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Sample records for bile acid excretion

  1. Urinary excretion of bile acid glucosides and glucuronides in extrahepatic cholestasis.

    Science.gov (United States)

    Wietholtz, H; Marschall, H U; Reuschenbach, R; Matern, H; Matern, S

    1991-04-01

    Recently the formation of bile acid glucosides has been described as a novel conjugation mechanism in vitro and in vivo. In 10 patients with extrahepatic cholestasis caused by carcinoma of the head of the pancreas we investigated excretion rates and profiles of urinary bile acid glucosides. Urinary bile acid glucosides and, for comparison, bile acid glucuronides were extracted and characterized according to established methods. In controls total urinary bile acid glucoside excretion was 0.22 +/- 0.03 mumol/24 hr (mean +/- S.E.M.)-in the range of bile acid glucuronide excretion (0.41 +/- 0.06 mumol/24 hr; mean +/- S.E.M.). A gas chromatography-mass spectrometry-characterized trihydroxy bile acid glucoside of still-unknown hydroxyl positions accounted for 65% of total urinary bile acid glucosides. In extrahepatic cholestasis total urinary bile acid glucoside excretion was 0.52 +/- 0.13 mumol/24 hr (mean +/- SEM), yet significantly lower than bile acid glucuronide excretion (1.53 +/- 0.13 mumol/24 hr; mean +/- SEM; p less than 0.001). In cholestasis the primary bile acid derivatives cholic and chenodeoxycholic acid glucosides amounted to 90%, whereas the trihydroxy bile acid glucoside had decreased to 5% of total bile acid glucoside excretion, indicating its alteration during enterohepatic circulation. The data establish the composition and quantity of urinary bile acid glucosides in healthy controls and cholestasis and constitute a quantitative comparison with another glycosidic conjugation reaction, bile acid glucuronidation.

  2. Cheese intake lowers plasma cholesterol concentrations without increasing bile acid excretion

    OpenAIRE

    Hjerpsted, Julie Bousgaard; Dragsted, Lars Ove; Tholstrup, Tine

    2016-01-01

    Purpose Cheese is a dairy product with high calcium content. It has been suggested that calcium intake may increase fecal excretion of bile acids that would cause a regeneration of bile acids from hepatic cholesterol and thereby result in a lowering of plasma cholesterol concentrations. We aimed to test this hypothesis by assessing bile acid and calcium concentrations in fecal samples from humans after intake of cheese and butter. Methods The study was a randomized, 2 × 6 weeks crossover, die...

  3. Cheese intake lowers plasma cholesterol concentrations without increasing bile acid excretion

    DEFF Research Database (Denmark)

    Hjerpsted, Julie Bousgaard; Dragsted, Lars Ove; Tholstrup, Tine

    2016-01-01

    Purpose Cheese is a dairy product with high calcium content. It has been suggested that calcium intake may increase fecal excretion of bile acids that would cause a regeneration of bile acids from hepatic cholesterol and thereby result in a lowering of plasma cholesterol concentrations. We aimed...... with 13% energy from cheese or butter. Results After 6 weeks of intervention cheese resulted in higher amounts of calcium excreted in feces compared to butter. However, no difference was observed in fecal bile acid output despite lower serum total, LDL and HDL cholesterol concentrations observed...

  4. Red Yeast Rice Increases Excretion of Bile Acids in Hamsters

    Institute of Scientific and Technical Information of China (English)

    KA-YING MA; ZE-SHENG ZHANG; SHU-XIN ZHAO; QI CHANG; YIN-MEI WONG; SAI YING VENUS YEUNG; YU HUANG; ZHEN-YU CHEN

    2009-01-01

    Objectives To investigate the hypocholesterolemic activity of red yeast rice (RYR) and its underlying mechanism. Methods Three groups of hamsters were fed either the control diet or one of the two experimental diets containing by weight 0.1% RYR (0.1RYR) or 0.3% RYR (0.3RYR). Blood (0.5 mL) was collected from the retro-orbital sinus into a heparinized capillary tube at the end of week 0,3, and 6.Plasma lipoproteins were measured using enzymatic kits, while fecal neutral and acidic sterols were quantified using a gas-liquid chromatography. Results Plasma total cholesterol was reduced by 12% in 0.1RYR group and by 18% in 0.3RYR group compared with the control value. Similarly, plasma triacylglycerol was decreased by ll% in 0.1RYR group and by 24% in 0.3RYR group. Western blotting analysis demonstrated that RYR had no effect on sterol regulatory element binding protein 2, liver X receptor, 3-hydroxy-3-methylglutary-CoA reductase, LDL receptor, and cholesterol-7α-hydroxylase. HPLC analysis confirmed that RYR contained 0.88% monacolin K.It was recently found that RYR supplementation increased excretion of fecal acidic sterols by 3-4 folds compared with the control value. Conclusion Hypocholesterolemic activity of RYR is mediated at least partially by enhancement of acidic sterol excretion.

  5. Effects of dietary fiber from wheat, corn, and soy hull bran on excretion of fecal bile acids in humans.

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    Bell, E W; Emken, E A; Klevay, L M; Sandstead, H H

    1981-06-01

    Effects of dietary fiber on bile acid excretion and fecal bile acid concentration have been studied for seven subjects fed 26 g of either soft white wheat bran, corn bran, soybean hulls, or hard red spring wheat bran. Results indicate that even in a controlled study using a metabolic word, individual subject variation has a major impact on fecal bile acid excretion. This observation has not been fully appreciated in previous human studies. No significant change in the composition of fecal bile acids could be associated with the decrease in serum lipid levels previously reported. A method for the isolation and quantitation of fecal bile acids is described which does not require purification by thin-layer chromatography. A preliminary study of lyophilized fecal samples stored at -10 to -30 degrees C showed very little or no change in bile acid content. Samples stored at room temperatures for 11 months showed a substantial reduction in bile acid content.

