbladder epithelial cells. Mucin secretion was studied by measuring the secretion of [3H]N-acetyl-d-glucosamine-labelled glycoproteins. We also attempted to alter the fluidity of the apical membrane of the cells through extraction of cholesterol with beta-cyclodextrin (2.5-15 mM). The effect on TUDC-induced mucin secretion was studied. Cell viability was assessed by measuring lactate dehydrogenase (LDH) leakage or 51Cr release. 3. In contrast with the bile salts, the detergents were not able to cause an increase in mucin secretion without causing concomitant cell lysis. Concentrations of detergent that increased mucin release (>100 microM Triton X-100, >0.8 mM Tween-20), caused increased LDH release. Incubation with beta-cyclodextrin resulted in effective extraction of cholesterol without causing an increase in 51Cr release. However, no effect of the presumed altered membrane fluidity on TUDC (10 mM)-induced mucin secretion was observed. 4. The stimulatory effect of bile salts on mucin secretion by gallbladder epithelial cells is not affected by the fluidity of the apical membrane of the cells and also cannot be mimicked by other detergents. We conclude that the ability of bile salts to cause mucin secretion by the gallbladder epithelium is not determined by their detergent properties.

  15. 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...

  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. Impact of bile salt adaptation of Lactobacillus delbrueckii subsp. lactis 200 on its interaction capacity with the gut.

    Science.gov (United States)

    Burns, Patricia; Reinheimer, Jorge; Vinderola, Gabriel

    2011-10-01

    In a previous work, bile-salt-resistant derivatives were obtained from non-intestinal lactobacilli. The aim of this work was to investigate the impact of bile adaptation of Lactobacillus delbrueckii subsp. lactis 200 on morphology, surface properties, in vivo interaction capacity with the gut and ability to activate the gut immune response. Electron microscopy studies, growth kinetics in the presence of bovine and porcine bile, the capacity to deconjugate bile acids, hydrophobicity, autoaggregation and co-aggregation capacities were studied for the parental strain and its bile-resistant derivative in vitro. Additionally, survival in intestinal fluid, the interaction with the gut and the immunomodulating capacities were studied in mice. Bile salt adaptation conferred upon the adapted strain a higher capacity to withstand physiological concentrations of bile salts and greater survival capacity in intestinal fluid. However, bile salt exposure reduced cell hydrophobicity, autoaggregation and adhesion capacities, resulting in reduced persistence in the intestinal lumen and delayed capacity to activate the gut immune response. Insight into the effects of bile salts upon the interaction and immunomodulating capacity of lactobacilli with the gut is provided, relating in vitro and in vivo results. Copyright © 2011 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

  18. 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

  19. Vectorial transport of bile salts across MDCK cells expressing both rat Na+-taurocholate cotransporting polypeptide and rat bile salt export pump.

    Science.gov (United States)

    Mita, Sachiko; Suzuki, Hiroshi; Akita, Hidetaka; Stieger, Bruno; Meier, Peter J; Hofmann, Alan F; Sugiyama, Yuichi

    2005-01-01

    Bile salts are predominantly taken up by hepatocytes via the basolateral Na(+)-taurocholate cotransporting polypeptide (NTCP/SLC10A1) and secreted into the bile by the bile salt export pump (BSEP/ABCB11). In the present study, we transfected rat Ntcp and rat Bsep into polarized Madin-Darby canine kidney cells and characterized the transport properties of these cells for eight bile salts. Immunohistochemical staining demonstrated that Ntcp was expressed at the basolateral domains, whereas Bsep was expressed at the apical domains. Basal-to-apical transport of taurocholate across the monolayer expressing only Ntcp and that coexpressing Ntcp/Bsep was observed, whereas the flux across the monolayer of control and Bsep-expressing cells was symmetrical. Basal-to-apical transport of taurocholate across Ntcp/Bsep-coexpressing monolayers was significantly higher than that across monolayers expressing only Ntcp. Kinetic analysis of this vectorial transport of taurocholate gave an apparent K(m) value of 13.9 +/- 4.7 microM for cells expressing Ntcp alone, which is comparable with 22.2 +/- 4.5 microM for cells expressing both Ntcp and Bsep and V(max) values of 15.8 +/- 4.2 and 60.8 +/- 9.0 pmol.min(-1).mg protein(-1) for Ntcp alone and Ntcp and Bsep-coexpressing cells, respectively. Transcellular transport of cholate, glycocholate, taurochenodeoxycholate, chenodeoxycholate, glycochenodeoxycholate, tauroursodeoxycholate, ursodeoxycholate, and glycoursodeoxycholate, but not that of lithocholate was also observed across the double transfectant. This double-expressing system can be used as a model to clarify vectorial transport of bile salts across hepatocytes under physiological conditions.

  20. 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

  1. Possible Correlation Between Bile Salt Hydrolysis and AHL Deamidation: Staphylococcus epidermidis RM1, a Potent Quorum Quencher and Bile Salt Hydrolase Producer.

    Science.gov (United States)

    Mukherji, Ruchira; Prabhune, Asmita

    2015-05-01

    The aim of the present work was to isolate a bile salt hydrolase (BSH) producer from fermented soy curd and explore the ability of the BSH produced to cleave bacterial quorum sensing signals. Bacterial isolates with possible ability to deconjugate bile salts were enriched and isolated on De Man, Rogosa and Sharpe (MRS) medium containing 0.2% bile salts. BSH-producing positive isolate with orange-pink-pigmented colonies was isolated and was identified as a strain of Staphylococcus epidermidis using biochemical and phylogenetic tools. S. epidermidis RM1 was shown to possess both potent BSH and N-acyl homoserine lactone (AHL) cleavage activity. Genetic basis of this dual-enzyme activity was explored by means of specific primers designed using S. epidermidis ATCC 12228 genome as template. It was observed that a single enzyme was not responsible for both the activity. Two different genetic elements corresponding to each of the enzymatic activity were successfully amplified from the genomic DNA of the isolate.

  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 role of bile salt toxicity in the pathogenesis of bile duct injury after non-heart-beating porcine liver transplantation

    NARCIS (Netherlands)

    Yska, Marit J.; Buis, Carlijn I.; Monbaliu, Diethard; Schuurs, Theo A.; Gouw, Annette S. H.; Kahmann, Olivier N. H.; Visser, Dorien S.; Pirenne, Jacques; Porte, Robert J.

    2008-01-01

    Background. Intrahepatic bile duct strictures are a serious complication after non-heart-beating (NHB) liver transplantation. Bile salt toxicity has been identified as an important factor in the pathogenesis of bile duct injury and cholangiopathies. The role of bile salt toxicity in the development

  4. Determination of the faecal excretion of labelled bile salts after i.v. administration of 14 C-cholic

    International Nuclear Information System (INIS)

    Andersson, H.; Filipsson, S.; Hulten, L.

    1978-01-01

    By measuring total faecal radioactivity, correlated to 24-hour enterohepatic circulation following i.v. administration of 14 C-cholic acid, bile salt malabsorption was evaluated before and/or after surgery in 80 patients with Crohn's disease localized to the ileum and/or the colon and the results related to the length of ileum diseased or resected. Before operation bile salt malabsorption was observed only in patients with inflammation of the terminal ileum, but no significant correlation was found between bile salt excretion and the extent of ileal disease. In patients subjected to ileal resection with sacrifice of the ileocaecal valve, bile salt malabsorption correlated strongly to the length of ileum resected. This correlation was about the same in ileostomy patients and in patients subjected to restorative operation. It is concluded that determination of 14 C in faeces is a more sensitive test than the Schilling test and the faecal fat excretion test in reflecting ileal dysfunction, at least in patients with ileal resections. (Auth.)

  5. Angiotensin II protects primary rat hepatocytes against bile salt-induced apoptosis.

    Directory of Open Access Journals (Sweden)

    Golnar Karimian

    Full Text Available UNLABELLED: Angiotensin II (AT-II is a pro-fibrotic compound that acts via membrane-bound receptors (AT-1R/AT-2R and thereby activates hepatic stellate cells (HSCs. AT-II receptor blockers (ARBs are thus important candidates in the treatment of liver fibrosis. However, multiple case reports suggest that AT-1R blockers may induce hepatocyte injury. Therefore, we investigated the effect of AT-II and its receptor blockers on cytokine-, oxidative stress- and bile salt-induced cell death in hepatocytes. Primary rat hepatocytes were exposed to TNF-α/Actinomycin D, the ROS-generating agent menadione or the bile salts: glycochenodeoxycholic acid (GCDCA and tauro-lithocholic acid-3 sulfate (TLCS, to induce apoptosis. AT-II (100 nmol/L was added 10 minutes prior to the cell death-inducing agent. AT-1R antagonists (Sartans and the AT-2R antagonist PD123319 were used at 1 µmol/L. Apoptosis (caspase-3 activity, acridine orange staining and necrosis (Sytox green staining were quantified. Expression of CHOP (marker for ER stress and AT-II receptor mRNAs were quantified by Q-PCR. AT-II dose-dependently reduced GCDCA-induced apoptosis of hepatocytes (-50%, p<0.05 without inducing necrosis. In addition, AT-II reduced TLCS-induced apoptosis of hepatocytes (-50%, p<0.05. However, AT-II did not suppress TNF/Act-D and menadione-induced apoptosis. Only the AT-1R antagonists abolished the protective effect of AT-II against GCDCA-induced apoptosis. AT-II increased phosphorylation of ERK and a significant reversal of the protective effect of AT-II was observed when signaling kinases, including ERK, were inhibited. Moreover, AT-II prevented the GCDCA-induced expression of CHOP (the marker of the ER-mediated apoptosis. CONCLUSION: Angiotensin II protects hepatocytes from bile salt-induced apoptosis through a combined activation of PI3-kinase, MAPKs, PKC pathways and inhibition of bile salt-induced ER stress. Our results suggest a mechanism for the observed hepatocyte

  6. 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.)

  7. 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

  8. 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

  9. EVALUASI IN VITRO TERHADAP KEMAMPUAN ISOLAT BAKTERI ASAM LAKTAT ASAL AIR SUSU IBU UNTUK MENGASIMILASI KOLESTEROL DAN MENDEKONJUGASI GARAM EMPEDU [In Vitro Evaluation of Cholesterol Assimilation and Bile Salt Deconjugation by Lactic Acid Bacteria Isolated from Breast Milk

    Directory of Open Access Journals (Sweden)

    Lilis Nuraida1,2*

    2011-06-01

    Full Text Available Hypercholesterolemia is a risk factor for cardiovascular disease, the leading cause of death in many countries. Several studies have shown that reduction of excessive levels of cholesterol in the blood decreases the risk of cardiovascular disease. It is therefore important to develop ways of reducing serum cholesterol. Based on in vitro and in vivo studies, some of lactic acid bacteria (LAB having potential probiotic properties can reduce total cholesterol and low-density lipoprotein cholesterol levels. The aim of this study was to evaluate the ability of LAB isolated from breast milk in reducing cholesterol by assimilation and by bile salt deconjugation activity in vitro.Thirteen strains of LABs were evaluated for their acid and bile salt resistance and selected to test their ability to assimilate cholesterol and to deconjugate bile salt (natrium taurocholate in vitro. Cholesterol assimilation activity was determined by measuring the difference between the remaining cholesterol in broth medium inoculated with LAB with cholesterol in control after incubation. Bile salt deconjugation activity was determined by measuring free cholic acid released in broth medium after incubation with LAB. The results shows that most of the isolates was susceptible to low pH and all isolates used were able to survive in the presence of 0.5% bile salt. The LAB were also able to assimilate cholesterol at varying levels ranging from 0.86-14.97 µg/ml, with the highest activity showed by Pediococcus pentosaceus 1-A38, Pediococcus pentosaceus 2-B2 and Pediococcus pentosaceus 2-A16. Taurocholate deconjugation assay showed that the isolates have weak bile salts deconjugation activity as indicated by free cholic acid released ranging from 0.06-0.25 µmol/ml, with the highest release in Pediococcus pentosaceus 1-A38 and Pediococcus pentosaceus 1-A22. The present study suggest that Pediococcus pentosaceus 1-A38 was potential for the development of probiotic products with

  10. Bile salt receptor complex activates a pathogenic type III secretion system

    Science.gov (United States)

    Li, Peng; Rivera-Cancel, Giomar; Kinch, Lisa N; Salomon, Dor; Tomchick, Diana R; Grishin, Nick V; Orth, Kim

    2016-01-01

    Bile is an important component of the human gastrointestinal tract with an essential role in food absorption and antimicrobial activities. Enteric bacterial pathogens have developed strategies to sense bile as an environmental cue to regulate virulence genes during infection. We discovered that Vibrio parahaemolyticus VtrC, along with VtrA and VtrB, are required for activating the virulence type III secretion system 2 in response to bile salts. The VtrA/VtrC complex activates VtrB in the presence of bile salts. The crystal structure of the periplasmic domains of the VtrA/VtrC heterodimer reveals a β-barrel with a hydrophobic inner chamber. A co-crystal structure of VtrA/VtrC with bile salt, along with biophysical and mutational analysis, demonstrates that the hydrophobic chamber binds bile salts and activates the virulence network. As part of a family of conserved signaling receptors, VtrA/VtrC provides structural and functional insights into the evolutionarily conserved mechanism used by bacteria to sense their environment. DOI: http://dx.doi.org/10.7554/eLife.15718.001 PMID:27377244

  11. Bile salt receptor complex activates a pathogenic type III secretion system

    Energy Technology Data Exchange (ETDEWEB)

    Li, Peng; Rivera-Cancel, Giomar; Kinch, Lisa N.; Salomon, Dor; Tomchick, Diana R.; Grishin, Nick V.; Orth, Kim

    2016-07-05

    Bile is an important component of the human gastrointestinal tract with an essential role in food absorption and antimicrobial activities. Enteric bacterial pathogens have developed strategies to sense bile as an environmental cue to regulate virulence genes during infection. We discovered thatVibrio parahaemolyticusVtrC, along with VtrA and VtrB, are required for activating the virulence type III secretion system 2 in response to bile salts. The VtrA/VtrC complex activates VtrB in the presence of bile salts. The crystal structure of the periplasmic domains of the VtrA/VtrC heterodimer reveals a β-barrel with a hydrophobic inner chamber. A co-crystal structure of VtrA/VtrC with bile salt, along with biophysical and mutational analysis, demonstrates that the hydrophobic chamber binds bile salts and activates the virulence network. As part of a family of conserved signaling receptors, VtrA/VtrC provides structural and functional insights into the evolutionarily conserved mechanism used by bacteria to sense their environment.

  12. 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

  13. 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

  14. Self-assembly of micelles in organic solutions of lecithin and bile salt: Mesoscale computer simulation

    Science.gov (United States)

    Markina, A.; Ivanov, V.; Komarov, P.; Khokhlov, A.; Tung, S.-H.

    2016-11-01

    We propose a coarse-grained model for studying the effects of adding bile salt to lecithin organosols by means of computer simulation. This model allows us to reveal the mechanisms of experimentally observed increasing of viscosity upon increasing the bile salt concentration. We show that increasing the bile salt to lecithin molar ratio induces the growth of elongated micelles of ellipsoidal and cylindrical shape due to incorporation of disklike bile salt molecules. These wormlike micelles can entangle into transient network displaying perceptible viscoelastic properties.

  15. Hepatic handling of bile salts and protein in the rat during intrahepatic cholestasis

    Energy Technology Data Exchange (ETDEWEB)

    Goldsmith, M.A.; Huling, S.; Jones, A.L.

    1983-05-01

    17 alpha-Ethynyl estradiol-induced cholestasis was used to study the relationship of protein to bile salt transport in liver. The biliary secretion of horseradish peroxidase was unaltered in treated animals despite a 56% reduction in bile flow. Cytochemistry confirmed that estradiol caused no alteration in the handling of tracer. In a second study, the peak biliary secretion of (/sup 14/C)taurocholate was reduced by approximately 46% in treated animals. The kinetics of /sup 125/I-cholyglycylhistamine, a bile salt derivative, were identical to those of taurocholate in control and cholestatic animals. Taurocholate and cholylglycylhistamine secretion were markedly reduced in control animals during competition with unlabeled taurocholate. Quantitative electron microscopic autoradiography with /sup 125/I-cholylglycylhistamine revealed a high concentration of grains over the endoplasmic reticulum and the Golgi complex including associated lysosomes and vesicles. These data demonstrate that estradiol markedly inhibits bile salt transport, but not vesicular transport of horseradish peroxidase. Furthermore, estradiol may alter the movement of bile salts through these organelles.

  16. Bile salt-induced increases in duodenal brush-border membrane proton permeability, fluidity, and fragility

    International Nuclear Information System (INIS)

    Zhao, D.L.; Hirst, B.H.