  6. Fecal excretion pattern of bile acids in rats fed high fat diets and neomycin in induced colon tumorigenesis.

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    Panda, S K; Broitman, S A

    1999-09-06

    Neomycin augments colon tumorigenesis in 1,2 - dimethylhydrazine treated rats fed polyunsaturated fat diet and decreases fecal cholic acid excretion, while it inhibits tumorigenesis with increased cholic acid and decreased deoxycholic acid excretions in rats fed high cholesterol diet. Participation of other fecal bile acids seems to be insignificant in relation to colon carcinogenesis.

  7. Effect of rye bran on excretion of bile acids, cholesterol, nitrogen, and fat in human subjects with ileostomies.

    Science.gov (United States)

    Zhang, J X; Lundin, E; Hallmans, G; Adlercreutz, H; Andersson, H; Bosaeus, I; Aman, P; Stenling, R; Dahlgren, S

    1994-02-01

    The excretion of bile acids, cholesterol, dry matter, nitrogen, fat, and energy in ileostomy effluent, and plasma lipid concentrations were studied in eight subjects with ileostomies. The subjects consumed a wheat bread-based, low-fiber diet (LFD) for 3 wk and a rye bran bread-based, high-fiber diet (HFD) for 3 wk. The ileal excretion of dry matter, nitrogen, fat, and energy was higher during the HFD period. The daily excretion and the percentage of conjugated bile acids were significantly higher and the percentage of free bile acids lower in the ileostomy effluents during the HFD as compared with the LFD period. No significant difference in the excretion of cholesterol, net cholesterol, sterol, or net sterol was noted between the HFD and LFD periods. No significant differences in plasma concentrations of HDL-, LDL-, and total cholesterol, and apolipoprotein A-I and B were observed between the two 3-wk dietary periods.

  8. Activation of Constitutive Androstane Receptor (CAR) in Mice Results in Maintained Biliary Excretion of Bile Acids Despite a Marked Decrease of Bile Acids in Liver.

    Science.gov (United States)

    Lickteig, Andrew J; Csanaky, Iván L; Pratt-Hyatt, Matthew; Klaassen, Curtis D

    2016-06-01

    Activation of Constitutive Androstane Receptor (CAR) protects against bile acid (BA)-induced liver injury. This study was performed to determine the effect of CAR activation on bile flow, BA profile, as well as expression of BA synthesis and transport genes. Synthetic CAR ligand 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) was administered to mice for 4 days. BAs were quantified by UPLC-MS/MS (ultraperformance liquid chromatography-tandem mass spectrometry). CAR activation decreases total BAs in livers of male (49%) and female mice (26%), largely attributable to decreases of the 12α-hydroxylated BA taurocholic acid (T-CA) (males (M) 65%, females (F) 45%). Bile flow in both sexes was increased by CAR activation, and the increases were BA-independent. CAR activation did not alter biliary excretion of total BAs, but overall BA composition changed. Excretion of muricholic (6-hydroxylated) BAs was increased in males (101%), and the 12α-OH proportion of biliary BAs was decreased in both males (37%) and females (28%). The decrease of T-CA in livers of males and females correlates with the decreased mRNA of the sterol 12α-hydroxylase Cyp8b1 in males (71%) and females (54%). As a response to restore BAs to physiologic concentrations in liver, mRNA of Cyp7a1 is upregulated following TCPOBOP (males 185%, females 132%). In ilea, mRNA of the negative feedback regulator Fgf15 was unaltered by CAR activation, indicating biliary BA excretion was sufficient to maintain concentrations of total BAs in the small intestine. In summary, the effects of CAR activation on BAs in male and female mice are quite similar, with a marked decrease in the major BA T-CA in the liver.

  9. Fecal bile acid excretion and messenger RNA expression levels of ileal transporters in high risk gallstone patients

    Directory of Open Access Journals (Sweden)

    Miquel Juan

    2009-12-01

    Full Text Available Abstract Background Cholesterol gallstone disease (GS is highly prevalent among Hispanics and American Indians. In GS, the pool of bile acids (BA is decreased, suggesting that BA absorption is impaired. In Caucasian GS patients, mRNA levels for ileal BA transporters are decreased. We aimed to determine fecal BA excretion rates, mRNA levels for ileal BA transporter genes and of regulatory genes of BA synthesis in Hispanic GS patients. Results Excretion of fecal BA was measured in seven GS females and in ten GS-free individuals, all with a body mass index 2O3 (300 mg/day for 10 days, and fecal specimens were collected on the last 3 days. Chromium was measured by a colorimetric method, and BA was quantitated by gas chromatography/mass spectroscopy. Intake of calories, nutrients, fiber and cholesterol were similar in the GS and GS-free subjects. Mean BA excretion levels were 520 ± 80 mg/day for the GS-free group, and 461 ± 105 mg/day for the GS group. Messenger RNA expression levels were determined by RT-PCR on biopsy samples obtained from ileum during diagnostic colonoscopy (14 GS-free controls and 16 GS patients and from liver during surgery performed at 8 and 10 AM (12 GS and 10 GS-free patients operated on for gastrointestinal malignancies, all with a body mass index Conclusion Hispanics with GS have fecal BA excretion rates and mRNA levels of genes for ileal BA transporters that are similar to GS-free subjects. However, mRNA expression levels of Cyp7A1 are increased in GS, indicating that regulation of BA synthesis is abnormal in Hispanics with GS.

  10. Colonic mucosal gene expression and genotype in irritable bowel syndrome patients with normal or elevated fecal bile acid excretion.