    1990-01-01

    Rabbit duodenal brush-border membrane vesicles were treated in vitro with deoxycholate, glycodeoxycholate, or taurodeoxycholate. Intravesicular [14C]glucose space at equilibrium, 0.54 microliters/mg protein, was reduced by exposure to the three bile salts in a concentration (0.1-5.0 mM)-dependent manner, equatable with increased membrane fragility. Net proton permeability (Pnet), determined by acridine orange fluorescence quenching, was increased from 6.3 x 10(-4) cm/sec in untreated vesicles, by approximately 120, 150, and 170%, by treatment with bile salts at 0.1, 0.5 and 1.0 mM, respectively. The three bile salts were equipotent. The increases in membrane fragility and Pnet were not accompanied by significant increases in membrane fluidity, as assessed from steady-state and time-resolved diphenylhexatriene fluorescence anisotropy. The data demonstrate direct effects of bile salts on duodenal apical membrane fragility and proton permeability that are likely to be early events in bile salt-induced mucosal damage

  17. Bile Salt Homeostasis in Normal and Bsep Gene Knockout Rats with Single and Repeated Doses of Troglitazone.

    Science.gov (United States)

    Cheng, Yaofeng; Chen, Shenjue; Freeden, Chris; Chen, Weiqi; Zhang, Yueping; Abraham, Pamela; Nelson, David M; Humphreys, W Griffith; Gan, Jinping; Lai, Yurong

    2017-09-01

    The interference of bile acid secretion through bile salt export pump (BSEP) inhibition is one of the mechanisms for troglitazone (TGZ)-induced hepatotoxicity. Here, we investigated the impact of single or repeated oral doses of TGZ (200 mg/kg/day, 7 days) on bile acid homoeostasis in wild-type (WT) and Bsep knockout (KO) rats. Following oral doses, plasma exposures of TGZ were not different between WT and KO rats, and were similar on day 1 and day 7. However, plasma exposures of the major metabolite, troglitazone sulfate (TS), in KO rats were 7.6- and 9.3-fold lower than in WT on day 1 and day 7, respectively, due to increased TS biliary excretion. With Bsep KO, the mRNA levels of multidrug resistance-associated protein 2 (Mrp2), Mrp3, Mrp4, Mdr1, breast cancer resistance protein (Bcrp), sodium taurocholate cotransporting polypeptide, small heterodimer partner, and Sult2A1 were significantly altered in KO rats. Following seven daily TGZ treatments, Cyp7A1 was significantly increased in both WT and KO rats. In the vehicle groups, plasma exposures of individual bile acids demonstrated variable changes in KO rats as compared with WT. WT rats dosed with TGZ showed an increase of many bile acid species in plasma on day 1, suggesting the inhibition of Bsep. Conversely, these changes returned to base levels on day 7. In KO rats, alterations of most bile acids were observed after seven doses of TGZ. Collectively, bile acid homeostasis in rats was regulated through bile acid synthesis and transport in response to Bsep deficiency and TGZ inhibition. Additionally, our study is the first to demonstrate that repeated TGZ doses can upregulate Cyp7A1 in rats. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  18. The canalicular bile salt export pump BSEP (ABCB11) as a potential therapeutic target

    NARCIS (Netherlands)

    Stieger, Bruno; Beuers, Ulrich

    2011-01-01

    Bile formation is a key function of the liver and is driven by active secretion of bile salts and other organic compounds into the biliary tree. Bile salts represent the major organic constituent of bile. They are released with bile into the small intestine, where they are almost quantitatively

  19. 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

  20. 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.

  1. Structural transition in aqueous lipid/bile salt [DPPC/NaDC] supramolecular aggregates: SANS and DLS study

    International Nuclear Information System (INIS)

    Kiselev, M.A.; Janich, M.; Hildebrand, A.; Strunz, P.; Neubert, R.H.H.; Lombardo, D.

    2013-01-01

    Highlights: • Self-assembly in model DPPC lipids and NaDC bile salt by SANS and DLS experiments. • Bile salt creates structural interference against cohesive tendency of DPPC bilayers. • NaDC steric interactions cause transition toward different supramolecular structures. - Abstract: Small angle neutron scattering (SANS) and dynamic light scattering (DLS) were used to study different aggregation states in sodium deoxycholate (NaDC)-phosphatidylcholine systems at T = 60 °C. Size and shape of the aggregates investigated as a function of the NaDC bile salt concentration (at the constant DPPC concentration of 6 mM) indicate a strong dependence of the size and morphology of the generated aggregates on the relative amount of NaDC bile salt. More specifically large occupied area of the bile salt induces a steric interaction which promotes the transition toward a variety of supramolecular structures ranging from ellipsoidal vesicles, ribbon-like structures, up to final spherical mixed micelles at the large amount of bile salt of 10 mM NaDC. The findings of the obtained results give important insight for understanding the formation of different topologies in aqueous lipid–bile salt mixtures as well as stimulate new routes for liposome reconstitution–solubilisation processes suitable for technological applications

  2. 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

  3. 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

  4. Bile salt toxicity aggravates cold ischemic injury of bile ducts after liver transplantation in Mdr2+/- mice

    NARCIS (Netherlands)

    Hoekstra, H; Porte, RJ; Tian, Y; Jochum, W; Stieger, B; Moritz, W; Slooff, MJH; Graf, R; Clavien, PA

    Intrahepatic bile duct strictures are a serious complication after orthotopic liver transplantation (OLT). We examined the role of endogenous bile salt toxicity in the pathogenesis of bile duct injury after OLT. Livers from wild-type mice and mice heterozygous for disruption of the multidrug

  5. 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.

  6. 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

  7. Altered intestinal bile salt biotransformation in a cystic fibrosis (Cftr-/-) mouse model with hepato-biliary pathology.

    Science.gov (United States)

    Bodewes, Frank A J A; van der Wulp, Mariëtte Y M; Beharry, Satti; Doktorova, Marcela; Havinga, Rick; Boverhof, Renze; James Phillips, M; Durie, Peter R; Verkade, Henkjan J

    2015-07-01

    Cftr(-/-tm1Unc) mice develop progressive hepato-biliary pathology. We hypothesize that this liver pathology is related to alterations in biliary bile hydrophobicity and bile salt metabolism in Cftr(-/-tm1Unc) mice. We determined bile production, biliary and fecal bile salt- and lipid compositions and fecal bacterial composition of C57BL/6J Cftr(-/-tm1Unc) and control mice. We found no differences between the total biliary bile salt or lipid concentrations of Cftr(-/-) and controls. Compared to controls, Cftr(-/-) mice had a ~30% higher bile production and a low bile hydrophobicity, related to a ~7 fold higher concentration of the choleretic and hydrophilic bile salt ursocholate. These findings coexisted with a significantly smaller quantity of fecal Bacteroides bacteria. Liver pathology in Cftr(-/-tm1Unc) is not related to increased bile hydrophobicity. Cftr(-/-) mice do however display a biliary phenotype characterized by increased bile production and decreased biliary hydrophobicity. Our findings suggest Cftr dependent, alterations in intestinal bacterial biotransformation of bile salts. Copyright © 2014. Published by Elsevier B.V.

  8. 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

  9. 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...

  10. Inhibitory Activity of Lactid Acid Bacteria Isolated from Tape Waterlily Seed to Enteric Pathogenic Bacteria (Vibrio cholera, Salmonella typhi, Shigella disentri, and E.coli and Its’ Susceptibility to Antibiotic, Bile Salt and Acidic Condition

    Directory of Open Access Journals (Sweden)

    Iin Khusnul Khotimah

    2012-03-01

    Full Text Available The aim of this research was to observe inhibitory activity of LAB isolated from tape waterlily seed to enteric pathogenic bacteria (Vibrio cholera, Salmonella typhi, Shigella disentri, E.coli ATCC 25922 and it’s susceptibility to antibiotic, in bile salt and under acidic condition. Microbia in the tape ( a fermented product of waterlily seed to showed were Streptococcus thermophilus (IKH-1, Pediococcus pentosaceus (IKH-2 and Leuconostoc mesentroides (IKH-8. Streptococcus thermophillus showed inhibition against the growth of Shigella disentri with inhibition zones 16,28 mm, but did not against the growth of V. Cholera, S. typhi, E.coli. Pediococcus pentosaceus inhibit Vibrio cholera, dan Salmonella thypi with inhibition zones 18,59 mm dan 7,91 mm. So that, Leuconostoc mesenteroides inhibit Salmonella thypi with zones inhibits average 8,25 mm. Chloramfenicol at 0.05 mg concentrations did not show inhibition against the growth of isolated Streptococcus thermophillus, Pediococcus pentosaceus and Leuconostoc mesentroides. These isolates could survive too in bile salt (2% and acidified media (pH 3.   Keyword : The tape of  waterlily seed, LAB, probiotic and enteric pathogenic   KEMAMPUAN PENGHAMBATAN BAKTERI ASAM LAKTAT DARI TAPE BIJI TERATAI TERHADAP PATOGENIK ENTERIK (VIBRIO CHOLERA, SALMONELLA THYPI, SHIGELLA DISENTRI, E. COLI, ANTIBIOTIK, KETAHANANNYA TERHADAP BILE SALT DAN ASAM   ABSTRAK   Penelitian ini bertujuan untuk menguji kemampuan penghambatan bakteri asam laktat yang diisolasi dari tape biji teratai terhadap patogenik enterik (Vibrio cholera, Salmonella thypi, Shigella disentri, E. Coli ATCC 25922, antibiotik, bile salt dan asam. Jenis bakteri yang diketahui tumbuh selama fermentasi tape biji teratai adalah Streptococcus thermopilus (IKH-1, Pediococcus pentosaceus(IKH-2, dan Leuconostoc mesentroides (IKH-8. Pengamatan terhadap uji penghambatan patogenik enterik (Vibrio cholera, Salmonella thypi, Shigella disentri, dan E. Coli ATCC

  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. Sphingomyelin exhibits greatly enhanced protection compared with egg yolk phosphatidylcholine against detergent bile salts

    NARCIS (Netherlands)

    Moschetta, A.; vanBerge-Henegouwen, G. P.; Portincasa, P.; Palasciano, G.; Groen, A. K.; van Erpecum, K. J.

    2000-01-01

    Inclusion of phosphatidylcholine within bile salt micelles protects against bile salt-induced cytotoxicity. In addition to phosphatidylcholine, bile may contain significant amounts of sphingomyelin, particularly under cholestatic conditions. We compared protective effects of egg yolk

  13. 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

  14. Mixtures of lecithin and bile salt can form highly viscous wormlike micellar solutions in water.

    Science.gov (United States)

    Cheng, Chih-Yang; Oh, Hyuntaek; Wang, Ting-Yu; Raghavan, Srinivasa R; Tung, Shih-Huang

    2014-09-02

    The self-assembly of biological surfactants in water is an important topic for study because of its relevance to physiological processes. Two common types of biosurfactants are lecithin (phosphatidylcholine) and bile salts, which are both present in bile and involved in digestion. Previous studies on lecithin-bile salt mixtures have reported the formation of short, rodlike micelles. Here, we show that lecithin-bile salt micelles can be further induced to grow into long, flexible wormlike structures. The formation of long worms and their resultant entanglement into transient networks is reflected in the rheology: the fluids become viscoelastic and exhibit Maxwellian behavior, and their zero-shear viscosity can be up to a 1000-fold higher than that of water. The presence of worms is further confirmed by data from small-angle neutron and X-ray scattering and from cryo-transmission electron microscopy (cryo-TEM). We find that micellar growth peaks at a specific molar ratio (near equimolar) of bile salt:lecithin, which suggests a strong binding interaction between the two species. In addition, micellar growth also requires a sufficient concentration of background electrolyte such as NaCl or sodium citrate that serves to screen the electrostatic repulsion of the amphiphiles and to "salt out" the amphiphiles. We postulate a mechanism based on changes in the molecular geometry caused by bile salts and electrolytes to explain the micellar growth.

  15. 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

  16. 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.

  17. 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

  18. 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;

  19. Na+-taurocholate cotransporting polypeptide (NTCP/SLC10A1) ortholog in the marine skate Leucoraja erinacea is not a physiological bile salt transporter.

    Science.gov (United States)

    Yu, Dongke; Zhang, Han; Lionarons, Daniel A; Boyer, James L; Cai, Shi-Ying

    2017-04-01

    The Na + -dependent taurocholate cotransporting polypeptide (NTCP/SLC10A1) is a hepatocyte-specific solute carrier, which plays an important role in maintaining bile salt homeostasis in mammals. The absence of a hepatic Na + -dependent bile salt transport system in marine skate and rainbow trout raises a question regarding the function of the Slc10a1 gene in these species. Here, we have characterized the Slc10a1 gene in the marine skate, Leucoraja erinacea The transcript of skate Slc10a1 (skSlc10a1) encodes 319 amino acids and shares 46% identity to human NTCP (hNTCP) with similar topology to mammalian NTCP. SkSlc10a1 mRNA was mostly confined to the brain and testes with minimal expression in the liver. An FXR-bile salt reporter assay indicated that skSlc10a1 transported taurocholic acid (TCA) and scymnol sulfate, but not as effectively as hNTCP. An [ 3 H]TCA uptake assay revealed that skSlc10a1 functioned as a Na + -dependent transporter, but with low affinity for TCA ( K m = 92.4 µM) and scymnol sulfate ( K i = 31 µM), compared with hNTCP (TCA, K m = 5.4 µM; Scymnol sulfate, K i = 3.5 µM). In contrast, the bile salt concentration in skate plasma was 2 µM, similar to levels seen in mammals. Interestingly, skSlc10a1 demonstrated transport activity for the neurosteroids dehydroepiandrosterone sulfate and estrone-3-sulfate at physiological concentration, similar to hNTCP. Together, our findings indicate that skSlc10a1 is not a physiological bile salt transporter, providing a molecular explanation for the absence of a hepatic Na + -dependent bile salt uptake system in skate. We speculate that Slc10a1 is a neurosteroid transporter in skate that gained its substrate specificity for bile salts later in vertebrate evolution. Copyright © 2017 the American Physiological Society.

  20. 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....

  1. Increased expression of clp genes in Lactobacillus delbrueckii UFV H2b20 exposed to acid stress and bile salts.

    Science.gov (United States)

    Ferreira, A B; De Oliveira, M N V; Freitas, F S; Alfenas-Zerbini, P; Da Silva, D F; De Queiroz, M V; Borges, A C; De Moraes, C A

    2013-12-01

    The ability to survive in harsh environments is an important criterion to select potential probiotics strains. The objective of this study was to identify and carry out phylogenetic and expression analysis by quantitative real-time PCR of the clpP, clpE, clpL and clpX genes in the probiotic strain Lactobacillus delbrueckii UFV H2b20 exposed to the conditions prevailing in the gastrointestinal tract (GIT). Phylogenetic trees reconstructed by Bayesian inference showed that the L. delbrueckii UFV H2b20 clpP, clpL and clpE genes and the ones from L. delbrueckii ATCC 11842 were grouped. The exposure of cells to MRS broth of pH 3.5 for 30 and 60 min resulted in an increased expression of the four genes. Exposure of the L. delbrueckii UFV H2b20 cells for 30 and 60 min to MRS broth containing 0.1% bile salts increased the expression of the clpP and clpE genes, while the expression level of the clpL and clpX genes increased only after 30 min of exposure. The involvement of the studied genes in the responses to acid stress and bile salts suggests a possible central role of these genes in the survival of L. delbrueckii UFV H2b20 during the passage through the GIT, a characteristic necessary for probiotic strains.

  2. 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.

  3. Cholesterol-Lowering Potentials of Lactic Acid Bacteria Based on Bile-Salt Hydrolase Activity and Effect of Potent Strains on Cholesterol Metabolism In Vitro and In Vivo

    Directory of Open Access Journals (Sweden)

    Cheng-Chih Tsai

    2014-01-01

    Full Text Available This study collected different probiotic isolates from animal and plant sources to evaluate the bile-salt hydrolase activity of probiotics in vitro. The deconjugation potential of bile acid was determined using high-performance liquid chromatography. HepG2 cells were cultured with probiotic strains with high BSH activity. The triglyceride (TG and apolipoprotein B (apo B secretion by HepG2 cells were evaluated. Our results show that the BSH activity and bile-acid deconjugation abilities of Pediococcus acidilactici NBHK002, Bifidobacterium adolescentis NBHK006, Lactobacillus rhamnosus NBHK007, and Lactobacillus acidophilus NBHK008 were higher than those of the other probiotic strains. The cholesterol concentration in cholesterol micelles was reduced within 24 h. NBHK007 reduced the TG secretion by 100% after 48 h of incubation. NBHK002, NBHK006, and NBHK007 could reduce apo B secretion by 33%, 38%, and 39%, respectively, after 24 h of incubation. The product PROBIO S-23 produced a greater decrease in the total concentration of cholesterol, low-density lipoprotein, TG, and thiobarbituric acid reactive substance in the serum or livers of hamsters with hypercholesterolemia compared with that of hamsters fed with a high-fat and high-cholesterol diet. These results show that the three probiotic strains of lactic acid bacteria are better candidates for reducing the risk of cardiovascular disease.

  4. Binding orientation and interaction of bile salt in its ternary complex with pancreatic lipase-colipase system.

    Science.gov (United States)

    Haque, Neshatul; Prakash Prabhu, N

    2018-05-23

    The interfacial activity of pancreatic lipases (PL) depends on the presence of colipase and bile salt. The activity of PL is inhibited by micellar concentrations of bile salt which can be restored by the addition of colipase. Though the formation of 1:1:1 tertiary complex by lipase-colipase-bile salt micelle is well accepted, the residue-level interactions between lipase-colipase and bile salt are yet to be clearly understood. Molecular dynamic simulations of lipase-colipase complex, lipase and colipase were performed in the presence of a model bile salt, sodium taurocholate (NaTC), at its near-CMC and supra-micellar concentrations. From the interactions obtained from the molecular dynamic simulations, the ternary complex was modelled and compared with earlier reports. The analysis suggested that a micelle of NaTC consisting of nine monomers was formed at the concave groove between lipase and colipase chain and it mainly interacted with the fourth finger of colipase. This complex was mainly stabilized by van der Waals interactions. Interestingly, the C-terminal domain of lipase which holds the colipase did not show any significant role in formation or stabilization of NaTC micelle. Copyright © 2018 Elsevier Inc. All rights reserved.

  5. 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 ...

  6. 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

  7. Bile salt deconjugation and cholesterol removal from media by Lactobacillus strains used as probiotics in chickens.

    Science.gov (United States)

    Ramasamy, Kalavathy; Abdullah, Norhani; Wong, Michael Cvl; Karuthan, Chinna; Ho, Yin Wan

    2010-01-15

    Bile salt deconjugation by Lactobacillus strains is often closely linked to bile tolerance and survival of the strains in the gut and lowering of cholesterol in the host. The present study investigated the deconjugation of bile salts and removal of cholesterol by 12 Lactobacillus strains in vitro. The 12 strains were previously isolated from the gastrointestinal tract of chickens. The 12 Lactobacillus strains could deconjugate sodium glycocholate (GCA, 16.87-100%) and sodium taurocholate (TCA, 1.69-57.43%) bile salts to varying degrees, with all strains except L. salivarius I 24 having a higher affinity for GCA. The 12 Lactobacillus strains also showed significant (P strains (C1, C10 and C16) and between cholesterol removal and deconjugation of TCA (r = 0.38) and GCA (r = 0.70) among the L. brevis strains (I 12, I 23, I 25, I 211 and I 218). In contrast, although L. gallinarum I 16 and I 26 and L. panis C 17 showed high deconjugating activity, there was no correlation between cholesterol removal and deconjugation of bile salts in these strains. The results showed that the 12 Lactobacillus strains were able to deconjugate bile salts and remove cholesterol in vitro, but not all strains with high deconjugating activity removed cholesterol effectively. Copyright (c) 2009 Society of Chemical Industry.

  8. Pulmonary Complications of Gastric Fluid and Bile Salts Aspiration, an Experimental Study in Rat

    Directory of Open Access Journals (Sweden)

    Mitra Samareh Fekri

    2013-06-01

    Full Text Available   Objective(s: Gastroesophageal Reflux Disease (GERD is one of the most common digestive disorders that frequently lead to pulmonary complications due to gastric fluid aspiration. In the present experimental study, chronic aspiration of gastric fluid, its components and bile salts in rat lung was performed to find out the main factor(s causing pulmonary complications of gastric fluid aspiration.   Materials and Methods: Forty eight male rats weighted 250-300 g were selected in six groups. After anesthesia and tracheal cannulation, the animals received 0.5 ml/kg normal saline, 0.5 ml/kg of whole gastric fluid, 0.5 ml/kg pepsin (2.5 μg/ml, 0.5 ml/kg hydrochloric acid (pH=1.5 or 0.5 ml/kg bile salts (2.5 μg/ml by injection into their trachea and lungs. In sham group nothing was injected. Results: Parenchymal and airways inflammation and fibrosis of bronchi, bronchioles and parenchyma were significantly more in the test groups compared to saline and sham groups (P

  9. 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.

  10. 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

  11. [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.

  12. 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

  13. 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.

  14. 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

  15. 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....

  16. 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.

  17. 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.

  18. Interactions between selected bile salts and Triton X-100 or sodium lauryl ether sulfate

    OpenAIRE

    Ćirin Dejan M; Poša Mihalj M; Krstonošić Veljko S

    2011-01-01

    Abstract Background In order to develop colloidal drug carriers with desired properties, it is important to determine physico-chemical characteristics of these systems. Bile salt mixed micelles are extensively studied as novel drug delivery systems. The objective of the present investigation is to develop and characterize mixed micelles of nonionic (Triton X-100) or anionic (sodium lauryl ether sulfate) surfactant having oxyethylene groups in the polar head and following bile salts: cholate, ...

  19. Biochemical basis for activation of virulence genes by bile salts in Vibrio parahaemolyticus.

    Science.gov (United States)

    Rivera-Cancel, Giomar; Orth, Kim

    2017-07-04

    Bile salts act as a stressor to bacteria that transit the intestinal tract. Enteric pathogens have hijacked bile as an intestinal signal to regulate virulence factors. We recently demonstrated that Vibrio parahemolyticus senses bile salts via a heterodimeric receptor formed by the periplasmic domains of inner-membrane proteins VtrA and VtrC. Crystal structures of the periplasmic complex reveal that VtrA and VtrC form a β-barrel that binds bile salts in its hydrophobic interior to activate the VtrA cytoplasmic DNA-binding domain. Proteins with the same domain arrangement as VtrA and VtrC are widespread in Vibrio and related bacteria, where they are involved in regulating virulence and other unknown functions. Here we discuss our findings and review current knowledge on VtrA and VtrC homologs. We propose that signaling by these membrane-bound transcription factors can be advantageous for the regulation of membrane and secretory proteins.

  20. Biochemical basis for activation of virulence genes by bile salts in Vibrio parahaemolyticus

    Science.gov (United States)

    2017-01-01

    ABSTRACT Bile salts act as a stressor to bacteria that transit the intestinal tract. Enteric pathogens have hijacked bile as an intestinal signal to regulate virulence factors. We recently demonstrated that Vibrio parahemolyticus senses bile salts via a heterodimeric receptor formed by the periplasmic domains of inner-membrane proteins VtrA and VtrC. Crystal structures of the periplasmic complex reveal that VtrA and VtrC form a β-barrel that binds bile salts in its hydrophobic interior to activate the VtrA cytoplasmic DNA-binding domain. Proteins with the same domain arrangement as VtrA and VtrC are widespread in Vibrio and related bacteria, where they are involved in regulating virulence and other unknown functions. Here we discuss our findings and review current knowledge on VtrA and VtrC homologs. We propose that signaling by these membrane-bound transcription factors can be advantageous for the regulation of membrane and secretory proteins. PMID:28129014

  1. 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...

  2. 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.

  3. 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.

  4. Cyclosporin A and enterohepatic circulation of bile salts in rats : Decreased cholate synthesis but increased intestinal reabsorption

    NARCIS (Netherlands)

    Hulzebos, CV; Wolters, H; Plosch, T; Stengelin, S; Stellaard, F; Sauer, PJJ; Verkade, HJ; Kuipers, F

    Cyclosporin A (CsA) has been shown to inhibit synthesis and hepatobiliary transport of bile salts. However, effects of CsA on the enterohepatic circulation of bile salts in vivo are largely unknown. We characterized the effects of CsA on the enterohepatic circulation of cholate, with respect to

  5. 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....

  6. 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).

  7. Function and regulation of the human bile salt export pump

    NARCIS (Netherlands)

    Plass, Jacqueline Regina Maria

    2005-01-01

    During the past decade, important progress has been made in our understanding of the pathophysiology of cholestasis. Inherited disorders have been explained at the molecular level and were shown to be the result of mutations in enzymes involved in bile salt biosynthesis or transmembrane transporters

  8. [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.

  9. 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

  10. Parenteral nutrition dysregulates bile salt homeostasis in a rat model of parenteral nutrition-associated liver disease.

    Science.gov (United States)

    Koelfat, Kiran V K; Schaap, Frank G; Hodin, Caroline M J M; Visschers, Ruben G J; Svavarsson, Björn I; Lenicek, Martin; Shiri-Sverdlov, Ronit; Lenaerts, Kaatje; Olde Damink, Steven W M

    2017-10-01

    Parenteral nutrition (PN), a lifesaving therapy in patients with intestinal failure, has been associated with hepatobiliary complications including steatosis, cholestasis and fibrosis, collectively known as parenteral nutrition-associated liver disease (PNALD). To date, the pathogenesis of PNALD is poorly understood and therapeutic options are limited. Impaired bile salt homeostasis has been proposed to contribute PNALD. The objective of this study was to establish a PNALD model in rats and to evaluate the effects of continuous parenteral nutrition (PN) on bile salt homeostasis. Rats received either PN via the jugular vein or received normal diet for 3, 7 or 14 days. Serum biochemistry, hepatic triglycerides, circulating bile salts and C4, IL-6 and TNF-alpha, and lipogenic and bile salt homeostatic gene expression in liver and ileum were assessed. PN increased hepatic triglycerides already after 3 days of administration, and resulted in conjugated bilirubin elevation after 7 or more days. This indicates PN-induced steatosis and impaired canalicular secretion of bilirubin, the latter which is in line with reduced hepatic expression of Mrp2 mRNA. There was no histological evidence for liver inflammation after PN administration, and circulating levels of pro-inflammatory cytokines IL-6 and TNF-α, were comparable in all groups. Hepatic expression of Fxr mRNA was decreased after 7 days of PN, without apparent effect on expression of Fxr targets Bsep and Shp. Nonetheless, Cyp7a1 expression was reduced after 7 days of PN, indicative for lowered bile salt synthesis. Circulating levels of C4 (marker of bile salt synthesis) were also decreased after 3, 7 and 14 days of PN. Levels of circulating bile salts were not affected by PN. This study showed that PN in rats caused early mild steatosis and cholestasis, while hepatic and systemic inflammation were not present. The onset of these abnormalities was associated with alterations in bile salt synthesis and transport. This

  11. 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

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

    Energy Technology Data Exchange (ETDEWEB)

    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

  13. 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

  14. 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....

  15. 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.

  16. Allelic variation of bile salt hydrolase genes in Lactobacillus salivarius does not determine bile resistance levels.

    LENUS (Irish Health Repository)

    Fang, Fang

    2009-09-01

    Commensal lactobacilli frequently produce bile salt hydrolase (Bsh) enzymes whose roles in intestinal survival are unclear. Twenty-six Lactobacillus salivarius strains from different sources all harbored a bsh1 allele on their respective megaplasmids. This allele was related to the plasmid-borne bsh1 gene of the probiotic strain UCC118. A second locus (bsh2) was found in the chromosomes of two strains that had higher bile resistance levels. Four Bsh1-encoding allele groups were identified, defined by truncations or deletions involving a conserved residue. In vitro analyses showed that this allelic variation was correlated with widely varying bile deconjugation phenotypes. Despite very low activity of the UCC118 Bsh1 enzyme, a mutant lacking this protein had significantly lower bile resistance, both in vitro and during intestinal transit in mice. However, the overall bile resistance phenotype of this and other strains was independent of the bsh1 allele type. Analysis of the L. salivarius transcriptome upon exposure to bile and cholate identified a multiplicity of stress response proteins and putative efflux proteins that appear to broadly compensate for, or mask, the effects of allelic variation of bsh genes. Bsh enzymes with different bile-degrading kinetics, though apparently not the primary determinants of bile resistance in L. salivarius, may have additional biological importance because of varying effects upon bile as a signaling molecule in the host.

  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. 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

  19. 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...

  20. 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

  1. 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.

  2. 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.

  3. 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.

  4. 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

  5. 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

  6. 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.

  7. Allelic Variation of Bile Salt Hydrolase Genes in Lactobacillus salivarius Does Not Determine Bile Resistance Levels▿ †

    Science.gov (United States)

    Fang, Fang; Li, Yin; Bumann, Mario; Raftis, Emma J.; Casey, Pat G.; Cooney, Jakki C.; Walsh, Martin A.; O'Toole, Paul W.

    2009-01-01

    Commensal lactobacilli frequently produce bile salt hydrolase (Bsh) enzymes whose roles in intestinal survival are unclear. Twenty-six Lactobacillus salivarius strains from different sources all harbored a bsh1 allele on their respective megaplasmids. This allele was related to the plasmid-borne bsh1 gene of the probiotic strain UCC118. A second locus (bsh2) was found in the chromosomes of two strains that had higher bile resistance levels. Four Bsh1-encoding allele groups were identified, defined by truncations or deletions involving a conserved residue. In vitro analyses showed that this allelic variation was correlated with widely varying bile deconjugation phenotypes. Despite very low activity of the UCC118 Bsh1 enzyme, a mutant lacking this protein had significantly lower bile resistance, both in vitro and during intestinal transit in mice. However, the overall bile resistance phenotype of this and other strains was independent of the bsh1 allele type. Analysis of the L. salivarius transcriptome upon exposure to bile and cholate identified a multiplicity of stress response proteins and putative efflux proteins that appear to broadly compensate for, or mask, the effects of allelic variation of bsh genes. Bsh enzymes with different bile-degrading kinetics, though apparently not the primary determinants of bile resistance in L. salivarius, may have additional biological importance because of varying effects upon bile as a signaling molecule in the host. PMID:19592587

  8. 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.

  9. 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

  10. 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.

  11. 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

  12. 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

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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

  18. 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

  19. 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

  20. 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.

  1. 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...

  2. Biliary albumin excretion induced by bile salts in rats is a pathological phenomenon

    International Nuclear Information System (INIS)

    Ohta, M.; Kitani, K.; Kanai, S.

    1989-01-01

    The bile to plasma 125I-albumin concentration ratio (B/P ratio) was examined before and during various bile salt infusions in male Wistar rats that had previously received iv injection of 125I-albumin. Endogenous rat albumin and IgG concentrations in the bile were also determined by a single radial immunodiffusion method. Taurocholate (TC) infusion (1.0 mumol/min/100 g body wt) significantly increased the bile flow rate in the first hr but the flow began to decline in the second hr. The B/P ratio as well as rat albumin (and IgG) excretion into the bile significantly increased as early as 15 min after the start of TC infusion, and the increase became more pronounced in the second hr, when the bile flow began to decrease. Infusion of taurochenodeoxycholate (TCDC, 0.4 mumol/min/100 g) caused a reduction in bile flow 15 min after the start of infusion but the B/P ratio increased 40 times at its peak compared with the basal value before the bile salt infusion. Simultaneous infusion of tauroursodeoxycholate (TUDC, 0.6 mumol/min/100 g) and TCDC not only abolished the cholestasis induced by TCDC but maintained stable choleresis as long as for 2 hr. During this choleretic period, the B/P ration never exceeded the basal value. The choleresis induced by either taurodehydrocholate (TDHC) or bucolome was not accompanied by enhanced albumin excretion. In rats given TDHC infusion, albumin excretion started to increase only after the bile flow began to decline following the initial choleretic period. The enhanced excretion of albumin induced by TC and TCDC is therefore suggested to be caused not by the choleresis per se but by a possible concomitant increase in the communication between sinusoids and bile canaliculi, which eventually leads to cholestasis

  3. 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.

  4. Bile salt-stimulated lipase of human milk: characterization of the enzyme from preterm and term milk

    International Nuclear Information System (INIS)

    Freed, L.M.; Hamosh, P.; Hamosh, M.

    1986-01-01

    The bile salt-stimulated lipase (BSSL) of human milk is an important digestive enzyme in the newborn whose pancreatic function is immature. Milk from mothers delivering premature infants (preterm milk) has similar levels of BSSL activity to that of mothers of term infants (term milk). This study has determined whether the BSSL in preterm milk has the same characteristics as that in term milk. Milk samples were collected during the first 12 wk of lactation from seven mothers of infants born at 26-30 wk (very preterm, VPT), 31-37 wk (preterm, PT) and 37-42 wk (term, T) gestation. BSSL activity was measured using 3 H-triolein emulsion as substrate. Time course, bile salt and enzyme concentration, pH and pH stability were studied, as well as inhibition of BSSL by eserine. The characteristics of BSSL from preterm and term milk were identical as were comparisons between colostrum and mature milk BSSL. BSSL from all milk sources had a neutral-to-alkaline pH optimum (pH 7.3-8.9), was stable at low pH for 60 min, and was 95-100% inhibited by eserine (greater than or equal to 0.6 mM). BSSL activity, regardless of enzyme source, was bile-salt dependent and was stimulated only by primary bile salts (taurocholate, glycocholate). The data indicate that the BSSL in milks of mothers delivering as early as 26 wk gestation is identical to that in term milk

  5. 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

  6. Thermodynamics and structure of inclusion compounds of tauro- and glyco-conjugated bile salts and beta-cyclodextrin

    DEFF Research Database (Denmark)

    Holm, Rene; Shi, Wei; Andersen Hartvig, Rune

    2009-01-01

    The interaction between natural beta-cyclodextrin and bile salts common in rat, dog and man, taurocholate, tauro-beta-muricholate, taurodeoxycholate, taurochenodeoxycholate, glycocholate, glycodeoxycholate and glycochenodeoxycholate, was studied using isothermal titration calorimetry, and the str......The interaction between natural beta-cyclodextrin and bile salts common in rat, dog and man, taurocholate, tauro-beta-muricholate, taurodeoxycholate, taurochenodeoxycholate, glycocholate, glycodeoxycholate and glycochenodeoxycholate, was studied using isothermal titration calorimetry......, and the structural differences in the interaction were investigated by H-1-ROESY NMR and molecular modeling. The beta-cyclodextrin was selected based upon its frequent use in preformulation and drug formulation as oral excipients for the solubilization of drug substances with low aqueous solubility. All...

  7. Interactions between selected bile salts and Triton X-100 or sodium lauryl ether sulfate

    Directory of Open Access Journals (Sweden)

    Ćirin Dejan M

    2011-12-01

    Full Text Available Abstract Background In order to develop colloidal drug carriers with desired properties, it is important to determine physico-chemical characteristics of these systems. Bile salt mixed micelles are extensively studied as novel drug delivery systems. The objective of the present investigation is to develop and characterize mixed micelles of nonionic (Triton X-100 or anionic (sodium lauryl ether sulfate surfactant having oxyethylene groups in the polar head and following bile salts: cholate, deoxycholate and 7-oxodeoxycholate. Results The micellization behaviour of binary anionic-nonionic and anionic-anionic surfactant mixtures was investigated by conductivity and surface tension measurements. The results of the study have been analyzed using Clint's, Rubingh's, and Motomura's theories for mixed binary systems. The negative values of the interaction parameter indicate synergism between micelle building units. It was noticed that Triton X-100 and sodium lauryl ether sulfate generate the weakest synergistic interactions with sodium deoxycholate, while 7-oxodeoxycholate creates the strongest attractive interaction with investigated co-surfactants. Conclusion It was concluded that increased synergistic interactions can be attributed to the larger number of hydrophilic groups at α side of the bile salts. Additionally, 7-oxo group of 7-oxodeoxycholate enhance attractive interactions with selected co-surfactants more than 7-hydroxyl group of sodium cholate.

  8. Interactions between selected bile salts and Triton X-100 or sodium lauryl ether sulfate.

    Science.gov (United States)

    Cirin, Dejan M; Poša, Mihalj M; Krstonošić, Veljko S

    2011-12-29

    In order to develop colloidal drug carriers with desired properties, it is important to determine physico-chemical characteristics of these systems. Bile salt mixed micelles are extensively studied as novel drug delivery systems. The objective of the present investigation is to develop and characterize mixed micelles of nonionic (Triton X-100) or anionic (sodium lauryl ether sulfate) surfactant having oxyethylene groups in the polar head and following bile salts: cholate, deoxycholate and 7-oxodeoxycholate. The micellization behaviour of binary anionic-nonionic and anionic-anionic surfactant mixtures was investigated by conductivity and surface tension measurements. The results of the study have been analyzed using Clint's, Rubingh's, and Motomura's theories for mixed binary systems. The negative values of the interaction parameter indicate synergism between micelle building units. It was noticed that Triton X-100 and sodium lauryl ether sulfate generate the weakest synergistic interactions with sodium deoxycholate, while 7-oxodeoxycholate creates the strongest attractive interaction with investigated co-surfactants. It was concluded that increased synergistic interactions can be attributed to the larger number of hydrophilic groups at α side of the bile salts. Additionally, 7-oxo group of 7-oxodeoxycholate enhance attractive interactions with selected co-surfactants more than 7-hydroxyl group of sodium cholate.

  9. 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...

  10. Bile Formation and Secretion

    Science.gov (United States)

    Boyer, James L.