    Science.gov (United States)

    Camilleri, Michael; Carlson, Paula; Acosta, Andres; Busciglio, Irene

    2015-07-01

    The mucosal gene expression in rectosigmoid mucosa (RSM) in irritable bowel syndrome with diarrhea (IBS-D) is unknown. Our objectives were, first, to study mRNA expression [by RT(2) PCR of 19 genes pertaining to tight junctions, immune activation, intestinal ion transport and bile acid (BA) homeostasis] in RSM in IBS-D patients (n = 47) and healthy controls (n = 17) and study expression of a selected protein (PDZD3) in 10 IBS-D patients and 4 healthy controls; second, to assess RSM mRNA expression according to genotype and fecal BA excretion (high ≥ 2,337 μmol/48 h); and third, to determine whether genotype or mucosal mRNA expression is associated with colonic transit or BA parameters. Fold changes were corrected for false detection rate for 19 genes studied (P colonic transit. We concluded that mucosal ion transport mRNA (for several genes and PDZD3 protein) is upregulated and barrier protein mRNA downregulated in IBS-D compared with healthy controls, independent of genotype. There are no differences in gene expression in IBS-D with high compared with normal fecal BA excretion.

  11. A Grape Seed Procyanidin Extract Ameliorates Fructose-Induced Hypertriglyceridemia in Rats via Enhanced Fecal Bile Acid and Cholesterol Excretion and Inhibition of Hepatic Lipogenesis.

    Directory of Open Access Journals (Sweden)

    Laura E Downing

    Full Text Available The objective of this study was to determine whether a grape seed procyanidin extract (GSPE exerts a triglyceride-lowering effect in a hyperlipidemic state using the fructose-fed rat model and to elucidate the underlying molecular mechanisms. Rats were fed either a starch control diet or a diet containing 65% fructose for 8 weeks to induce hypertriglyceridemia. During the 9th week of the study, rats were maintained on their respective diet and administered vehicle or GSPE via oral gavage for 7 days. Fructose increased serum triglyceride levels by 171% after 9 weeks, compared to control, while GSPE administration attenuated this effect, resulting in a 41% decrease. GSPE inhibited hepatic lipogenesis via down-regulation of sterol regulatory element binding protein 1c and stearoyl-CoA desaturase 1 in the fructose-fed animals. GSPE increased fecal bile acid and total lipid excretion, decreased serum bile acid levels and increased the expression of genes involved in cholesterol synthesis. However, bile acid biosynthetic gene expression was not increased in the presence of GSPE and fructose. Serum cholesterol levels remained constant, while hepatic cholesterol levels decreased. GSPE did not modulate expression of genes responsible for esterification or biliary export of the newly synthesized cholesterol, but did increase fecal cholesterol excretion, suggesting that in the presence of GSPE and fructose, the liver may secrete more free cholesterol into the plasma which may then be shunted to the proximal small intestine for direct basolateral to apical secretion and subsequent fecal excretion. Our results demonstrate that GSPE effectively lowers serum triglyceride levels in fructose-fed rats after one week administration. This study provides novel insight into the mechanistic actions of GSPE in treating hypertriglyceridemia and demonstrates that it targets hepatic de novo lipogenesis, bile acid homeostasis and non-biliary cholesterol excretion as

  12. A Grape Seed Procyanidin Extract Ameliorates Fructose-Induced Hypertriglyceridemia in Rats via Enhanced Fecal Bile Acid and Cholesterol Excretion and Inhibition of Hepatic Lipogenesis.

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    Downing, Laura E; Heidker, Rebecca M; Caiozzi, Gianella C; Wong, Brian S; Rodriguez, Kelvin; Del Rey, Fernando; Ricketts, Marie-Louise

    2015-01-01

    The objective of this study was to determine whether a grape seed procyanidin extract (GSPE) exerts a triglyceride-lowering effect in a hyperlipidemic state using the fructose-fed rat model and to elucidate the underlying molecular mechanisms. Rats were fed either a starch control diet or a diet containing 65% fructose for 8 weeks to induce hypertriglyceridemia. During the 9th week of the study, rats were maintained on their respective diet and administered vehicle or GSPE via oral gavage for 7 days. Fructose increased serum triglyceride levels by 171% after 9 weeks, compared to control, while GSPE administration attenuated this effect, resulting in a 41% decrease. GSPE inhibited hepatic lipogenesis via down-regulation of sterol regulatory element binding protein 1c and stearoyl-CoA desaturase 1 in the fructose-fed animals. GSPE increased fecal bile acid and total lipid excretion, decreased serum bile acid levels and increased the expression of genes involved in cholesterol synthesis. However, bile acid biosynthetic gene expression was not increased in the presence of GSPE and fructose. Serum cholesterol levels remained constant, while hepatic cholesterol levels decreased. GSPE did not modulate expression of genes responsible for esterification or biliary export of the newly synthesized cholesterol, but did increase fecal cholesterol excretion, suggesting that in the presence of GSPE and fructose, the liver may secrete more free cholesterol into the plasma which may then be shunted to the proximal small intestine for direct basolateral to apical secretion and subsequent fecal excretion. Our results demonstrate that GSPE effectively lowers serum triglyceride levels in fructose-fed rats after one week administration. This study provides novel insight into the mechanistic actions of GSPE in treating hypertriglyceridemia and demonstrates that it targets hepatic de novo lipogenesis, bile acid homeostasis and non-biliary cholesterol excretion as important mechanisms for

  13. Perilla Oil Supplementation Ameliorates High-Fat/High-Cholesterol Diet Induced Nonalcoholic Fatty Liver Disease in Rats via Enhanced Fecal Cholesterol and Bile Acid Excretion

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    Tian, Yu; He, Lei; Shao, Yang; Li, Na

    2016-01-01

    Recent experimental studies and clinical trials have shown that hepatic cholesterol metabolic disorders are closely related to the development of nonalcoholic fatty liver disease (NAFLD). The main goal of this study was to investigate the efficacy of the perilla oil rich in alpha-linolenic acid (ALA) against NASH and gain a deep insight into its potential mechanisms. Rats were fed a high-fat/high-cholesterol diet (HFD) supplement with perilla oil (POH) for 16 weeks. Routine blood biochemical tests and histological staining illustrated that the perilla oil administration improved HFD-induced hyperlipidemia, reduced hepatic steatosis, and inhibited hepatic inflammatory infiltration and fibrosis. Perilla oil also increased fecal bile acid and cholesterol excretion. Hepatic RNA-Seq analysis found that the long time perilla oil supplement notably modified the gene expression involved in cholesterol metabolism. Our results implicate that, after long-term high level dietary cholesterol feeding, rat liver endogenous synthesis of cholesterol and cholesterol-rich low density lipoprotein uptake was significantly inhibited, and perilla oil did not modulate expression of genes responsible for cholesterol synthesis but did increase cholesterol removed from hepatocytes by conversion to bile acids and increased fecal cholesterol excretion. PMID:27642591

  14. Perilla Oil Supplementation Ameliorates High-Fat/High-Cholesterol Diet Induced Nonalcoholic Fatty Liver Disease in Rats via Enhanced Fecal Cholesterol and Bile Acid Excretion.