    2014-01-01

    Bile is a unique and vital aqueous secretion of the liver that is formed by the hepatocyte and modified down stream by absorptive and secretory properties of the bile duct epithelium. Approximately 5% of bile consists of organic and inorganic solutes of considerable complexity. The bile-secretory unit consists of a canalicular network which is formed by the apical membrane of adjacent hepatocytes and sealed by tight junctions. The bile canaliculi (~1 μm in diameter) conduct the flow of bile countercurrent to the direction of portal blood flow and connect with the canal of Hering and bile ducts which progressively increase in diameter and complexity prior to the entry of bile into the gallbladder, common bile duct, and intestine. Canalicular bile secretion is determined by both bile salt-dependent and independent transport systems which are localized at the apical membrane of the hepatocyte and largely consist of a series of adenosine triphosphate-binding cassette transport proteins that function as export pumps for bile salts and other organic solutes. These transporters create osmotic gradients within the bile canalicular lumen that provide the driving force for movement of fluid into the lumen via aquaporins. Species vary with respect to the relative amounts of bile salt-dependent and independent canalicular flow and cholangiocyte secretion which is highly regulated by hormones, second messengers, and signal transduction pathways. Most determinants of bile secretion are now characterized at the molecular level in animal models and in man. Genetic mutations serve to illuminate many of their functions. PMID:23897680

  11. 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

  12. 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

  13. 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

  14. Liver Receptor Homolog-1 Is Critical for Adequate Up-regulation of Cyp7a1 Gene Transcription and Bile Salt Synthesis During Bile Salt Sequestration

    NARCIS (Netherlands)

    Out, Carolien; Hageman, Jurre; Bloks, Vincent W.; Gerrits, Han; Gelpke, Maarten D. Sollewijn; Bos, Trijnie; Havinga, Rick; Smit, Martin J.; Kuipers, Folkert; Groen, Albert K.

    Liver receptor homolog-1 (LRH-1) is a nuclear receptor that controls a variety of metabolic pathways. In cultured cells, LRH-1 induces the expression of CYP7A1 and CYP8B1, key enzymes in bile salt synthesis. However, hepatic Cyp7a1 mRNA levels were not reduced upon hepatocyte-specific Lrh-1 deletion

  15. 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

  16. Evaluation of resistance to low pH and bile salts of human Lactobacillus spp. isolates.

    Science.gov (United States)

    Fuochi, Virginia; Petronio, Giulio Petronio; Lissandrello, Edmondo; Furneri, Pio Maria

    2015-09-01

    There are nearly 100 trillion bacteria in the intestine that together form the intestinal microbiota. They are 'good' bacteria because they help to maintain a physiological balance and are called probiotics. Probiotics must have some important characteristics: be safe for humans, be resistant to the low pH in the stomach, as well as bile salts and pancreatic juice. Indeed, their survival is the most important factor, so that they can arrive alive in the intestine and are able to form colonies, at least temporarily. The aim of our study was the evaluation of resistance of Lactobacillus isolates from fecal and oral swabs compared to that found in a commercial product. Seven strains were randomly chosen: L. jensenii, L. gasseri, L. salivarius, L. fermentum, L. rhamnosus, L. crispatus, and L. delbrueckii. We observed a large variability in the results: L. gasseri and L. fermentum were the most resistance to low pH, while only L. gasseri showed the best survival rate to bile salts. Interestingly, the commercial product did not show tolerance to both low pH and bile salts. © The Author(s) 2015.

  17. 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

  18. 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

  19. 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)

  20. Hepatic farnesoid X-receptor isoforms α2 and α4 differentially modulate bile salt and lipoprotein metabolism in mice.

    Directory of Open Access Journals (Sweden)

    Marije Boesjes

    Full Text Available The nuclear receptor FXR acts as an intracellular bile salt sensor that regulates synthesis and transport of bile salts within their enterohepatic circulation. In addition, FXR is involved in control of a variety of crucial metabolic pathways. Four FXR splice variants are known, i.e. FXRα1-4. Although these isoforms show differences in spatial and temporal expression patterns as well as in transcriptional activity, the physiological relevance hereof has remained elusive. We have evaluated specific roles of hepatic FXRα2 and FXRα4 by stably expressing these isoforms using liver-specific self-complementary adeno-associated viral vectors in total body FXR knock-out mice. The hepatic gene expression profile of the FXR knock-out mice was largely normalized by both isoforms. Yet, differential effects were also apparent; FXRα2 was more effective in reducing elevated HDL levels and transrepressed hepatic expression of Cyp8b1, the regulator of cholate synthesis. The latter coincided with a switch in hydrophobicity of the bile salt pool. Furthermore, FXRα2-transduction caused an increased neutral sterol excretion compared to FXRα4 without affecting intestinal cholesterol absorption. Our data show, for the first time, that hepatic FXRα2 and FXRα4 differentially modulate bile salt and lipoprotein metabolism in mice.

  1. 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)

  2. 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...

  3. 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.

  4. 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.

  5. Building a Better Microreactor: Enzyme Catalysis in AOT/Bile Salt Reversed Micelles

    National Research Council Canada - National Science Library

    McGown, Linda

    2001-01-01

    .... We have shown that trihydroxy bile salts modify the interfacial properties of AOT reversed micelles, thereby affecting the reversed micellar structure, the biological activity of entrapped enzymes...

  6. 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.

  7. 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...

  8. 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

  9. A study of salt effects on the complexation between beta-cyclodextrins and bile salts based on the Hofmeister series

    DEFF Research Database (Denmark)

    Holm, Rene; Schonbeck, Christian; Somprasirt, Pitchayanun

    2014-01-01

    bound drug molecules. The influence of Hofmeister ions on the binding constants of complexes between CDs (β-CD and hydroxypropylated β-CD) and bile salts (glycocholate and glycochenodeoxycholate) were examined by isothermal titration calorimetry. The chaotropic anions tended to weaken these inclusion...

  10. 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).

  11. 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.

  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. [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.

  14. 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.

  15. 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.

  16. 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....

  17. 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.

  18. Response to Bile Salts in Clinical Strains of Acinetobacter baumannii Lacking the AdeABC Efflux Pump: Virulence Associated with Quorum Sensing

    Directory of Open Access Journals (Sweden)

    Maria López

    2017-05-01

    Full Text Available Introduction:Acinetobacter baumannii is an opportunistic nosocomial pathogen associated with multiple infections. This pathogen usually colonizes (first stage of microbial infection host tissues that are in contact with the external environment. As one of the sites of entry in human hosts is the gastrointestinal tract, the pathogen must be capable of tolerating bile salts. However, studies analyzing the molecular characteristics involved in the response to bile salts in clinical strains of A. baumannii are scarce.Material and Methods: Microbiological and transcriptional studies (arrays and RT-PCR in the response to bile salts were carried out in isogenic (A. baumanni ΔadeB ATCC 17978 and A. baumannii ΔadeL ATCC 17978 and clinical strains from clone ST79/PFGE-HUI-1 which is characterized by lacking the AdeABC efflux pump and by overexpression the AdeFGH efflux pump.Results and Discussion: In presence of bile salts, in addition to the glutamate/aspartate transporter were found overexpressed in A. baumannii ΔadeB ATCC 17978, the virulence factors (surface motility, biofilm, and Type VI Secretion System which are associated with activation of the Quorum Sensing system. Overexpression of these factors was confirmed in clinical strains of clone ST79/PFGE-HUI-1.Conclusions: This the first study about the adaptive response to bile salts investigating the molecular and microbiological characteristics in response to bile salts of an isogenic model of A. baumannii ATCC 17978 and clinical isolates of A. baumannii (clinical strains of ST79/PFGE-HUI-1 lacking the main RND efflux pump (AdeABC. Clinical isolates of A. baumannii lacking the AdeABC efflux pump (clone ST79/PFGE-HUI-1 displayed a new clinical profile (increased invasiveness possibly associated with the response to stress conditions (such as the presence of bile salts.

  19. Response to Bile Salts in Clinical Strains of Acinetobacter baumannii Lacking the AdeABC Efflux Pump: Virulence Associated with Quorum Sensing.

    Science.gov (United States)

    López, Maria; Blasco, Lucia; Gato, Eva; Perez, Astrid; Fernández-Garcia, Laura; Martínez-Martinez, Luis; Fernández-Cuenca, Felipe; Rodríguez-Baño, Jesús; Pascual, Alvaro; Bou, German; Tomás, Maria

    2017-01-01

    Introduction: Acinetobacter baumannii is an opportunistic nosocomial pathogen associated with multiple infections. This pathogen usually colonizes (first stage of microbial infection) host tissues that are in contact with the external environment. As one of the sites of entry in human hosts is the gastrointestinal tract, the pathogen must be capable of tolerating bile salts. However, studies analyzing the molecular characteristics involved in the response to bile salts in clinical strains of A. baumannii are scarce. Material and Methods: Microbiological and transcriptional studies (arrays and RT-PCR) in the response to bile salts were carried out in isogenic ( A. baumanni Δ adeB ATCC 17978 and A. baumannii Δ adeL ATCC 17978) and clinical strains from clone ST79/PFGE-HUI-1 which is characterized by lacking the AdeABC efflux pump and by overexpression the AdeFGH efflux pump. Results and Discussion: In presence of bile salts, in addition to the glutamate/aspartate transporter were found overexpressed in A. baumannii Δ adeB ATCC 17978, the virulence factors (surface motility, biofilm, and Type VI Secretion System) which are associated with activation of the Quorum Sensing system. Overexpression of these factors was confirmed in clinical strains of clone ST79/PFGE-HUI-1. Conclusions: This the first study about the adaptive response to bile salts investigating the molecular and microbiological characteristics in response to bile salts of an isogenic model of A. baumannii ATCC 17978 and clinical isolates of A. baumannii (clinical strains of ST79/PFGE-HUI-1) lacking the main RND efflux pump (AdeABC). Clinical isolates of A. baumannii lacking the AdeABC efflux pump (clone ST79/PFGE-HUI-1) displayed a new clinical profile (increased invasiveness) possibly associated with the response to stress conditions (such as the presence of bile salts).

  20. 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

  1. 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.)

  2. 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 ...

  3. Effect of Bile Salt on Permeation Characteristics of the Oral Mucosal ...

    African Journals Online (AJOL)

    An attempt was made to study the effect of bile salt [sodium glycocholate (SG)] as a permeation enhancer on mucoadhesive buccal patches of diltiazem hydrochloride (anti-anginal drug) using various polymers like hydroxypropyl methyl cellulosee (HPMC), Eudragit RL100, ethyl cellulose alone and in combination with PVP.

  4. 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....

  5. 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

  6. Bile salt/phospholipid mixed micelle precursor pellets prepared by fluid-bed coating

    Directory of Open Access Journals (Sweden)

    Dong F

    2013-04-01

    Full Text Available Fuxia Dong,1,2 Yunchang Xie,1 Jianping Qi,1 Fuqiang Hu,3 Yi Lu,1 Sanming Li,2 Wei Wu1 1School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery of Ministry of Education and PLA, Shanghai, People’s Republic of China; 2School of Pharmacy, Shenyang Pharmaceutical University, Liaoning, People’s Republic of China; 3School of Pharmacy, Zhejiang University, Hangzhou, People’s Republic of China Abstract: Bile salt/phospholipid mixed micelles (MMs are potent carriers used for oral absorption of drugs that are poorly soluble in water; however, there are many limitations associated with liquid formulations. In the current study, the feasibility of preparing bile salt/phospholipid MM precursor (preMM pellets with high oral bioavailability, using fluid-bed coating technology, was examined. In this study, fenofibrate (FB and sodium deoxycholate (SDC were used as the model drug and the bile salt, respectively. To prepare the MMs and to serve as the micellular carrier, a weight ratio of 4:6 was selected for the sodium deoxycholate/phospholipids based on the ternary phase diagram. Polyethylene glycol (PEG 6000 was selected as the dispersion matrix for precipitation of the MMs onto pellets, since it can enhance the solubilizing ability of the MMs. Coating of the MMs onto the pellets using the fluid-bed coating technology was efficient and the pellets were spherical and intact. MMs could be easily reconstituted from preMM pellets in water. Although they existed in a crystalline state in the preMM pellets, FB could be encapsulated into the reconstituted MMs, and the MMs were redispersed better than solid dispersion pellets (FB:PEG = 1:3 and Lipanthyl®. The redispersibility of the preMM pellets increased with the increase of the FB/PEG/micellar carrier. PreMM pellets with a FB:PEG:micellar carrier ratio of 1:1.5:1.5 showed 284% and 145% bioavailability relative to Lipanthyl® and solid dispersion pellets (FB:PEG = 1:3, respectively. Fluid

  7. Complexation and sensing behavior of dansyl-appended cyclodextrins and cyclodextrin dimers with bile salts

    NARCIS (Netherlands)

    Jong, de M.R.; Berthault, P.; Hoek, van A.; Visser, A.J.W.G.; Huskens, J.; Reinhoudt, D.N.

    2002-01-01

    The dansyl-modified cyclodextrin derivatives 2 and 3 form complexes with the steroidal bile salts. The selectivity of the monomeric derivative 3 is similar to that of native g-cyclodextrin. All binding constants with 3 are lowered compared to g-cyclodextrin because of the competition for the cavity

  8. Complexation and sensing behavior of dansyl-appended cyclodextrins and cyclodextrin dimers with bile salts

    NARCIS (Netherlands)

    de Jong, M.R.; Berthault, Patrick; van Hoek, Arie; Visser, Antonie J.W.G.; Huskens, Jurriaan; Reinhoudt, David

    2002-01-01

    The dansyl-modified cyclodextrin derivatives 2 and 3 form complexes with the steroidal bile salts. The selectivity of the monomeric derivative 3 is similar to that of native β-cyclodextrin. All binding constants with 3 are lowered compared to β-cyclodextrin because of the competition for the cavity

  9. 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.

  10. 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.

  11. Data for the size of cholesterol-fat micelles as a function of bile salt concentration and the physico-chemical properties of six liquid experimental pine-derived phytosterol formulations in a cholesterol-containing artificial intestine fluid

    Directory of Open Access Journals (Sweden)

    Jinsoo Yi

    2017-02-01

    Full Text Available The data in this paper are additional information to the research article entiltled “Inhibition of cholesterol transport in an intestine cell model by pine-derived phytosterols” (Yi et al.,2016 [1]. The data derived from the measurement on six liquid formulations of commercial pine-derived phytosterol (CPP by dynamic light scattering. The data cover micelle size and the zeta-potential for formulations with cholesterol including monoglyceride, oleic acid, and bile salt. The data demonstrate the critical effect of the bile salt concentration on the size of cholesterol-digested fat micelles.

  12. 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.

  13. Membranolytic Activity of Bile Salts: Influence of Biological Membrane Properties and Composition

    Directory of Open Access Journals (Sweden)

    Alfred Blume

    2007-10-01

    Full Text Available The two main steps of the membranolytic activity of detergents: 1 the partitioning of detergent molecules in the membrane and 2 the solubilisation of the membrane are systematically investigated. The interactions of two bile salt molecules, sodium cholate (NaC and sodium deoxycholate (NaDC with biological phospholipid model membranes are considered. The membranolytic activity is analysed as a function of the hydrophobicity of the bile salt, ionic strength, temperature, membrane phase properties, membrane surface charge and composition of the acyl chains of the lipids. The results are derived from calorimetric measurements (ITC, isothermal titration calorimetry. A thermodynamic model is described, taking into consideration electrostatic interactions, which is used for the calculation of the partition coefficient as well as to derive the complete thermodynamic parameters describing the interaction of detergents with biological membranes (change in enthalpy, change in free energy, change in entropy etc. The solubilisation properties are described in a so-called vesicle-to-micelle phase transition diagram. The obtained results are supplemented and confirmed by data obtained from other biophysical techniques (DSC differential scanning calorimetry, DLS dynamic light scattering, SANS small angle neutron scattering.

  14. 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.

  15. 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.

  16. 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.

  17. 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

  18. 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.

  19. 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 ...

  20. 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

  1. Intestinal bile salt absorption in Atp8b1 deficient mice

    NARCIS (Netherlands)

    Groen, Annemiek; Kunne, Cindy; Paulusma, Coen C.; Kramer, Werner; Agellon, Luis B.; Bull, Laura N.; Elferink, Ronald P. J. Oude

    2007-01-01

    BACKGROUND/AIMS: Mutations in the ATP8B1 gene can cause Progressive Familial Intrahepatic Cholestasis type 1. We have previously reported that Atp8b1(G308V/G308V) mice, a model for PFIC1, have slightly, but significantly, higher baseline serum bile salt (BS) concentrations compared to wt mice. Upon

  2. Probing interactions between B-glucan and bile salts at atomic detail by 1H-13C NMR assays

    DEFF Research Database (Denmark)

    Mikkelsen, Mette Skau; Cornali, Sofia Bolvig; Jensen, Morten G

    2014-01-01

    Polysaccharides are prospective hosts for the delivery and sequestration of bioactive guest molecules. Polysaccharides of dietary fiber, specifically cereal (1 → 3)(1 → 4)-β-glucans, play a role in lowering the blood plasma cholesterol level in humans. Direct host-guest interactions between β...... salts and β-glucans. Experiments are consistent with stronger interactions at pH 5.3 than at pH 6.5 in this in vitro assay. The changes in bile salt and β-glucan signals suggest a stabilization of bile salt micelles and concomitant conformational changes in β-glucans....

  3. 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.

  4. 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

  5. Hydrophilic bile salts enhance differential distribution of sphingomyelin and phosphatidylcholine between micellar and vesicular phases: potential implications for their effects in vivo

    NARCIS (Netherlands)

    Moschetta, A.; vanBerge-Henegouwen, G. P.; Portincasa, P.; Renooij, W. L.; Groen, A. K.; van Erpecum, K. J.

    2001-01-01

    The hepatocyte canalicular membrane outer leaflet contains both phosphatidylcholine (PC) and sphingomyelin (SM). Normally, PC is the exclusive phospholipid in bile. We examined effects of bile salt hydrophobicity on cytotoxicity and on differential SM and PC distribution between detergent-resistant

  6. 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

  7. 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

  8. 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.

  9. 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...

  10. [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.

  11. 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

  12. 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...

  13. 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...

  14. 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

  15. 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

  16. 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.

  17. 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.

  18. 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.

  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. 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

  1. Severe bile salt export pump deficiency : 82 different ABCB11 mutations in 109 families

    NARCIS (Netherlands)

    Strautnieks, Sandra S.; Byrne, Jane A.; Pawlikowska, Ludmila; Cebecauerova, Dita; Rayner, Anne; Dutton, Laura; Meier, Yvonne; Antoniou, Anthony; Stieger, Bruno; Arnell, Henrik; Ozcay, Figen; Al-Hussaini, Hussa F.; Bassas, Atif F.; Verkade, Henkjan J.; Fischler, Bjorn; Nemeth, Antal; Kotalova, Radana; Shneider, Benjamin L.; Cielecka-Kuszyk, Joanna; McClean, Patricia; Whitington, Peter F.; Sokal, Etienne; Jirsa, Milan; Wali, Sami H.; Jankowska, Irena; Pawlowska, Joanna; Mieli-Vergani, Giorgina; Knisely, A. S.; Bull, Laura N.; Thompson, Richard J.

    Background & Aims: Patients with severe bile salt export pump (BSEP) deficiency present as infants with progressive cholestatic liver disease. We characterized mutations of ABCB11 (encoding BSEP) in such patients and correlated genotypes with residual protein detection and risk of malignancy.

  2. 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.

  3. 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

  4. Structural transition in aqueous lipid/bile salt [DPPC/NaDC] supramolecular aggregates: SANS and DLS study

    Czech Academy of Sciences Publication Activity Database

    Kiselev, M. A.; Janich, M.; Hildebrand, A.; Strunz, Pavel; Neubert, R.H.H.; Lombardo, D.

    2013-01-01

    Roč. 424, OCT (2013), s. 93-99 ISSN 0301-0104 Institutional support: RVO:61389005 Keywords : bile salt * phospholipids * phosphatidylcholine (DPPC) * small angle neutron scattering * Vesicle-micelle transition Subject RIV: BM - Solid Matter Physics ; Magnetism Impact factor: 2.028, year: 2013

  5. 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

  6. 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.

  7. 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.

  8. Multifaceted applications of bile salts in pharmacy: an emphasis on nanomedicine

    Directory of Open Access Journals (Sweden)

    Elnaggar YS

    2015-06-01

    Full Text Available Yosra SR Elnaggar Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt Abstract: The human body has long provided pharmaceutical science with biomaterials of interesting applications. Bile salts (BSs are biomaterials reminiscent of traditional surfactants with peculiar structure and self-assembled topologies. In the pharmaceutical field, BSs were employed on the basis of two different concepts. The first concept exploited BSs’ metabolic and homeostatic functions in disease modulation, whereas the second one utilized BSs’ potential to modify drug-delivery characteristics, which recently involved nanotechnology. This review is the first to gather major pharmaceutical applications of BSs from endogenous organotropism up to integration into nanomedicine, with a greater focus on the latter domain. Endogenous applications highlighted the role of BS in modulating hypercholesterolemia and cancer therapy in view of enterohepatic circulation. In addition, recent BS-integrated nanomedicines have been surveyed, chiefly size-tunable cholate nanoparticles, BS-lecithin mixed micelles, bilosomes, probilosomes, and surface-engineered bilosomes. A greater emphasis has been laid on nanosystems for vaccine and cancer therapy. The comparative advantages of BS-integrated nanomedicines over conventional nanocarriers have been noted. Paradoxical effects, current pitfalls, future perspectives, and opinions have also been outlined. Keywords: bile salt, nanomedicine, bilosomes, liposomes, size-tunable nanoparticles 

  9. 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.

  10. 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

  11. Response to Bile Salts in Clinical Strains of Acinetobacter baumannii Lacking the AdeABC Efflux Pump: Virulence Associated with Quorum Sensing

    OpenAIRE

    L?pez, Maria; Blasco, Lucia; Gato, Eva; Perez, Astrid; Fern?ndez-Garcia, Laura; Mart?nez-Martinez, Luis; Fern?ndez-Cuenca, Felipe; Rodr?guez-Ba?o, Jes?s; Pascual, Alvaro; Bou, German; Tom?s, Maria

    2017-01-01

    Introduction: Acinetobacter baumannii is an opportunistic nosocomial pathogen associated with multiple infections. This pathogen usually colonizes (first stage of microbial infection) host tissues that are in contact with the external environment. As one of the sites of entry in human hosts is the gastrointestinal tract, the pathogen must be capable of tolerating bile salts. However, studies analyzing the molecular characteristics involved in the response to bile salts in clinical strains of ...

  12. 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.

  13. 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

  14. Modifying the Aggregation Behavior of Poly (N-Isopropylacrylamide) Thermoreversible Gel by a Bile Salt

    Energy Technology Data Exchange (ETDEWEB)

    Kumar, Anitha C [Department of Chemistry, Indian Institute of Technology Madras, Chennai 600 036 (India); Boral, Shilpi [Polymer and Biophysics Laboratory, School of Physical Sciences, Jawaharlal Nehru University, New Delhi-110 067 (India); Bohidar, H B [Polymer and Biophysics Laboratory, School of Physical Sciences, Jawaharlal Nehru University, New Delhi-110 067 (India); Mishra, Ashok K [Department of Chemistry, Indian Institute of Technology Madras, Chennai 600 036 (India)

    2007-09-15

    One possible method of altering the critical solution temperature (CST) of poly (N-isopropylacrylamide) (PNIPAM) gel is the addition of surfactants. Because of the biological origin of bile salts, their inclusion in PNIPAM could lead to better biocompatibility when the materials are used for biomedical applications. The gelling behaviour of PNIPAM was studied at various concentrations: PNIPAM concentrations in the range of 1% to 12% (w/v) and sodium cholate (NaC) concentrations varied from 0 to 20 mM. From fluorescence, DLS, rheology and turbidity studies it was found that in the presence of NaC, the CST shifts to lower temperature. This effect of the bile salt is in contrast to the effect of conventional surfactants which are known to shift the CST to higher values, due to mutual solubilization. A study of fluorescence spectroscopic parameters like fluorescence anisotropy, spectral shift, intensity and DLS measurements suggest that a NaC-induced aggregation could be responsible for this unusual observation.

  15. 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...

  16. Bile salt-stimulated lipase: an animal model for human lactation

    International Nuclear Information System (INIS)

    Hamosh, M.; Freed, L.M.; York, C.M.; Sturman, J.A.; Hamosh, P.

    1986-01-01

    To date, bile salt-stimulated lipase (BSSL), an important digestive enzyme for the newborn, has only been described in the milk of primates - human and gorilla. The authors report the presence of BSSL in milks of dog and cat. Serial collections from two dogs (day 1-49) and cats (day 5-57) were analyzed for BSSL activity using a 3 H-triolein emulsion as substrate. Comparable analyses of pooled, term human milk were made for comparison. BSSL activity in individual dog milks (x = 32.0; range: 4.8-107.4 U/ml) was similar, while that in cat milk (x = 6.6; range: 2.2-16.9 U/ml) was lower than in human milk (x = 37.0; range: 10-80 U/ml; n = 35). Longitudinal patterns for BSSL differed depending upon the enzyme source. Dog, cat and human milk BSSL all showed a neutral to alkaline pH optimum (pH 7.0-8.4), stability at low pH, and 95-100% inhibition (at concentrations of 0.6 mM) by NaCl and eserine. BSSL activity from all sources had an obligate requirement for primary bile salts. These data are the first to show BSSL activity in milk from mammals other than human and gorilla. Presence of BSSL in nonprimate milk will permit the careful study of BSSL biology in the mammary gland as well as its role in neonatal fat digestion

  17. 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

  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. 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.

  20. Relative gene expression of bile salt hydrolase and surface proteins in two putative indigenous Lactobacillus plantarum strains under in vitro gut conditions.

    Science.gov (United States)

    Duary, Raj Kumar; Batish, Virender Kumar; Grover, Sunita

    2012-03-01

    Probiotic bacteria must overcome the toxicity of bile salts secreted in the gut and adhere to the epithelial cells to enable their better colonization with extended transit time. Expression of bile salt hydrolase and other proteins on the surface of probiotic bacteria can help in better survivability and optimal functionality in the gut. Two putative Lactobacillus plantarum isolates i.e., Lp9 and Lp91 along with standard strain CSCC5276 were used. A battery of six housekeeping genes viz. gapB, dnaG, gyrA, ldhD, rpoD and 16S rRNA were evaluated by using geNorm 3.4 excel based application for normalizing the expression of bile salt hydrolase (bsh), mucus-binding protein (mub), mucus adhesion promoting protein (mapA), and elongation factor thermo unstable (EF-Tu) in Lp9 and Lp91. The maximal level of relative bsh gene expression was recorded in Lp91 with 2.89 ± 0.14, 4.57 ± 0.37 and 6.38 ± 0.19 fold increase at 2% bile salt concentration after 1, 2 and 3 h, respectively. Similarly, mub and mapA genes were maximally expressed in Lp9 at the level of 20.07 ± 1.28 and 30.92 ± 1.51 fold, when MRS was supplemented with 0.05% mucin and 1% each of bile and pancreatin (pH 6.5). However, in case of EF-Tu, the maximal expression of 42.84 ± 5.64 fold was recorded in Lp91 in the presence of mucin alone (0.05%). Hence, the expression of bsh, mub, mapA and EF-Tu could be considered as prospective biomarkers for screening of novel probiotic lactobacillus strains for optimal functionality in the gut.

  1. Response to Bile Salts in Clinical Strains of Acinetobacter baumannii Lacking the AdeABC Efflux Pump: Virulence Associated with Quorum Sensing

    OpenAIRE

    Maria López; Maria López; Lucia Blasco; Eva Gato; Eva Gato; Astrid Perez; Astrid Perez; Laura Fernández-Garcia; Laura Fernández-Garcia; Luis Martínez-Martinez; Luis Martínez-Martinez; Luis Martínez-Martinez; Felipe Fernández-Cuenca; Felipe Fernández-Cuenca; Felipe Fernández-Cuenca

    2017-01-01

    Introduction:Acinetobacter baumannii is an opportunistic nosocomial pathogen associated with multiple infections. This pathogen usually colonizes (first stage of microbial infection) host tissues that are in contact with the external environment. As one of the sites of entry in human hosts is the gastrointestinal tract, the pathogen must be capable of tolerating bile salts. However, studies analyzing the molecular characteristics involved in the response to bile salts in clinical strains of A...

  2. 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)

  3. 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

  4. 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

  5. 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.

  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. 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.

  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. 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

  11. 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

  12. Structure of human milk bile salt activated lipase

    International Nuclear Information System (INIS)

    Baba, T.; Downs, D.; Jackson, K.W.; Tang, J.; Wang, Chi-Sun

    1991-01-01

    The structure and some functional sites of human milk bile salt activated lipase (BAL) were studied by cDNA cloning and chemical analysis of the enzyme. Eighteen cDNA clones of human BAL were identified from lactating human breast cDNA libraries in λgt11 and λgt10 with antibody and synthetic oligonucleotides as probes. The sequence of four clones was sufficient to construct a 3018-bp BAL cDNA structure. This sequence codes for an open reading frame of 742 amino acid residues. There is a putative signal sequence of 20 residues which is followed by the amino-terminal sequence of BAL, and the mature BAL contains 722 amino acid residues. The cDNA sequence also contains a 678-base 5'-untranslated sequence, a 97-base 3'-untranslated region, and a 14-base poly(A) tail. The sequence of a 1.8-kbp insert of clone G10-4A differs from that of the other cDNA in that it contains a deletion of 198 bases (1966-2163) corresponding to 66 amino acid residues. By use of BAL cDAN as probe, it was found that the major molecular species of BAL mRNA in human mammary gland HBL-100 cells had a size of 2.9 kb and two minor species had sizes of 3.8 and 5.1 kb by Northern blot analyses. These chemical studies established that the active site of human milk BAL is located at serine-194, the N-glycosylation site is present at asparagine-187, the O-glycosylation region is in the 16 repeating units near the C-terminus, and the heparin binding domain is in the N-terminal region. The authors have also determined the location of disulfide bridges as Cys64-Cys80 and Cys246-Cys257. The cyanogen bromide cleavage and the partial sequencing of CNBr peptides also confirmed the location of methionines in the polypeptide chain as well as the deduced cDNA sequence of BAL

  13. 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.

  14. 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.

  15. 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.

  16. 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 ...

  17. 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

  18. 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

  19. 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...

  20. 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 ...

  1. 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

  2. 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

  3. 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.

  4. Pulmonary Complications of Gastric Fluid and Bile Salts Aspiration, an Experimental Study in Rat

    OpenAIRE

    Samareh Fekri, Mitra; Poursalehi, Hamid Reza; Najafipour, Hamid; Dabiri, Shahriar; Shokoohi, Mostafa; Siahposht Khacheki, Ali; Shahrokhi, Nader; Malekpour Afshar, Reza; Lashkarizadeh, Mohammad Reza

    2013-01-01

    Objective(s): Gastroesophageal Reflux Disease (GERD) is one of the most common digestive disorders that frequently lead to pulmonary complications due to gastric fluid aspiration. In the present experimental study, chronic aspiration of gastric fluid, its components and bile salts in rat lung was performed to find out the main factor(s) causing pulmonary complications of gastric fluid aspiration. Materials and Methods: Forty eight male rats weighted 250-300 g were selected in six groups. Afte...

  5. Determination of stability constants of tauro- and glyco-conjugated bile salts with the negatively charged sulfobutylether-β-cyclodextrin: comparison of affinity capillary electrophoresis and isothermal titration calorimetry and thermodynamic analysis of the interaction

    DEFF Research Database (Denmark)

    Holm, René; Østergaard, Jesper; Schönbeck, Jens Christian Sidney

    2014-01-01

    The aim of the present work was to investigate the interaction between bile salts present in the intestine of man, dog and rat with the negatively charged cyclodextrin (CD), sulfobutylether-β-cyclodextrin (SBEβCD). The interactions between bile salts and CDs are of importance for the release of C...

  6. 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

  7. 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.

  8. Integrated transcriptomic and proteomic analysis of the bile stress response in probiotic Lactobacillus salivarius LI01.

    Science.gov (United States)

    Lv, Long-Xian; Yan, Ren; Shi, Hai-Yan; Shi, Ding; Fang, Dai-Qiong; Jiang, Hui-Yong; Wu, Wen-Rui; Guo, Fei-Fei; Jiang, Xia-Wei; Gu, Si-Lan; Chen, Yun-Bo; Yao, Jian; Li, Lan-Juan

    2017-01-06

    Lactobacillus salivarius LI01, isolated from healthy humans, has demonstrated probiotic properties in the prevention and treatment of liver failure. Tolerance to bile stress is crucial to allow lactobacilli to survive in the gastrointestinal tract and exert their benefits. In this work, we used a Digital Gene Expression transcriptomic and iTRAQ LC-MS/MS proteomic approach to examine the characteristics of LI01 in response to bile stress. Using culture medium with or without 0.15% ox bile, 591 differentially transcribed genes and 347 differentially expressed proteins were detected in LI01. Overall, we found the bile resistance of LI01 to be based on a highly remodeled cell envelope and a reinforced bile efflux system rather than on the activity of bile salt hydrolases. Additionally, some differentially expressed genes related to regulatory systems, the general stress response and central metabolism processes, also play roles in stress sensing, bile-induced damage prevention and energy efficiency. Moreover, bile salts appear to enhance proteolysis and amino acid uptake (especially aromatic amino acids) by LI01, which may support the liver protection properties of this strain. Altogether, this study establishes a model of global response mechanism to bile stress in L. salivarius LI01. L. salivarius strain LI01 exhibits not only antibacterial and antifungal properties but also exerts a good health-promoting effect in acute liver failure. As a potential probiotic strain, the bile-tolerance trait of strain LI01 is important, though this has not yet been explored. In this study, an analysis based on DGE and iTRAQ was performed to investigate the gene expression in strain LI01 under bile stress at the mRNA and protein levels, respectively. To our knowledge, this work also represents the first combined transcriptomic and proteomic analysis of the bile stress response mechanism in L. salivarius. Copyright © 2016. Published by Elsevier B.V.

  9. 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.

  10. Thermodynamic study on competitive solubilization of cholesterol and beta-sitosterol in bile salt micelles.

    Science.gov (United States)

    Matsuoka, Keisuke; Hirosawa, Takashi; Honda, Chikako; Endo, Kazutoyo; Moroi, Yoshikiyo; Shibata, Osamu

    2007-07-01

    Differences in the preferential solubilization of cholesterol and competitive solubilizates (beta-sitosterol and aromatic compounds) in bile salt micelles was systematically studied by changing the molar ratio of cholesterol to competitive solubilizates. The cholesterol solubility in a mixed binary system (cholesterol and beta-sitosterol) was almost half that of the cholesterol alone system, regardless of the excess beta-sitosterol quantity added. On the other hand, the mutual solubilities of cholesterol and pyrene were not inhibited by their presence in binary mixed crystals. Finally, the cholesterol solubility was measured by changing the alkyl chain length of n-alkylbenzenes. When tetradecylbenzene was added to the bile solution, the cholesterol solubility decreased slightly and was below the original cholesterol solubility. Based on Gibbs energy change (DeltaG degrees ) for solubilization, chemicals that inhibit cholesterol solubility in their combined crystal systems showed a larger negative DeltaG degrees value than cholesterol alone.

  11. 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

  12. 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%)

  13. 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

  14. 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

  15. 21 CFR 172.350 - Fumaric acid and salts of fumaric acid.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Fumaric acid and salts of fumaric acid. 172.350... HUMAN CONSUMPTION Special Dietary and Nutritional Additives § 172.350 Fumaric acid and salts of fumaric acid. Fumaric acid and its calcium, ferrous, magnesium, potassium, and sodium salts may be safely used...

  16. 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

  17. 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)

  18. Density, viscosity, and N2O solubility of aqueous amino acid salt and amine amino acid salt solutions

    International Nuclear Information System (INIS)

    Aronu, Ugochukwu E.; Hartono, Ardi; Svendsen, Hallvard F.

    2012-01-01

    Highlights: ► Density of amino acid salt and amine amino acid salt. ► Viscosity of amino acid salt and amine amino acid salt. ► Henry’s law constant/N 2 O solubility of amino acid salt and amine amino acid salt. ► Schumpe model. Correlations for density, viscosity, and N 2 O solubility. - Abstract: Physicochemical properties of aqueous amino acid salt (AAS), potassium salt of sarcosine (KSAR) and aqueous amine amino acid salt (AAAS), 3-(methylamino)propylamine/sarcosine (SARMAPA) have been studied. Densities of KSAR were measured for sarcosine mole fraction 0.02 to 0.25 for temperature range 298.15 K to 353.15 K, the viscosities were measured for 0.02 to 0.10 mole fraction sarcosine (293.15 K to 343.15 K) while the N 2 O solubilities were measured from 0.02 to 0.10 mole fraction sarcosine solutions (298.15 K to 363.15 K). Densities of SARMAPA were measured for sarcosine mole fraction 0.02 to 0.23 for temperature range (298.15 K to 353.15 K), viscosities were measured for 0.02 to 0.16 mole fraction sarcosine (293.15 K to 343.15 K) while the N 2 O solubilities were measured from 0.02 to 0.16 mole fraction sarcosine solutions (298.15 K to 343.15 K). Experimental results were correlated well with empirical correlations and N 2 O solubility results for KSAR were predicted adequately by a Schumpe model. The solubilities of N 2 O in AAS and AAAS are significantly lower than values for amines. The solubilities vary as: amine > AAAS > AAS.