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    Chen, Ting; Yuan, Fahu; Wang, Hualin; Tian, Yu; He, Lei; Shao, Yang; Li, Na; Liu, Zhiguo

    2016-01-01

    Recent experimental studies and clinical trials have shown that hepatic cholesterol metabolic disorders are closely related to the development of nonalcoholic fatty liver disease (NAFLD). The main goal of this study was to investigate the efficacy of the perilla oil rich in alpha-linolenic acid (ALA) against NASH and gain a deep insight into its potential mechanisms. Rats were fed a high-fat/high-cholesterol diet (HFD) supplement with perilla oil (POH) for 16 weeks. Routine blood biochemical tests and histological staining illustrated that the perilla oil administration improved HFD-induced hyperlipidemia, reduced hepatic steatosis, and inhibited hepatic inflammatory infiltration and fibrosis. Perilla oil also increased fecal bile acid and cholesterol excretion. Hepatic RNA-Seq analysis found that the long time perilla oil supplement notably modified the gene expression involved in cholesterol metabolism. Our results implicate that, after long-term high level dietary cholesterol feeding, rat liver endogenous synthesis of cholesterol and cholesterol-rich low density lipoprotein uptake was significantly inhibited, and perilla oil did not modulate expression of genes responsible for cholesterol synthesis but did increase cholesterol removed from hepatocytes by conversion to bile acids and increased fecal cholesterol excretion.

  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. Soya protein stimulates bile acid excretion by the liver and intestine through direct and indirect pathways influenced by the presence of dietary cholesterol.

    Science.gov (United States)

    Arellano-Martínez, Gloria Leticia; Granados, Omar; Palacios-González, Berenice; Torres, Nimbe; Medina-Vera, Isabel; Tovar, Armando R

    2014-06-28

    Several studies using different animal models have demonstrated that the consumption of soya protein (SP) reduces serum cholesterol concentrations by increasing the excretion of bile acids (BA). However, the mechanism by which SP enhances BA excretion is not fully understood. Therefore, the aim of the present study was to determine whether the consumption of SP regulates the expression of key enzymes involved in hepatic BA synthesis and the transporters involved in reverse cholesterol transport (RCT) via fibroblast growth factor 15 (FGF15) and/or small heterodimer protein (SHP) in rats. To achieve this aim, four groups of rats were fed experimental diets containing 20 % casein (C) or SP with or without the addition of 0·2 % cholesterol and the expression of hepatic genes involved in BA synthesis and the ileal and hepatic RCT was measured. Rats fed the SP diet had higher concentrations of ileal FGF15 and hepatic FGF15 receptor (FGFR4) and increased expression of SHP and liver receptor homolog 1 (LRH1) than those fed the C diet; as a result, the excretion of faecal BA was greater. The addition of cholesterol to the diet repressed the protein abundance of FGF15 and FGFR4; however, SP increased the expression of SHP and LRH1 to a lesser extent. Nonetheless, the expression of ABCG5/8 was increased in the intestine of rats fed the SP diet, and the effect was enhanced by the addition of cholesterol to the diet. In conclusion, SP in the presence of cholesterol increases BA synthesis via the repressions of FGF15 and SHP and accelerates BA excretion to prevent cholesterol overload in the enterocytes by increasing RCT.

  17. The gut microbiome, probiotics, bile acids axis, and human health.

    Science.gov (United States)

    Jones, Mitchell Lawrence; Tomaro-Duchesneau, Catherine; Prakash, Satya

    2014-06-01

    The human gut microbiome produces potent ligands to bile acid receptors, and probiotics could act as therapeutics of bile acid dysmetabolism. A recent study in Cell Reports demonstrates that probiotic VSL#3 affects bile acid deconjugation and excretion, as well as the gut-liver FXR-FGF15 axis.

  18. Bile acid biosynthesis and its regulation

    Directory of Open Access Journals (Sweden)

    Areta Hebanowska

    2010-10-01

    Full Text Available Bile acid biosynthesis is the main pathway of cholesterol catabolism. Bile acids are more soluble than cholesterol so are easier to excrete. As amphipathic molecules they participate in lipid digestion and absorption in the intestine and they help to excrete free cholesterol with bile. They are also ligands for nuclear receptors regulating the expression of genes involved in cholesterol metabolism. Interconversion of cholesterol into bile acids is an important point of its homeostasis. Seventeen enzymes are engaged in this process and many of them are cytochromes P450. Bile acid synthesis initiation may proceed with the “classical” pathway (starting with cholesterol hydroxylation at the C7α position or the “alternative” pathway (starting with cholesterol hydroxylation at the C27 position. Two additional pathways are possible, though their quantitative significance is small (initiated with cholesterol hydroxylations of C24 and C25 positions. Oxysterols produced are not only intermediates of bile acid biosynthesis but also important regulators of metabolism. Bile acid biosynthesis takes place in the liver, but some enzymes are also present in other organs, where they participate in regulation of cholesterol metabolism. Those enzymes are potential targets for new drugs against cholesterol metabolism disturbances. This article is a brief description of the bile acid biosynthesis pathway and participating enzymes.

  19. CONVERSION OF LIPOSOMAL 5-FLUORO-2'-DEOXYURIDINE AND ITS DIPALMITOYL DERIVATIVE TO BILE-ACID CONJUGATES OF ALPHA-FLUORO-BETA-ALANINE AND THEIR EXCRETION INTO RAT BILE

    NARCIS (Netherlands)

    WAALKES, MV; KUIPERS, F; HAVINGA, R; SCHERPHOF, GL

    1993-01-01

    We studied the hepatic processing and biliary excretion of metabolites of the radiolabeled cytostatic agent 5-fluoro,-2'-deoxy[6-H-3]uridine (FUdR) and its lipophilic derivative FUdR-dipalmitate incorporated in liposomes. After intracardial injection in rats, free FUdR was cleared from the circulati

  20. Bile acid metabolism in ileostomy patients.

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    Huibregtse, K; Hoek, F; Sanders, G T; Tytgat, G N

    1977-04-01

    In ten ileostomy patients, a 14C-cholylglycine breath test was performed. The 14CO2 in the exhaled air and the 14C bile acid quantity and composition and fat content in the subsequent 24 h ileostomy effluent were determined and compared to the values in twenty healthy controls. The results show that in ileostomy patients only minor bile acid-deconjugation occurs in vivo. Deconjugation in the ileostomy bags was found to be mainly responsible for the absence of conjugated bile acids in many of the ileostomy effluent samples. Secondary bile acids were not present in these patients, as determined by TLC. The fecal fat and bile acid excretion was found to be in the normal range in ileostomy patients provided no concomitant ileum resection was present.

  1. Hypocholesterolemic activity of grape seed proanthocyanidin is mediated by enhancement of bile acid excretion and up-regulation of CYP7A1.

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    Jiao, Rui; Zhang, Zesheng; Yu, Hongjian; Huang, Yu; Chen, Zhen-Yu

    2010-11-01

    Interest in grape seed proanthocyanidin (GSP) as a cholesterol-lowering nutraceutical is growing. This study was to investigate the effect of GSP on blood cholesterol level and gene expression of cholesterol-regulating enzymes in Golden Syrian hamsters maintained on a 0.1% cholesterol diet. Results affirmed supplementation of 0.5% or 1.0% GSP could decrease plasma total cholesterol and triacylglycerol level. Western blot and real-time polymerase chain reaction analyses demonstrated GSP did not affect sterol regulatory element binding protein-2 and low-density lipoprotein receptor; however, it increased mRNA 3-hydroxy-3-methylglutaryl coenzyme A reductase. GSP had no effect on the protein mass of liver X receptor alpha (LXRα) but it decreased mRNA LXRα. Most importantly, GSP increased not only the protein level of cholesterol-7α-hydroxylase (CYP7A1) but also mRNA CYP7A1. It was concluded that the hypocholesterolemic activity of GSP was most likely mediated by enhancement of bile acid excretion and up-regulation of CYP7A1.

  2. 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....

  3. Supplementary dietary calcium stimulates faecal fat and bile acid excretion, but does not protect against obesity and insulin resistance in C57BL/6J mice

    NARCIS (Netherlands)

    Wit, de N.J.W.; Bosch-Vermeulen, H.; Oosterink, E.; Müller, M.R.; Meer, van der R.

    2011-01-01

    There is increased interest in the potential protective role of dietary Ca in the development of metabolic disorders related to the metabolic syndrome. Ca-induced intestinal precipitation of fatty acids and bile acids as well as systemic metabolic effects of Ca on adipose tissue is proposed to play

  4. Bile acid interactions with cholangiocytes

    Institute of Scientific and Technical Information of China (English)

    Xuefeng Xia; Heather Francis; Shannon Glaser; Gianfranco Alpini; Gene LeSage

    2006-01-01

    Cholangiocytes are exposed to high concentrations of bile acids at their apical membrane. A selective transporter for bile acids, the Apical Sodium Bile Acid Cotransporter (ASBT) (also referred to as Ibat; gene name Slc10a2)is localized on the cholangiocyte apical membrane. On the basolateral membrane, four transport systems have been identified (t-ASBT, multidrug resistance (MDR)3,an unidentified anion exchanger system and organic solute transporter (Ost) heteromeric transporter, OstαOstβ. Together, these transporters unidirectionally move bile acids from ductal bile to the circulation. Bile acids absorbed by cholangiocytes recycle via the peribiliaryplexus back to hepatocytes for re-secretion into bile.This recycling of bile acids between hepatocytes and cholangiocytes is referred to as the cholehepatic shunt pathway. Recent studies suggest that the cholehepatic shunt pathway may contribute in overall hepatobiliary transport of bile acids and to the adaptation to chronic cholestasis due to extrahepatic obstruction. ASBT is acutely regulated by an adenosine 3', 5'-monophosphate (cAMP)-dependent translocation to the apical membrane and by phosphorylation-dependent ubiquitination and proteasome degradation. ASBT is chronically regulated by changes in gene expression in response to biliary bile acid concentration and inflammatory cytokines.Another potential function of cholangiocyte ASBT is to allow cholangiocytes to sample biliary bile acids in order to activate intracellular signaling pathways. Bile acids trigger changes in intracellular calcium, protein kinase C (PKC), phosphoinositide 3-kinase (PI3K), mitogenactivated protein (MAP) kinase and extracellular signalregulated protein kinase (ERK) intracellular signals.Bile acids significantly alter cholangiocyte secretion,proliferation and survival. Different bile acids have differential effects on cholangiocyte intracellular signals,and in some instances trigger opposing effects on cholangiocyte secretion

  5. Profiling of urinary bile acids in piglets by a combination of enzymatic deconjugation and targeted LC-MRM-MS

    Science.gov (United States)

    Bile acids (BAs) have an important role in the control of fat, glucose and cholesterol metabolism. Synthesis of bile acids is the major pathway for the metabolism of cholesterol and for the excretion of excess cholesterol in mammals. Bile acid intermediates and/or their metabolites are excreted in...

  6. 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....

  7. [Bile acids in the bile in diabetes mellitus].