  19. 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.

  20. Bile salts-containing vesicles: promising pharmaceutical carriers for oral delivery of poorly water-soluble drugs and peptide/protein-based therapeutics or vaccines.

    Science.gov (United States)

    Aburahma, Mona Hassan

    2016-07-01

    Most of the new drugs, biological therapeutics (proteins/peptides) and vaccines have poor performance after oral administration due to poor solubility or degradation in the gastrointestinal tract (GIT). Though, vesicular carriers exemplified by liposomes or niosomes can protect the entrapped agent to a certain extent from degradation. Nevertheless, the harsh GIT environment exemplified by low pH, presence of bile salts and enzymes limits their capabilities by destabilizing them. In response to that, more resistant bile salts-containing vesicles (BS-vesicles) were developed by inclusion of bile salts into lipid bilayers constructs. The effectiveness of orally administrated BS-vesicles in improving the performance of vesicles has been demonstrated in researches. Yet, these attempts did not gain considerable attention. This is the first review that provides a comprehensive overview of utilizing BS-vesicles as a promising pharmaceutical carrier with a special focus on their successful applications in oral delivery of therapeutic macromolecules and vaccines. Insights on the possible mechanisms by which BS-vesicles improve the oral bioavailability of the encapsulated drug or immunological response of entrapped vaccine are explained. In addition, methods adopted to prepare and characterize BS-vesicles are described. Finally, the gap in the scientific researches tackling BS-vesicles that needs to be addressed is highlighted.

  1. 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...

  2. 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

  3. 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.

  4. Adaptation and Preadaptation of Salmonella enterica to Bile

    Science.gov (United States)

    Hernández, Sara B.; Cota, Ignacio; Ducret, Adrien; Aussel, Laurent; Casadesús, Josep

    2012-01-01

    Bile possesses antibacterial activity because bile salts disrupt membranes, denature proteins, and damage DNA. This study describes mechanisms employed by the bacterium Salmonella enterica to survive bile. Sublethal concentrations of the bile salt sodium deoxycholate (DOC) adapt Salmonella to survive lethal concentrations of bile. Adaptation seems to be associated to multiple changes in gene expression, which include upregulation of the RpoS-dependent general stress response and other stress responses. The crucial role of the general stress response in adaptation to bile is supported by the observation that RpoS− mutants are bile-sensitive. While adaptation to bile involves a response by the bacterial population, individual cells can become bile-resistant without adaptation: plating of a non-adapted S. enterica culture on medium containing a lethal concentration of bile yields bile-resistant colonies at frequencies between 10−6 and 10−7 per cell and generation. Fluctuation analysis indicates that such colonies derive from bile-resistant cells present in the previous culture. A fraction of such isolates are stable, indicating that bile resistance can be acquired by mutation. Full genome sequencing of bile-resistant mutants shows that alteration of the lipopolysaccharide transport machinery is a frequent cause of mutational bile resistance. However, selection on lethal concentrations of bile also provides bile-resistant isolates that are not mutants. We propose that such isolates derive from rare cells whose physiological state permitted survival upon encountering bile. This view is supported by single cell analysis of gene expression using a microscope fluidic system: batch cultures of Salmonella contain cells that activate stress response genes in the absence of DOC. This phenomenon underscores the existence of phenotypic heterogeneity in clonal populations of bacteria and may illustrate the adaptive value of gene expression fluctuations. PMID:22275872

  5. 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.

  6. Studies on the mechanism of cholesterol uptake and on the effects of bile salts on this uptake by brush-border membranes isolated from rabbit small intestine.

    Science.gov (United States)

    Proulx, P; Aubry, H; Brglez, I; Williamson, D G

    1984-12-19

    The effect of bile salts and other surfactants on the rate of incorporation of cholesterol into isolated brush-border membranes was tested. At constant cholesterol concentration, a stimulatory effect of taurocholate was noticed which increased as the bile salt concentration was raised to 20 mM. Taurodeoxycholate was as effective as taurocholate at concentrations of up to 5 mM and inhibited at higher concentrations. Glycocholate was only moderately stimulatory whereas cholate was nearly as effective as taurocholate at concentrations above 5 mM. Other surfactants such as sodium lauryl sulfate and Triton X-100 were very inhibitory at all concentrations tried whereas cetyltrimethyl ammonium chloride was stimulatory only at a very low range of concentrations. These micellizing agents all caused some disruption of the membranes and the greater effectiveness of taurocholate in stimulating sterol uptake was partly relatable to the weaker membrane solubilizing action of this bile salt. Preincubation of membranes with 20 mM taurocholate followed by washing and exposure to cholesterol-containing lipid suspensions lacking bile salt, did not enhance the incorporation of the sterol. In the absence of bile salt the incorporation of cholesterol was unaffected by stirring of the incubation mixtures. Increasing the cholesterol concentration in the mixed micelle while keeping the concentration of bile salt constant caused an increase in rate of sterol incorporation. This increased rate was seen whether the cholesterol suspension was turbid, i.e., contained non-micellized cholesterol, or whether it was optically-clear and contained only monomers and micelles. When the concentration of taurocholate and cholesterol were increased simultaneously such that the concentration ratio of these two components was kept constant, there resulted a corresponding increase in rate of cholesterol uptake. The initial rates of cholesterol incorporation from suspensions containing micellar and monomer

  7. 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

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. Complexation of tauro- and glyco-conjugated bile salts with alpha-cyclodextrin and hydroxypropyl-alpha-cyclodextrin studied by affinity capillary electrophoresis and molecular modelling

    DEFF Research Database (Denmark)

    Holm, Rene; Schönbeck, Jens Christian Sidney; Askjær, Sune

    2011-01-01

    The interaction of the bile salts taurocholate, taurodeoxycholate, taurochenodeoxycholate, glycocholate, glycodeoxycholate, and glycochenodeoxycholate present in man, dog, and rat with α-cyclodextrin and 2-hydroxypropyl-α-cyclodextrin was investigated by mobility shift affinity capillary electrop...

  14. 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.

  15. 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.

  16. 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.

  17. 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

  18. 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

  19. 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

  20. Purification and characterization of recombinant human bile salt-stimulated lipase expressed in milk of transgenic cloned cows

    Science.gov (United States)

    Ding, Fangrong; Wang, Tao; Liu, Wenjie; Lindquist, Susanne; Hernell, Olle; Wang, Jianwu; Li, Jing; Li, Ling; Zhao, Yaofeng; Dai, Yunping; Li, Ning

    2017-01-01

    Bile salt-stimulated lipase (BSSL) is a lipolytic digestive enzyme with broad substrate specificity secreted from exocrine pancreas into the intestinal lumen in all species and from the lactating mammary gland into the milk of some species, notably humans but not cows. BSSL in breast milk facilitates digestion and absorption of milk fat and promotes growth of small for gestational age preterm infants. Thus, purified recombinant human BSSL (rhBSSL) can be used for treatment of patients with fat malabsorption and expressing rhBSSL in the milk of transgenic cloned cows would therefore be a mean to meet a medical need. In the present study, a vector pBAC-hLF-hBSSL was constructed, which efficiently expressed active rhBSSL in milk of transgenic cloned cows to a concentration of 9.8 mg/ml. The rhBSSL purified from cow milk had the same enzymatic activity, N-terminal amino acid sequence, amino acid composition and isoelectric point and similar physicochemical characteristics as human native BSSL. Our study supports the use of transgenic cattle for the cost-competitive, large-scale production of therapeutic rhBSSL. PMID:28475629

  1. 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

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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

  10. 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

  11. 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.

  12. 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

  13. 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.

  14. Hydration Differences Explain the Large Variations in the Complexation Thermodynamics of Modified γ-Cyclodextrins with Bile Salts

    DEFF Research Database (Denmark)

    Køhler, Jonatan; Schönbeck, Jens Christian Sidney; Westh, Peter

    2016-01-01

    The structure and thermodynamics of inclusion complexes of seven different γ-cyclodextrins (γCDs) and three biologically relevant bile salts (BS) were investigated in the present study. Natural γCD and six modified γCDs [two methyl-γCDs, one sulfobutyl ether-γCD (SBEγCD), and three 2-hydroxypropyl...

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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'

  20. 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...

  1. 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...

  2. 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

  3. Salt and cocrystals of sildenafil with dicarboxylic acids: solubility and pharmacokinetic advantage of the glutarate salt.

    Science.gov (United States)

    Sanphui, Palash; Tothadi, Srinu; Ganguly, Somnath; Desiraju, Gautam R

    2013-12-02

    Sildenafil is a drug used to treat erectile dysfunction and pulmonary arterial hypertension. Because of poor aqueous solubility of the drug, the citrate salt, with improved solubility and pharmacokinetics, has been marketed. However, the citrate salt requires an hour to reach its peak plasma concentration. Thus, to improve solubility and bioavailability characteristics, cocrystals and salts of the drug have been prepared by treating aliphatic dicarboxylic acids with sildenafil; the N-methylated piperazine of the drug molecule interacts with the carboxyl group of the acid to form a heterosynthon. Salts are formed with oxalic and fumaric acid; salt monoanions are formed with succinic and glutaric acid. Sildenafil forms cocrystals with longer chain dicarboxylic acids such as adipic, pimelic, suberic, and sebacic acids. Auxiliary stabilization via C-H···O interactions is also present in these cocrystals and salts. Solubility experiments of sildenafil cocrystal/salts were carried out in 0.1N HCl aqueous medium and compared with the solubility of the citrate salt. The glutarate salt and pimelic acid cocrystal dissolve faster than the citrate salt in a two hour dissolution experiment. The glutarate salt exhibits improved solubility (3.2-fold) compared to the citrate salt in water. Solubilities of the binary salts follow an inverse correlation with their melting points, while the solubilities of the cocrystals follow solubilities of the coformer. Pharmacokinetic studies on rats showed that the glutarate salt exhibits doubled plasma AUC values in a single dose within an hour compared to the citrate salt. The high solubility of glutaric acid, in part originating from the strained conformation of the molecule and its high permeability, may be the reason for higher plasma levels of the drug.

  4. [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)

  5. 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

  6. 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

  7. 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

  8. 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.

  9. 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

  10. Lecithin in mixed micelles attenuates the cytotoxicity of bile salts in Caco-2 cells.

    Science.gov (United States)

    Tan, Ya'nan; Qi, Jianping; Lu, Yi; Hu, Fuqiang; Yin, Zongning; Wu, Wei

    2013-03-01

    This study was designed to investigate the cytotoxicity of bile salt-lecithin mixed micelles on the Caco-2 cell model. Cell viability and proliferation after mixed micelles treatments were evaluated with the MTT assay, and the integrity of Caco-2 cell monolayer was determined by quantitating the transepithelial electrical resistance and the flux of tracer, FITC-dextran 4400. The apoptosis induced by mixed micelles treatments was investigated with the annexin V/PI protocol. The particle size of mixed micelles was all smaller than 100 nm. The mixed micelles with lower than 0.2mM sodium deoxycholate (SDC) had no significant effects on cell viability and proliferation. When the level of SDC was higher than 0.4mM and the lecithin/SDC ratio was lower than 2:1, the mixed micelles caused significant changes in cell viability and proliferation. Furthermore, the mixed micelles affected tight junctions in a composition-dependent manner. Specifically, the tight junctions were transiently opened rather than damaged by the mixed micelles with SDC of between 0.2 and 0.6mM. The mixed micelles with more lecithin also induced less apoptosis. These results demonstrate that relatively higher concentrations of mixed micelles are toxic to Caco-2 cells, while phospholipids can attenuate the toxicity of the bile salts. Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.

  11. 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...

  12. PENGIKATAN GARAM EMPEDU OLEH SUSU KEDELAI TERFERMENTASI DAN STABILITASNYA TERHADAP PEPSIN DAN PANKREATIN [Binding of Bile Salts by Fermented Soymilk and Its Stability Against Pepsin and Pancreatin

    Directory of Open Access Journals (Sweden)

    Yusmarini1*

    2013-06-01

    Full Text Available Processed soybean products especially the fermented ones have beneficial health effects since they are capable of reducing the level of plasmacholesterol (hypocholesterolemic effect. One of the mechanisms is by increasing the binding of bile salt. This research was aimed to assess the ability of soymilk, fermented soymilk products and fermented soymilk products combined with enzymatic hydrolysis to bind bile salts. The stability of the binding against hydrolysis by digestive enzymes (pepsin and pancreatin was also evaluated. Fermented soybean products inoculated with isolates of L. plantarum 1 R.11.1.2 was be able to bind 1.40 μmol/100 mg protein (62.26% of natrium taurocholate. This binding ability is slightly higher than that of soymilk to natrium taurocholate, i.e.1.33 μmol/100 mg protein (59.04%. Addition of a protease enzyme specific to hydrophobic amino acid (thermolysin on fermented soymilk products was able to enhance the ability of bind natrium taurocholate. Enzymatic hydrolysis products having a molecular weight of <7 kDa could bind 1.51 μmol/100 mg protein natrium taurocholate (67.4%. There was a significant increase in the binding, i.e. 7.9% by the fermented products or an increase of 13.5% from soymilk. Meanwhile peptides measuring ≥7 kDa showed no binding ability against natrium taurocholate.

  13. Production of carboxylic acid and salt co-products

    Science.gov (United States)

    Hanchar, Robert J.; Kleff, Susanne; Guettler, Michael V.

    2014-09-09

    This invention provide processes for producing carboxylic acid product, along with useful salts. The carboxylic acid product that is produced according to this invention is preferably a C.sub.2-C.sub.12 carboxylic acid. Among the salts produced in the process of the invention are ammonium salts.

  14. 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...

  15. 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...

  16. 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.

  17. 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.

  18. 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...

  19. Bile Salt Hydrolase Activities: A Novel Target to Screen Anti-Giardia Lactobacilli?

    Directory of Open Access Journals (Sweden)

    Thibault Allain

    2018-02-01

    Full Text Available Giardia duodenalis is a protozoan parasite responsible for giardiasis, a disease characterized by intestinal malabsorption, diarrhea and abdominal pain in a large number of mammal species. Giardiasis is one of the most common intestinal parasitic diseases in the world and thus a high veterinary, and public health concern. It is well-established that some probiotic bacteria may confer protection against this parasite in vitro and in vivo and we recently documented the implication of bile-salt hydrolase (BSH-like activities from strain La1 of Lactobacillus johnsonii as mediators of these effects in vitro. We showed that these activities were able to generate deconjugated bile salts that were toxic to the parasite. In the present study, a wide collection of lactobacilli strains from different ecological origins was screened to assay their anti-giardial effects. Our results revealed that the anti-parasitic effects of some of the strains tested were well-correlated with the expression of BSH-like activities. The two most active strains in vitro, La1 and Lactobacillus gasseri CNCM I-4884, were then tested for their capacity to influence G. duodenalis infection in a suckling mice model. Strikingly, only L. gasseri CNCM I-4884 strain was able to significantly antagonize parasite growth with a dramatic reduction of the trophozoites load in the small intestine. Moreover, this strain also significantly reduced the fecal excretion of Giardia cysts after 5 days of treatment, which could contribute to blocking the transmission of the parasite, in contrast of La1 where no effect was observed. This study represents a step toward the development of new prophylactic strategies to combat G. duodenalis infection in both humans and animals.

  20. 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.

  1. 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.

  2. Swertianlarin, an Herbal Agent Derived from Swertia mussotii Franch, Attenuates Liver Injury, Inflammation, and Cholestasis in Common Bile Duct-Ligated Rats

    Directory of Open Access Journals (Sweden)

    Liangjun Zhang

    2015-01-01

    Full Text Available Swertianlarin is an herbal agent abundantly distributed in Swertia mussotii Franch, a Chinese traditional herb used for treatment of jaundice. To study the therapeutic effect of swertianlarin on cholestasis, liver injury, serum proinflammatory cytokines, and bile salt concentrations were measured by comparing rats treated with swertianlarin 100 mg/kg/d or saline for 3, 7, or 14 days after bile duct ligation (BDL. Serum alanine aminotransferase (ATL and aspartate aminotransferase (AST levels were significantly decreased in BDL rats treated with swertianlarin for 14 days (P<0.05. The reduced liver injury in BDL rats by swertianlarin treatment for 14 days was further confirmed by liver histopathology. Levels of serum tumor necrosis factor alpha (TNFα were decreased by swertianlarin in BDL rats for 3 and 7 days (P<0.05. Moreover, reductions in serum interleukins IL-1β and IL-6 levels were also observed in BDL rats treated with swertianlarin (P<0.05. In addition, most of serum toxic bile salt concentrations (e.g., chenodeoxycholic acid (CDCA and deoxycholic acid (DCA in cholestatic rats were decreased by swertianlarin (P<0.05. In conclusion, the data suggest that swertianlarin derived from Swertia mussotii Franch attenuates liver injury, inflammation, and cholestasis in bile duct-ligated rats.

  3. Enhanced oral bioavailability of silymarin using liposomes containing a bile salt: preparation by supercritical fluid technology and evaluation in vitro and in vivo

    Science.gov (United States)

    Yang, Gang; Zhao, Yaping; Zhang, Yongtai; Dang, Beilei; Liu, Ying; Feng, Nianping

    2015-01-01

    The aim of this investigation was to develop a procedure to improve the dissolution and bioavailability of silymarin (SM) by using bile salt-containing liposomes that were prepared by supercritical fluid technology (ie, solution-enhanced dispersion by supercritical fluids [SEDS]). The process for the preparation of SM-loaded liposomes containing a bile salt (SM-Lip-SEDS) was optimized using a central composite design of response surface methodology with the ratio of SM to phospholipids (w/w), flow rate of solution (mL/min), and pressure (MPa) as independent variables. Particle size, entrapment efficiency (EE), and drug loading (DL) were dependent variables for optimization of the process and formulation variables. The particle size, zeta potential, EE, and DL of the optimized SM-Lip-SEDS were 160.5 nm, −62.3 mV, 91.4%, and 4.73%, respectively. Two other methods to produce SM liposomes were compared to the SEDS method. The liposomes obtained by the SEDS method exhibited the highest EE and DL, smallest particle size, and best stability compared to liposomes produced by the thin-film dispersion and reversed-phase evaporation methods. Compared to the SM powder, SM-Lip-SEDS showed increased in vitro drug release. The in vivo AUC0−t of SM-Lip-SEDS was 4.8-fold higher than that of the SM powder. These results illustrate that liposomes containing a bile salt can be used to enhance the oral bioavailability of SM and that supercritical fluid technology is suitable for the preparation of liposomes. PMID:26543366

  4. 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 ...