    Science.gov (United States)

    Slivka, O Ia; Zelinskiĭ, B A; Zelinskiĭ, S Ts

    1979-01-01

    Hepatic and gall bladder bile of healthy persons (8) and of patients with severe form of diabetes mellitus (17) was studied. Paer chromatography was applied for determination of cholic, chenodeoxycholic, deoxycholic bile acids and their conjugates with glycin and taurine. An absolute content and percentage of glycodeoxycholic and glycochenodeoxycholic bile acids were increased, and glycochenodeoxycholic acid content and taurates proportion were decreased in the gall bladder and hepatic bile of diabetic patients. The data obtained pointed to disturbed hepatic function in severe diabetes mellitus; it was expressed in suppression of bile acids synthesis and conjugation, and also in depression of transformation of deoxycholic into cholic acid.

  8. 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 ...

  9. Endocrine and paracrine role of bile acids

    Institute of Scientific and Technical Information of China (English)

    Verena Keitel; Ralf Kubitz; Dieter H(a)ussinger

    2008-01-01

    Bile acids are not only important for the absorption of dietary lipids and fat soluble vitamins but are signalling molecules with diverse endocrine and paracrine functions.Bile acids regulate bile acid,lipid and glucose metabolism and modulate temperature and energy homeostasis.Furthermore,bile acids can not only promote cell proliferation and liver regeneration but can also induce programmed cell death.Bile acid functions are mediated through different pathways which comprise the activation of nuclear hormone receptors,of intracellular kinases and of the plasma membranebound,G-protein coupled bile acid receptor TGR5/Gpbar-1.

  10. 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....

  11. Different pathways of canalicular secretion of sulfated and non-sulfated fluorescent bile acids : a study in isolated hepatocyte couplets and TR- rats

    NARCIS (Netherlands)

    Mills, CO; Milkiewicz, P; Muller, M; Roma, MG; Havinga, R; Coleman, R; Kuipers, F; Jansen, PLM; Elias, E

    1999-01-01

    Background/Aims: Fluorescent bile acids have proved useful for characterizing bile salt transport mechanisms, The aim of this study was to further validate the use of lysyl-fluorescein conjugated bile acid analogues as surrogate bile acids, Methods: We analyzed biliary excretion kinetics of cholyl l

  12. 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.

  13. The role of sphinter of Boyden in bile excretion and its regulating factors

    Institute of Scientific and Technical Information of China (English)

    Jing Guo Wei; Yao Cheng Wang; Qing Jiang Meng

    2000-01-01

    AIM To investigate the role of sphincter of Boyden in bile excretion and its regulating factors.METHODS Perfusion manometry, choledocho-cineradiography, reaction of the sphincter of Boyden toendogenous cholecystokinin (CCK) and immunohistochemical quantitative analysis were performed in 16dogs to study the motility and morphology of the sphincter of Boyden in experimental (postcholecystectomy)group ( n = 8) and the control group (n = 8).RESULTS The bile duct surrounded by SB was a low-pressure lumen (10.0 ± 2.0 mmHg), in which thepressure was significantly different (P<0.01, t = 6. 195) from the basal pressure of the high-pressure area ofsphincter of Oddi (SO), its basal pressure (SOBP) was 16.9±0.5 mmHg. The SB was an enlarged ampulladuring bile excretion interval, and showed active contraction during bile excretion. Intrinsic CCK could causediastole of SO, but does not affect the systole and diastole of SB. After cholecystectomy, spastic contractionpersisted in SB, which could not be relieved by intrinsic CCK. The sensitivity to CCK of SO was decreased,and the evacuation time of media prolonged (27.0±3.4 min vs precholecystectomy 17.l±0.9min P<0.01,t =7.961). In immunohistochemistry analysis, the contents of a-actin, myosin in the SB of experimentalgroup showed no increase. Under electronic microscope, the main changes were 3D structuraldisarrangement of the cell framework, distortion of the microfilaments, swelling and aggregation ofmitochondria at the nuclear side.CONCLUSION The excretion of bile can be divided into two types, physiological bile excretion with a drivemainly caused by the contraction of SB, and the other, functional bile excretion with a drive mainly causedby the contraction of gallbladder. It seems that the function of SB was controlled by vagus, whereas SO wasmore sensitive to the intrinsic CCK, The intact gallbladder is an elemental factor of functional coordinationof SB and SO.

  14. 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

  15. Metabolism of Cholesterol and Bile Acids by the Gut Microbiota

    Directory of Open Access Journals (Sweden)

    Philippe Gérard

    2013-12-01

    Full Text Available The human gastro-intestinal tract hosts a complex and diverse microbial community, whose collective genetic coding capacity vastly exceeds that of the human genome. As a consequence, the gut microbiota produces metabolites from a large range of molecules that host’s enzymes are not able to convert. Among these molecules, two main classes of steroids, cholesterol and bile acids, denote two different examples of bacterial metabolism in the gut. Therefore, cholesterol is mainly converted into coprostanol, a non absorbable sterol which is excreted in the feces. Moreover, this conversion occurs in a part of the human population only. Conversely, the primary bile acids (cholic and chenodeoxycholic acids are converted to over twenty different secondary bile acid metabolites by the gut microbiota. The main bile salt conversions, which appear in the gut of the whole human population, include deconjugation, oxidation and epimerization of hydroxyl groups at C3, C7 and C12, 7-dehydroxylation, esterification and desulfatation. If the metabolisms of cholesterol and bile acids by the gut microbiota are known for decades, their consequences on human health and disease are poorly understood and only start to be considered.

  16. Restoration of cell polarity and bile excretion function of hepatocytes in sandwich-culture

    Institute of Scientific and Technical Information of China (English)

    ZHANG Xian-jie; WANG Ying; SUN Jia-bang; SONG Mao-min; QIAO Xin

    2007-01-01

    Objective:To investigate the nature of the restoration of cell polarity and bile excretion function in Sandwich-cultured hepatocytes.Methods:Freshly isolated hepatocytes from male Sprague-Dawley rats were cultured in a double layer collagen gel Sandwich configuration.Morphological changes were observed under a inverted microscope.The domain specific membrane associated protein DPP Ⅳ was tested by immunofluorescenee,and the bile excretion function was determined by using fluorescein diacetate.Hepatocytes cultured on a single layer of collagen gel were taken as control.Results:Adult rat hepatocytes cultured in a double layer collagen gel sandwich configuration regained its morphological and functional polarity and maintained polygonal morphology for at least 4 weeks.Immunofluorescence studies USing antibodies against DPP Ⅳ showed polarity restoration as early as 48 h.After cultured in the double layer collagen gel Sandwich configuration for 96 h the hepatocytes began to excrete bile;while hepatocytes cultured on a single layer collagen gel had no bile excretion.Conclusion:Hepatocytes cultured in a double layer collagen gel Sandwich configuration are able to regain their morphological and functional polarity givan certain conditions.Hepaotcyte culture is a useful tool for the study of polarity restoration.

  17. Mercury excretion and intravenous ascorbic acid.

    Science.gov (United States)

    Dirks, M J; Davis, D R; Cheraskin, E; Jackson, J A

    1994-01-01

    We tested the hypothesis that intravenous ascorbic acid increases urinary excretion of mercury in subjects with low mercury levels from dental amalgam, food, and other sources. From 89 adult volunteers we selected 28 subjects with the highest mercury excretions (2 to 14 micrograms/24 h). We administered intravenous infusions of 500 ml lactated Ringer's solution with and without addition of 750 mg of ascorbic acid/kg body weight, up to 60 g ascorbic acid. Average mercury excretion during the 24 h after infusion of ascorbic acid was 4.0 +/- 0.5 micrograms (mean +/- SEM), which was not significantly more than after infusion of Ringer's solution alone (3.7 +/- 0.5 micrograms). Lead excretion was similarly unaffected. If ascorbic acid administered intravenously benefits some persons with suspected adverse reactions to mercury, the benefit in subjects similar to ours appears unrelated to short-term enhanced excretion of mercury or lead.

  18. Effects of corn oil and wheat brans on bile acid metabolism in rats.

    Science.gov (United States)

    Gallaher, D D; Franz, P M

    1990-11-01

    High concentrations of colonic bile acids may promote tumor formation. Some studies have found that high levels of dietary fat increase fecal bile acid excretion, whereas others report no effect. Wheat bran appears to reduce fecal bile acid concentration. This study was conducted to determine the effect of different dietary fat levels and types of wheat bran on bile acid metabolism. Rats were fed diets containing either no fiber, 2% cholestyramine (CHO) or brans of hard red spring, soft white winter or durum wheat--at both a 5 or 20% fat level. Animals were fed for 7 wk, and feces were collected in the last week. Wheat bran (all types) significantly increased fecal mass approximately fourfold, and CHO significantly increased fecal mass twofold compared to the fiber-free diet. Increasing the fat level did not increase fecal bile acid excretion, nor did the addition of wheat bran. Addition of CHO, however, more than doubled it. CHO increased fecal bile acid concentration, all wheat brans decreased it and fat level had no effect. Bile acid pool size was increased slightly by fat level and cholestyramine feeding but not by wheat brans. These results indicate that fat level slightly alters bile acid metabolism but that wheat brans do not.

  19. Bile acids in health and disease

    DEFF Research Database (Denmark)

    Krag, E; Thaysen, E H

    1996-01-01

    improved. Important physiological research on the mechanisms of hepatic bile flow was conducted. An intestinal perfusion model served as a tool providing information on absorption kinetics and on transmucosal water and electrolyte movements. The gallstone disease, liver diseases, inflammatory bowel disease...... 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......, fat malabsorption, and other intestinal disorders were studied. The 'idiopathic ileopathy' as a cause for bile acid malabsorption causing diarrhoea was established as a new disorder. Thus, in the time period concerned, substantial Danish contributions emerged on major and minor topics of the bile acid...

  20. Transport and biological activities of bile acids.

    Science.gov (United States)

    Zwicker, Brittnee L; Agellon, Luis B

    2013-07-01

    Bile acids have emerged as important biological molecules that support the solubilization of various lipids and lipid-soluble compounds in the gut, and the regulation of gene expression and cellular function. Bile acids are synthesized from cholesterol in the liver and eventually released into the small intestine. The majority of bile acids are recovered in the distal end of the small intestine and then returned to the liver for reuse. The components of the mechanism responsible for the recycling of bile acids within the enterohepatic circulation have been identified whereas the mechanism for intracellular transport is less understood. Recently, the ileal lipid binding protein (ILBP; human gene symbol FABP6) was shown to be needed for the efficient transport of bile acids from the apical side to the basolateral side of enterocytes in the distal intestine. This review presents an overview of the transport of bile acids between the liver and the gut as well as within hepatocytes and enterocytes. A variety of pathologies is associated with the malfunction of the bile acid transport system.

  1. Circadian dysregulation disrupts bile acid homeostasis.

    Directory of Open Access Journals (Sweden)

    Ke Ma

    Full Text Available BACKGROUND: Bile acids are potentially toxic compounds and their levels of hepatic production, uptake and export are tightly regulated by many inputs, including circadian rhythm. We tested the impact of disrupting the peripheral circadian clock on integral steps of bile acid homeostasis. METHODOLOGY/PRINCIPAL FINDINGS: Both restricted feeding, which phase shifts peripheral clocks, and genetic ablation in Per1(-/-/Per2(-/- (PERDKO mice disrupted normal bile acid control and resulted in hepatic cholestasis. Restricted feeding caused a dramatic, transient elevation in hepatic bile acid levels that was associated with activation of the xenobiotic receptors CAR and PXR and elevated serum aspartate aminotransferase (AST, indicative of liver damage. In the PERDKO mice, serum bile acid levels were elevated and the circadian expression of key bile acid synthesis and transport genes, including Cyp7A1 and NTCP, was lost. This was associated with blunted expression of a primary clock output, the transcription factor DBP, which transactivates the promoters of both genes. CONCLUSIONS/SIGNIFICANCE: We conclude that disruption of the circadian clock results in dysregulation of bile acid homeostasis that mimics cholestatic disease.