  5. Identification and characterization of a bile salt hydrolase from Lactobacillus salivarius for development of novel alternatives to antibiotic growth promoters.

    Science.gov (United States)

    Wang, Zhong; Zeng, Ximin; Mo, Yiming; Smith, Katie; Guo, Yuming; Lin, Jun

    2012-12-01

    Antibiotic growth promoters (AGPs) have been used as feed additives to improve average body weight gain and feed efficiency in food animals for more than 5 decades. However, there is a worldwide trend to limit AGP use to protect food safety and public health, which raises an urgent need to discover effective alternatives to AGPs. The growth-promoting effect of AGPs has been shown to be highly correlated with the decreased activity of intestinal bile salt hydrolase (BSH), an enzyme that is produced by various gut microflora and involved in host lipid metabolism. Thus, BSH inhibitors are likely promising feed additives to AGPs to improve animal growth performance. In this study, the genome of Lactobacillus salivarius NRRL B-30514, a BSH-producing strain isolated from chicken, was sequenced by a 454 GS FLX sequencer. A BSH gene identified by genome analysis was cloned and expressed in an Escherichia coli expression system for enzymatic analyses. The BSH displayed efficient hydrolysis activity for both glycoconjugated and tauroconjugated bile salts, with slightly higher catalytic efficiencies (k(cat)/K(m)) on glycoconjugated bile salts. The optimal pH and temperature for the BSH activity were 5.5 and 41°C, respectively. Examination of a panel of dietary compounds using the purified BSH identified some potent BSH inhibitors, in which copper and zinc have been recently demonstrated to promote feed digestion and body weight gain in different food animals. In sum, this study identified and characterized a BSH with broad substrate specificity from a chicken L. salivarius strain and established a solid platform for us to discover novel BSH inhibitors, the promising feed additives to replace AGPs for enhancing the productivity and sustainability of food animals.

  6. 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.

  7. 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

  8. Bile Salt Micelles and Phospholipid Vesicles Present in Simulated and Human Intestinal Fluids

    DEFF Research Database (Denmark)

    Elvang, Philipp A; Hinna, Askell H; Brouwers, Joachim

    2016-01-01

    Knowledge about colloidal assemblies present in human intestinal fluids (HIFs), such as bile salt micelles and phospholipid vesicles, is regarded of importance for a better understanding of the in vivo dissolution and absorption behavior of poorly soluble drugs (Biopharmaceutics Classification...... System class II/IV drugs) because of their drug-solubilizing ability. The characterization of these potential drug-solubilizing compartments is a prerequisite for further studies of the mechanistic interplays between drug molecules and colloidal structures within HIFs. The aim of the present study...... and HIF indicate that the simulated intestinal fluids (FaSSIF-V1 and FeSSIF-V1) represent rather simplified models of the real human intestinal environment in terms of coexisting colloidal particles. It is hypothesized that the different supramolecular assemblies detected differ in their lipid composition...

  9. 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...

  10. 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

  11. 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

  12. 21 CFR 172.863 - Salts of fatty acids.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Salts of fatty acids. 172.863 Section 172.863 Food... Multipurpose Additives § 172.863 Salts of fatty acids. The food additive salts of fatty acids may be safely..., magnesium, potassium, and sodium salts of the fatty acids conforming with § 172.860 and/or oleic acid...

  13. 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.

  14. 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

  15. 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.

  16. 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

  17. Rapid increase of bile salt secretion is associated with bile duct injury after human liver transplantation

    NARCIS (Netherlands)

    Geuken, Erwin; Visser, Dorien; Kuipers, Folkert; Blokzijl, Hans; Leuvenink, Henri G. D.; de Jong, Koert P.; Peeters, Paul M. J. G.; Jansen, Peter L. M.; Slooff, Maarten J. H.; Gouw, Annette S. H.; Porte, Robert J.

    2004-01-01

    BACKGROUND/AIMS: Biliary strictures are a serious cause of morbidity after liver transplantation. We have studied the role of altered bile composition as a mechanism of bile duct injury after human liver transplantation. METHODS: In 28 liver transplant recipients, bile samples were collected daily

  18. Rapid increase of bile salt secretion is associated with bile duct injury after human liver transplantation

    NARCIS (Netherlands)

    Geuken, E; Visser, D; Kuipers, F; Blokzijl, H; Leuvenink, HGD; de Jong, KP; Peeters, PMJG; Jansen, PLM; Slooff, MJH; Gouw, ASH; Porte, RJ

    2004-01-01

    Background/Aims: Biliary strictures are a serious cause of morbidity after liver transplantation. We have studied the role of altered bile composition as a mechanism of bile duct injury after human liver transplantation. Methods: In 28 liver transplant recipients, bile samples were collected daily

  19. 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...

  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. Enhancement of bile resistance in Lactobacillus plantarum strains by soy lecithin.

    Science.gov (United States)

    Hu, B; Tian, F; Wang, G; Zhang, Q; Zhao, J; Zhang, H; Chen, W

    2015-07-01

    This study evaluated the effect of soy lecithin on the bile resistance of Lactobacillus plantarum. Six strains were cultured in MRS broth supplemented with soy lecithin at different concentrations. The strains incubated in MRS broth with 1·0% soy lecithin showed no inhibitory effect on cell growth. After culturing in MRS broth with 0·2-1·0% soy lecithin, the survival rate of harvested cells increased significantly (P bile challenge compared with the no added soy lecithin group. The cells incubated with 0·6% soy lecithin were able to grow in an MRS broth with a higher bile salt content. The surface hydrophobicity and cell leakage in the bile challenge were assessed to reveal the physical changes caused by the addition of soy lecithin. The cell surface hydrophobicity was enhanced and the membrane integrity in the bile challenge increased after culturing with soy lecithin. A shift in the fatty acid composition was also observed, illustrating the cell membrane change in the soy lecithin culture. In this study, we report for the first time the beneficial effect of adding soy lecithin to an MRS broth on subsequent bile tolerance of Lactobacillus plantarum. Soy lecithin had no inhibitory effect on strain viability but significantly enhanced bile resistance. Surface hydrophobicity and cell integrity increased in strains cultured with soy lecithin. The observed shift in the cell fatty acid composition indicated changes to the cell membrane. As soy lecithin is safe for use in the food industry, its protective effects can be harnessed for the development of bile-sensitive strains with health-benefit functions for use in probiotic products. © 2015 The Society for Applied Microbiology.

  2. 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.

  3. 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.

  4. 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

  5. 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.

  6. 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.

  7. 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...

  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. The effect of theophylline on canine bile flow, biliary excretion and concentration of ioglycamide

    International Nuclear Information System (INIS)

    Toetterman, S.

    1982-01-01

    Theophylline (TH), which has been shown in experimental dogs to increase bile-salt-independent bile flow, was studied in its effect on the biliary excretion and concentration of the intravenous contrast medium ioglycamide in cholecystectomized anesthetized dogs equipped with a Thomas cannula through which the common bile duct could be cannulated. One hour after cannulation, i.v. infusion of ioglycamide at the rate of 4 mol/min/kg was started. Two hours later, 10 mg/kg of TH was injected intravenously and the experiment continued for a further 75 minutes. Bile was collected at 15 min, intervals throughout the whole experiment and simultaneous intravenous blood samples were taken. In this study, TH increased bile flow and decreased biliary ioglycamide concentration. Although TH increased bile flow, it had no effect on the biliary excretion of ioglycamide. It may be postulated that the organic anion ioglycamide, and possibly other organic anions, are secreted into the bile by mechanisms, unaffected by drugs which increase bile-salt-independent bile flow in a similar manner to TH. (orig.)

  10. 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...

  11. 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, ...

  12. 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.

  13. 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

  14. 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...

  15. 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

  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. Distillation Separation of Hydrofluoric Acid and Nitric Acid from Acid Waste Using the Salt Effect on Vapor-Liquid Equilibrium

    Science.gov (United States)

    Yamamoto, Hideki; Sumoge, Iwao

    2011-03-01

    This study presents the distillation separation of hydrofluoric acid with use of the salt effect on the vapor-liquid equilibrium for acid aqueous solutions and acid mixtures. The vapor-liquid equilibrium of hydrofluoric acid + salt systems (fluorite, potassium nitrate, cesium nitrate) was measured using an apparatus made of perfluoro alkylvinylether. Cesium nitrate showed a salting-out effect on the vapor-liquid equilibrium of the hydrofluoric acid-water system. Fluorite and potassium nitrate showed a salting-in effect on the hydrofluoric acid-water system. Separation of hydrofluoric acid from an acid mixture containing nitric acid and hydrofluoric acid was tested by the simple distillation treatment using the salt effect of cesium nitrate (45 mass%). An acid mixture of nitric acid (5.0 mol · dm-3) and hydrofluoric acid (5.0 mol · dm-3) was prepared as a sample solution for distillation tests. The concentration of nitric acid in the first distillate decreased from 5.0 mol · dm-3 to 1.13 mol · dm-3, and the concentration of hydrofluoric acid increased to 5.41 mol · dm-3. This first distillate was further distilled without the addition of salt. The concentrations of hydrofluoric acid and nitric acid in the second distillate were 7.21 mol · dm-3 and 0.46 mol · dm-3, respectively. It was thus found that the salt effect on vapor-liquid equilibrium of acid mixtures was effective for the recycling of acids from acid mixture wastes.

  18. Triboelectrification of active pharmaceutical ingredients: week acids and their salts.

    Science.gov (United States)

    Fujinuma, Kenta; Ishii, Yuji; Yashihashi, Yasuo; Yonemochi, Estuo; Sugano, Kiyohiko; Tarada, Katsuhide

    2015-09-30

    The effect of salt formulation on the electrostatic property of active pharmaceutical ingredients was investigated. The electrostatic property of weak acids (carboxylic acids and amide-enole type acid) and their sodium salts was evaluated by a suction-type Faraday cage meter. Free carboxylic acids showed negative chargeability, whereas their sodium salts showed more positive chargeability than the free acids. However, no such trend was observed for amide-enole type acids. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. 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.

  20. 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.

  1. 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.

  2. 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

  3. 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

  4. 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

  5. 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.

  6. 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.

  7. 40 CFR 721.3620 - Fatty acid amine condensate, polycarboxylic acid salts.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Fatty acid amine condensate... Specific Chemical Substances § 721.3620 Fatty acid amine condensate, polycarboxylic acid salts. (a... a fatty acid amine condensate, polycarboxylic acid salts. (PMN P-92-445) is subject to reporting...

  8. 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.

  9. 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.

  10. 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

  11. Inside the adaptation process of Lactobacillus delbrueckii subsp. lactis to bile

    OpenAIRE

    Burns, Patricia; Sánchez García, Borja; Vinderola, Gabriel; Ruas-Madiedo, Patricia; Ruíz García, Lorena; Margolles Barros, Abelardo; Reinheimer, Jorge A.; González de los Reyes-Gavilán, Clara

    2010-01-01

    Progressive adaptation to bile might render some lactobacilli able to withstand physiological bile salt concentrations. In this work, the adaptation to bile was evaluated on previously isolated dairy strains of Lactobacillus delbrueckii subsp. lactis 200 and L. delbrueckii subsp. lactis 200+, a strain derived thereof with stable bile-resistant phenotype. The adaptation to bile was obtained by comparing cytosolic proteomes of both strains grown in the presence or absence of bile. Proteomics we...

  12. 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...

  13. 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.

  14. 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

  15. Computational modeling and molecular imprinting for the development of acrylic polymers with high affinity for bile salts.

    Science.gov (United States)

    Yañez, Fernando; Chianella, Iva; Piletsky, Sergey A; Concheiro, Angel; Alvarez-Lorenzo, Carmen

    2010-02-05

    This work has focused on the rational development of polymers capable of acting as traps of bile salts. Computational modeling was combined with molecular imprinting technology to obtain networks with high affinity for cholate salts in aqueous medium. The screening of a virtual library of 18 monomers, which are commonly used for imprinted networks, identified N-(3-aminopropyl)-methacrylate hydrochloride (APMA.HCl), N,N-diethylamino ethyl methacrylate (DEAEM) and ethyleneglycol methacrylate phosphate (EGMP) as suitable functional monomers with medium-to-high affinity for cholic acid. The polymers were prepared with a fix cholic acid:functional monomer mole ratio of 1:4, but with various cross-linking densities. Compared to polymers prepared without functional monomer, both imprinted and non-imprinted microparticles showed a high capability to remove sodium cholate from aqueous medium. High affinity APMA-based particles even resembled the performance of commercially available cholesterol-lowering granules. The imprinting effect was evident in most of the networks prepared, showing that computational modeling and molecular imprinting can act synergistically to improve the performance of certain polymers. Nevertheless, both the imprinted and non-imprinted networks prepared with the best monomer (APMA.HCl) identified by the modeling demonstrated such high affinity for the template that the imprinting effect was less important. The fitting of adsorption isotherms to the Freundlich model indicated that, in general, imprinting increases the population of high affinity binding sites, except when the affinity of the functional monomer for the target molecule is already very high. The cross-linking density was confirmed as a key parameter that determines the accessibility of the binding points to sodium cholate. Materials prepared with 9% mol APMA and 91% mol cross-linker showed enough affinity to achieve binding levels of up to 0.4 mmol g(-1) (i.e., 170 mg g(-1)) under flow

  16. 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.

  17. 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.

  18. 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

  19. 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.

  20. 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.

  1. Ambazone-lipoic acid salt: Structural and thermal characterization

    Energy Technology Data Exchange (ETDEWEB)

    Kacso, Irina [National Institute for Research and Development of Isotopic and Molecular Technologies, 65-103 Donath street, 400293 Cluj-Napoca (Romania); Racz, Csaba-Pal; Santa, Szabolcs [Babes-Bolyai' University, Faculty of Chemistry, 11 Arany Janos street, Cluj-Napoca (Romania); Rus, Lucia [' Iuliu Hatieganu' University of Medicine and Pharmacy, Faculty of Pharmacy, 6 Louis Pasteur street, 400349 Cluj-Napoca (Romania); Dadarlat, Dorin; Borodi, Gheorghe [National Institute for Research and Development of Isotopic and Molecular Technologies, 65-103 Donath street, 400293 Cluj-Napoca (Romania); Bratu, Ioan, E-mail: ibratu@gmail.com [National Institute for Research and Development of Isotopic and Molecular Technologies, 65-103 Donath street, 400293 Cluj-Napoca (Romania)

    2012-12-20

    Highlights: Black-Right-Pointing-Pointer Salt of Ambazone with lipoic acid obtained by solvent-drop grinding. Black-Right-Pointing-Pointer Ambazone lipoate salt crystallizes in monoclinic system. Black-Right-Pointing-Pointer FTIR data suggest the deprotonation of the lipoic acid. Black-Right-Pointing-Pointer Thermal behaviour different of ambazone salt as compared to the starting compounds. - Abstract: A suitable method for increasing the solubility, dissolution rate and consequently the bioavailability of poor soluble acidic or basic drugs is their salt formation. The aim of this study is to investigate the structural and thermal properties of the compound obtained by solvent drop grinding (SDG) method at room temperature, starting from the 1:1 molar ratios of ambazone (AMB) and {alpha}-lipoic acid (LA). The structural characterization was performed with X-ray powder diffraction (XRPD) and infrared spectroscopy (FTIR). The thermal behaviour of the obtained compound (AMB{center_dot}LA) was investigated by differential scanning calorimetry (DSC) and thermogravimetry (TG). The photopyroelectric calorimetry, in front detection configuration (FPPE), was applied to measure and compare the room temperature values of one dynamic thermal parameter (thermal effusivity) for starting and resulting compounds. Both structural and supporting calorimetric techniques pointed out a salt structure for AMB{center_dot}LA compound as compared to those of the starting materials.

  2. 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

  3. Taurocholate Deconjugation and Cholesterol Binding by Indigenous Dadih Lactic Acid Bacteria

    Directory of Open Access Journals (Sweden)

    USMAN PATO

    2005-09-01

    Full Text Available High serum cholesterol levels have been associated with an increased risk for human coronary heart disease. Lowering of serum cholesterol has been suggested to prevent the heart disease. To reduce serum cholesterol levels one may consumed diet supplementat of fermented dairy product such as dadih. Lactic acid bacteria present in dadih may alter serum cholesterol by directly bind to dietary cholesterol and/or deconjugation of bile salts. Acid and bile tolerance, deconjugation of sodium taurocholate, and the cholesterol-binding ability of lactic acid bacteria from dadih were examined. Among ten dadih lactic acid bacteria tested, six strains namely I-11, I-2775, K-5, I-6257, IS-7257, and B-4 could bind cholesterol and deconjugate sodium taurocholate. However, the last four strains were very sensitive to bile. Therefore, Lactobacillus fermentum I-11 and Leuconostoc lactis subsp. lactis I-2775 those were tolerant to acid and oxgall (bile and deconjugated sodium taurocholate and bound cholesterol could be recommended as probiotic to prevent coronary heart disease.

  4. 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

  5. Administration of phosphatidylcholine-cholesterol liposomes partially reconstitutes fat absorption in chronically bile-diverted rats

    NARCIS (Netherlands)

    Nishioka, T; Havinga, R; Tazuma, S; Stellaard, F; Kuipers, F; Verkade, HJ

    2004-01-01

    Background and aims: Intestinal bile deficiency in cholestatic patients leads to fat malabsorption. We addressed the potency of model bile, bile salts and phosphatidylcholine (PC)-cholesterol (CH) liposomes to reconstitute fat absorption in permanently bile-diverted (BD) rats. Methods: The plasma

  6. 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

  7. 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.

  8. 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...

  9. 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.

  10. 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.

  11. 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

  12. 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

  13. 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...

  14. 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.

  15. 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

  16. 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

  17. 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...

  18. 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

  19. 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

  20. De Novo Endotoxin-Induced Production of Antibodies against the Bile Salt Export Pump Associated with Bacterial Infection following Major Hepatectomy

    Directory of Open Access Journals (Sweden)

    Kun-Ming Chan

    2018-01-01

    Full Text Available Background. Clinically severe infection-related inflammation after major liver resection may cause hyperbilirubinemia. This study aims to clarify the impact of bacterial infection and endotoxins on the hepatobiliary transporter system and to explore possible mechanisms of endotoxin-related postoperative hyperbilirubinemia. Method. Mice that underwent major hepatectomy with removal of at least 70% of liver volume were exposed to lipopolysaccharide (LPS at different dosages. Subsequently, hepatobiliary transporter compounds related to bile salt excretion were further investigated. Results. The expression of genes related to hepatobiliary transporter compounds was not significantly different in the liver tissue of mice after major hepatectomy and LPS exposure. However, bile salt export pump (BSEP protein expression within the liver tissue of mice treated with LPS after major hepatectomy was relatively weaker and was even further reduced in the high-dose LPS group. The formation of antibodies against the BSEP in response to endotoxin exposure was also detected. Conclusion. This study illustrates a possible mechanism whereby the dysfunction of hepatobiliary transporter systems caused by endotoxin-induced autoantibodies may be involved in the development of postoperative jaundice associated with bacterial infection after major hepatectomy.

  1. 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

  2. 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.

  3. 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

  4. 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

  5. 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.

  6. 21 CFR 573.914 - Salts of volatile fatty acids.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Salts of volatile fatty acids. 573.914 Section 573... Food Additive Listing § 573.914 Salts of volatile fatty acids. (a) Identity. The food additive is a... contains ammonium or calcium salts of volatile fatty acids and shall conform to the following...

  7. Cesium Salts of Phosphotungstic Acid: Comparison of Surface ...

    African Journals Online (AJOL)

    NICO

    acidity and lowest solubility in reaction media in comparison with the other cesium content salts. KEYWORDS. Polyoxometalates, cesium ... insoluble salt of HPA is cesium salt of tungstophosphoric acid,. CsxH3-xPW12O40 (CsxPW), a ... of Cs2CO3, very fine particles (precipitates) were formed to make the solution milky.

  8. 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.

  9. 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

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. Sorption and pertechnetate by salts of molybdophosphoric acid

    International Nuclear Information System (INIS)

    Suess, M.; Pfrepper, G.

    1983-01-01

    The sorption of pertechnetate on salts of molybdophosphoric acid from nitric acid and in the presence of electrolytes was investigated. Distribution coefficients from 10 to 100 ml/g were found. The sorption of pertechnetate can be increased by the addition of K + , NH 4 + , Rb + and Cs + salts. A saturation capacity of proportional 0,19 mmol/g ammonium phosphomolybdate was found from the adsorption isotherms. The formation of alkali metal pertechnetate associates in the sorbent phase is supposed. (orig.)

  16. 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.

  17. Inside the adaptation process of Lactobacillus delbrueckii subsp. lactis to bile.

    Science.gov (United States)

    Burns, Patricia; Sánchez, Borja; Vinderola, Gabriel; Ruas-Madiedo, Patricia; Ruiz, Lorena; Margolles, Abelardo; Reinheimer, Jorge; de los Reyes-Gavilán, Clara G

    2010-08-15

    Progressive adaptation to bile might render some lactobacilli able to withstand physiological bile salt concentrations. In this work, the adaptation to bile was evaluated on previously isolated dairy strains of Lactobacillus delbrueckii subsp. lactis 200 and L. delbrueckii subsp. lactis 200+, a strain derived thereof with stable bile-resistant phenotype. The adaptation to bile was obtained by comparing cytosolic proteomes of both strains grown in the presence or absence of bile. Proteomics were complemented with physiological studies on both strains focusing on glycolytic end-products, the ability to adhere to the human intestinal epithelial cell line HT29-MTX and survival to simulated gastrointestinal conditions. Protein pattern comparison of strains grown with and without bile allowed us to identify 9 different proteins whose production was regulated by bile in both strains, and 17 proteins that showed differences in their levels between the parental and the bile-resistant derivative. These included general stress response chaperones, proteins involved in transcription and translation, in peptidoglycan/exopolysaccharide biosynthesis, in the lipid and nucleotide metabolism and several glycolytic and pyruvate catabolism enzymes. Differences in the level of metabolic end-products of the sugar catabolism were found between the strains 200 and 200+. A decrease in the adhesion of both strains to the intestinal cell line was detected in the presence of bile. In simulated gastric and intestinal juices, a protective effect was exerted by milk improving the survival of both microorganisms. These results indicate that bile tolerance in L. delbrueckii subsp. lactis involves several mechanisms responding to the deleterious impact of bile salts on bacterial physiology. Copyright 2010 Elsevier B.V. All rights reserved.

  18. 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.

  19. 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.

  20. 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

  1. 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.

  2. 40 CFR 721.3629 - Triethanolamine salts of fatty acids.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Triethanolamine salts of fatty acids... Substances § 721.3629 Triethanolamine salts of fatty acids. (a) Chemical substances and significant new uses subject to reporting. (1) The chemical substances identified generically as triethanolamine salts of fatty...

  3. 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.

  4. 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.

  5. 40 CFR 721.5278 - Substituted naphthalenesulfonic acid, alkali salt.

    Science.gov (United States)

    2010-07-01

    ..., alkali salt. 721.5278 Section 721.5278 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.5278 Substituted naphthalenesulfonic acid, alkali salt. (a) Chemical... as a substituted naphthalenesulfonic acid, alkali salt (PMN P-95-85) is subject to reporting under...

  6. 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.

  7. 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.

  8. 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

  9. Investigations of the enterohepatic bile salt circulation using the 14C-glycol cholate/14CO2 exhalation test in persons with Billroth-II stomach resection

    International Nuclear Information System (INIS)

    Raguse, G.

    1978-01-01

    A 14 C-glycol cholate/ 14 CO 2 exhalation test was carried out in 34 normal persons, 32 persons with a Billroth-II resection stomach, and 9 patients with a Billroth-II resection stomach and gastroenterological disorders. Persons with a normal stomach function after B-II resection and an objective lack of symptoms of a gastroenterological disease had normal test results in all cases. In 7 of the 9 B-II resected patients with various disorders or diseases of the intestinal tract of the liver gallbladder on pancreas, 14 CO 2 exhalation was pathologically increased. In agreement with the hypothesis that deconjugation of bile salts can only be caused by bacterial enzymes, a pathological finding can be explained by a pathological bacteria population in the upper intestinal tract or by a loss of bile salts. However, the clinical importance of pathological test results remains doubtful as 3 out of the 7 patients with pathological results presented with no clinical symptoms. (orig.) [de

  10. 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

  11. 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

  12. Bile loss in the acute intestinal radiation syndrome in rats

    International Nuclear Information System (INIS)

    Geraci, J.P.; Dunston, S.G.; Jackson, K.L.; Mariano, M.S.; Holeski, C.; Eaton, D.L.

    1987-01-01

    The effects of bile duct ligation (BDL), choledochostomy, bile acid sequestering within the intestinal lumen by cholestyramine, and fluid and electrolyte replacement on survival time and development of diarrhea after whole-body exposure to doses of ionizing radiation that result in death from acute intestinal injury were studied. BDL significantly prolonged survival and delayed the onset of diarrhea after exposure to 137 Cs gamma rays, fission neutrons, or cyclotron-produced neutrons in the range of doses that produce intestinal death or death from a combination of intestinal and hematopoietic injuries. Cannulation of the bile duct with exteriorized bile flow (choledochostomy) to protect the irradiated intestine from the mucolytic action of bile salts did not duplicate the effect of BDL in increasing survival time. Choledochostomy without fluid replacement eliminated the occurrence of diarrhea in 15.4 Gy irradiated rats. Diarrhea did occur in irradiated animals with choledochostomy if they received duodenal injections of fluid and electrolytes to replace the fluid lost as a result of bile drainage. Duodenal injection of fluid and electrolytes had no significant effect on survival time in irradiated rats. Injection of fluid and electrolytes into the peritoneal cavity of irradiated rats resulted in an increase in survival time that was comparable to that observed after BDL. Addition of antibiotics to the peritoneally injected fluid and electrolytes further increased survival time (up to 9 days). This survival time approached that seen in animals receiving the same radiation dose but which had the intestine exteriorized and shielded to minimize radiation injury to the intestine. Postmortem histological examinations of the irradiated small intestine showed mucosal regeneration in these long-term survivors receiving fluid and antibiotic therapy

  13. 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.

  14. 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.

  15. 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.

  16. 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....

  17. Selection of local extremophile lactic acid bacteria with high capacity ...

    African Journals Online (AJOL)

    This study is related to the isolation and identification of strains of local thermophilic lactic acid bacteria belonging to the species, Streptococcus thermophilus and Lactobacillus bulgaricus. These bacteria can exist under extreme conditions of the digestive tract (acidity and high concentration of bile salts) and have a high ...

  18. 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

  19. Viscosities of oxalic acid and its salts in water and binary aqueous ...

    Indian Academy of Sciences (India)

    Unknown

    Viscosities; oxalic acid and its salts; water + THF mixtures; structure-breakers. 1. Introduction ... has found its application in the organic syntheses as manifested from ... water. In other words, these results indicate that oxalic acid and its salts mix ...

  20. Bile salts at the air-water interface: adsorption and desorption.

    Science.gov (United States)

    Maldonado-Valderrama, J; Muros-Cobos, J L; Holgado-Terriza, J A; Cabrerizo-Vílchez, M A

    2014-08-01

    Bile salts (BS) are bio-surfactants which constitute a vital component in the process of fat digestion. Despite the importance of the interfacial properties in their biological role, these have been scarcely studied in the literature. In this work, we present the adsorption-desorption profiles of two BS (NaTC and NaGDC) including dilatational rheology. Findings from this study reveal very different surface properties of NaTC and NaGDC which originate from different complexation properties relevant to the digestion process. Dynamic adsorption curves show higher adsorption rates for NaTC and suggest the existence of various conformational regimes in contrast to NaGDC which presents only one conformational regime. This is corroborated by analysis of the adsorption isotherms and more in detail by the rheological behaviour. Accordingly, the dilatational response at 1Hz displays two maxima of the dilatational modulus for NaTC as a function of bulk concentration, in contrast to NaGDC which displays only one maximum. The desorption profiles reveal that NaTC adopts an irreversibly adsorbed form at high surface coverage whereas NaGDC fully desorbs from the surface within the whole range of concentrations used. Analysis of the adsorption-desorption profiles provides new insight into the surface properties of BS, suggesting a surface complexation of NaTC. This knowledge can be useful since through interfacial engineering we might control the extent of lipolysis providing the basis for the rational design of food products with tailored digestibility. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Bile salt receptor TGR5 is highly expressed in esophageal adenocarcinoma and precancerous lesions with significantly worse overall survival and gender differences

    Directory of Open Access Journals (Sweden)

    Pang CH

    2017-02-01

    Full Text Available Chunhong Pang,1,2 Amy LaLonde,3 Tony E Godfrey,4 Jianwen Que,5,6 Jun Sun,7 Tong Tong Wu,3 Zhongren Zhou2 1Department of Pathology, China-Japan Friendship Hospital, 2Department of Pathology and Laboratory Medicine, 3Department of Biostatistics and Computational Biology, University of Rochester, Rochester, NY, 4Department of Surgery, Boston University Medical Center, Boston, MA, 5Center for Human Development, 6Division of Digestive and Liver Diseases, Columbia University, New York, NY, 7Division of Gastroenterology and Hepatology, University of Illinois College of Medicine, Chicago, IL, USA Abstract: Bile acid reflux in the esophagus plays an important role in the carcinogenesis of esophageal adenocarcinoma (EAC. The G-protein coupled bile acid receptor (TGR5 has been associated with the development of gastrointestinal cancer. However, little is known regarding the role of TGR5 in esophageal carcinoma and precancerous lesions. We analyzed genomic DNA from 116 EACs for copy number aberrations via Affymetrix SNP6.0 microarrays. The TGR5 gene locus was amplified in 12.7% (14/116 of the EACs. The TGR5 protein expression was also assessed using immunohistochemistry from tissue microarrays, including Barrett’s esophagus (BE, low- (LGD and high-grade dysplasia (HGD, columnar cell metaplasia (CM, squamous epithelium (SE, EAC and squamous cell carcinoma. The TGR5 protein was highly expressed in 71% of EAC (75/106, 100% of HGD (11/11, 72% of LGD (13/18, 66% of BE (23/35, 84% of CM (52/62, and 36% of SE (30/83. The patients with high expression of TGR5 exhibited significantly worse overall survival compared to the patients with nonhigh expression. TGR5 high expression was significantly increased in the males compared to the females in all cases with an odds ratio of 1.9 times. The vitamin D receptor (VDR was significantly correlated with TGR5 expression. Our findings indicated that TGR5 may play an important role in the development and prognosis of EAC

  2. 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.

  3. Bile Sensing: The Activation of Vibrio parahaemolyticus Virulence

    Directory of Open Access Journals (Sweden)

    Bey-Hing Goh

    2017-04-01

    Full Text Available Bacteria must develop resistance to various inhospitable conditions in order to survive in the human gastrointestinal tract. Bile, which is secreted by the liver, and plays an important role in food digestion also has antimicrobial properties and is able to disrupt cellular homeostasis. Paradoxically, although bile is one of the guts defenses, many studies have reported that bacteria such as Vibrio parahaemolyticus can sense bile and use its presence as an environmental cue to upregulate virulence genes during infection. This article aims to discuss how bile is detected by V. parahaemolyticus and its role in regulating type III secretion system 2 leading to human infection. This bile–bacteria interaction pathway gives us a clearer understanding of the biochemical and structural analysis of the bacterial receptors involved in mediating a response to bile salts which appear to be a significant environmental cue during initiation of an infection.

  4. 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.

  5. 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...

  6. Inert Reassessment Document for Gluconic Acid and Sodium Salt

    Science.gov (United States)

    Gluconic acid and D-gluconic acid are classified as List 3 inert ingredients, sodium gluconate is classified as a List 4B inert ingredient, and D-gluconic acid, sodium salt has not been categorized as to inert ingredient list classification status.

  7. 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.

  8. 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.

  9. 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

  10. 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...

  11. 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...

  12. 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

  13. 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.

  14. 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

  15. 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.

  16. UJI SIFAT PROBIOTIK BAKTERI ASAM LAKTAT SEBAGAI KANDIDAT BAHAN PANGAN FUNGSIONAL [Probiotic Characteristics of laactic acid Bacteria as Candidate for Functional Food

    Directory of Open Access Journals (Sweden)

    Ida Susanti

    2007-12-01

    Full Text Available Lactic acid bacteria have been reported to be useful as a healt adjunct and are commonly added to food as delivery mechanism. As a probiotic, lactic acid bacteria should have the ability to survive in the digestion process such as resistance towards acidic pH, varieties of bile salt concentrations and enteric pathogan. In this study, lactic acid bacteria were isolated from various sources. Twenty isolated of lactic acid bacteria selected for their resistancy toeards acidic pH (pH 2.5, 0.3% bile salt and their antagonistic activity against enteric pathogan (Esherichia coli, Staphylococcus aureus and Bacillus cereus. The result showed that most of all strauns had good resistance to acidic pH and there were no significant difference among theme (p>0.05. More over, all strains showed tolerance to 0,3% bile salt concentration (varietis among isolates were significant p>0.05. All strains showed inhibition activity against enteric pathogan bacteria, this was estimated from the size of the diameter of the inhibition zones. (The inhibition were significantly different among them (p>0,05. The best five stains that fulfilled these properties L casei FNCC262, L. acidophilus FNCC116, KL-3 isolate, Da-1 isolate, and Db-2 isolate. These strains could be used as probiotics in further and applications.

  17. Effects of Spray Drying on Physicochemical Properties of Chitosan Acid Salts

    OpenAIRE

    Cervera, Mirna Fernández; Heinämäki, Jyrki; de la Paz, Nilia; López, Orestes; Maunu, Sirkka Liisa; Virtanen, Tommi; Hatanpää, Timo; Antikainen, Osmo; Nogueira, Antonio; Fundora, Jorge; Yliruusi, Jouko

    2011-01-01

    The effects of spray-drying process and acidic solvent system on physicochemical properties of chitosan salts were investigated. Chitosan used in spray dryings was obtained by deacetylation of chitin from lobster (Panulirus argus) origin. The chitosan acid salts were prepared in a laboratory-scale spray drier, and organic acetic acid, lactic acid, and citric acid were used as solvents in the process. The physicochemical properties of chitosan salts were investigated by means of solid-state CP...

  18. Hygroscopic behavior of atmospheric aerosols containing nitrate salts and water-soluble organic acids

    Science.gov (United States)

    Jing, Bo; Wang, Zhen; Tan, Fang; Guo, Yucong; Tong, Shengrui; Wang, Weigang; Zhang, Yunhong; Ge, Maofa

    2018-04-01

    While nitrate salts have critical impacts on environmental effects of atmospheric aerosols, the effects of coexisting species on hygroscopicity of nitrate salts remain uncertain. The hygroscopic behaviors of nitrate salt aerosols (NH4NO3, NaNO3, Ca(NO3)2) and their internal mixtures with water-soluble organic acids were determined using a hygroscopicity tandem differential mobility analyzer (HTDMA). The nitrate salt / organic acid mixed aerosols exhibit varying phase behavior and hygroscopic growth depending upon the type of components in the particles. Whereas pure nitrate salt particles show continuous water uptake with increasing relative humidity (RH), the deliquescence transition is still observed for ammonium nitrate particles internally mixed with organic acids such as oxalic acid and succinic acid with a high deliquescence point. The hygroscopicity of submicron aerosols containing sodium nitrate and an organic acid is also characterized by continuous growth, indicating that sodium nitrate tends to exist in a liquid-like state under dry conditions. It is observed that in contrast to the pure components, the water uptake is hindered at low and moderate RH for calcium nitrate particles containing malonic acid or phthalic acid, suggesting the potential effects of mass transfer limitation in highly viscous mixed systems. Our findings improve fundamental understanding of the phase behavior and water uptake of nitrate-salt-containing aerosols in the atmospheric environment.

  19. 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

  20. 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....