  2. Gut microbiota inhibit Asbt-dependent intestinal bile acid reabsorption via Gata4

    Science.gov (United States)

    Out, Carolien; Patankar, Jay V.; Doktorova, Marcela; Boesjes, Marije; Bos, Trijnie; de Boer, Sanna; Havinga, Rick; Wolters, Henk; Boverhof, Renze; van Dijk, Theo H.; Smoczek, Anna; Bleich, André; Sachdev, Vinay; Kratky, Dagmar; Kuipers, Folkert; Verkade, Henkjan J.; Groen, Albert K.

    2017-01-01

    Background & Aims Regulation of bile acid homeostasis in mammals is a complex process regulated via extensive cross-talk between liver, intestine and intestinal microbiota. Here we studied the effects of gut microbiota on bile acid homeostasis in mice. Methods Bile acid homeostasis was assessed in four mouse models. Germfree mice, conventionally-raised mice, Asbt-KO mice and intestinal-specific Gata4-iKO mice were treated with antibiotics (bacitracin, neomycin and vancomycin; 100 mg/kg) for five days and subsequently compared with untreated mice. Results Attenuation of the bacterial flora by antibiotics strongly reduced fecal excretion and synthesis of bile acids, but increased the expression of the bile acid synthesis enzyme CYP7A1. Similar effects were seen in germfree mice. Intestinal bile acid absorption was increased and accompanied by increases in plasma bile acid levels, biliary bile acid secretion and enterohepatic cycling of bile acids. In the absence of microbiota, the expression of the intestinal bile salt transporter Asbt was strongly increased in the ileum and was also expressed in more proximal parts of the small intestine. Most of the effects of antibiotic treatment on bile acid homeostasis could be prevented by genetic inactivation of either Asbt or the transcription factor Gata4. Conclusions Attenuation of gut microbiota alters Gata4-controlled expression of Asbt, increasing absorption and decreasing synthesis of bile acids. Our data support the concept that under physiological conditions microbiota stimulate Gata4, which suppresses Asbt expression, limiting the expression of this transporter to the terminal ileum. Our studies expand current knowledge on the bacterial control of bile acid homeostasis. PMID:26022694

  3. Bile acid signaling and biliary functions

    Directory of Open Access Journals (Sweden)

    Hannah Jones

    2015-03-01

    Full Text Available This review focuses on various components of bile acid signaling in relation to cholangiocytes. Their roles as targets for potential therapies for cholangiopathies are also explored. While many factors are involved in these complex signaling pathways, this review emphasizes the roles of transmembrane G protein coupled receptor (TGR5, farnesoid X receptor (FXR, ursodeoxycholic acid (UDCA and the bicarbonate umbrella. Following a general background on cholangiocytes and bile acids, we will expand the review and include sections that are most recently known (within 5–7 years regarding the field of bile acid signaling and cholangiocyte function. These findings all demonstrate that bile acids influence biliary functions which can, in turn, regulate the cholangiocyte response during pathological events.

  4. Bile acid formation in primary human hepatocytes

    Institute of Scientific and Technical Information of China (English)

    Curt Einarsson; Ewa Ellis; Anna Abrahamsson; Bo-G6ran Ericzon; Ingemar Bj rkhem; Magnus Axelson

    2000-01-01

    AIM To evaluate a culture system for bile acid formation in primary human hepatocytes in comparison with HepG2 cells. METHODS Hepatocytes were isolated from normal human liver tissue and were cultured in serum-free William's E medium. The medium was collected and renewed every 24 h. Bile acids and their precursors in media were finally analysed by gas chromatography-mass spectrometry. RESULTS Cholic acid ( CA ) andchenodeoxycholic acid (CDCA) conjugated with glycine or taurine accounted for 70% and 25% of total steroids. A third of CDCA was also conjugated with sulphuric acid. Dexamathasone and thyroid hormorm alone or in combination did not significantly effect bile acid formation. The addition of cyclosporin A (10 μmol/L) inhibited the synthesis of CA and CDCA by about 13% and 30%, respectively. CONCLUSION Isolated human hepatocytes in primary culture behave as in the intact liver by converting cholesterol to conjugated CA and CDCA. This is in contrast to cultured HepG2 cells, which release large amounts of bile acid precursors and unconjugated bile acids into the medium.

  5. Bile acid formation in primary human hepatocytes

    Institute of Scientific and Technical Information of China (English)

    Curt Einarsson; Ewa Ellis; Anna Abrahamsson; Bo-G ran Ericzon; Ingemar Bj rkhem; Magnus Axelson

    2000-01-01

    AIM To evaluate a system for bile acid formation in human hepatocytes in comparison with HepG2 cells.METHODS Hepatocytes were isolated from normal human liver tissue and were cultured in serum-freeWilliam's E medium. The medium was collected and renewed every 24 h. Bile acids and their precursors inmedia were finally analysed by gas chromatography-mass spectrometry.RESULTS Cholic acid (CA) and chenodeoxycholic acid (CDCA) conjugated with glycine or taurineaccounted for 70% and 25% of total steroids. One third of CDCA was also conjugated with sulphuric acid.Dexamethasone and thyroid hormone alone or in combination did not significantly affect bile acid formation.The addition of cyclosporin A (10 tm) inhibited the synthesis of CA and CDCA by about 13% and 30%,respectively.CONCLUSION Isolated human hepatocytes in primary culture behave as in the intact liver by convertingalmost quantitatively cholesterol to conjugated CA and CDCA. This is in contrast to cultured HepG2 cells,which release large amounts of bile acid precursors and unconjugated bile acids into the medium.

  6. Differential expression of cholangiocyte and ileal bile acid transporters following bile acid supplementation and depletion

    Institute of Scientific and Technical Information of China (English)

    N. Sertac Kip; Konstantinos N. Lazaridis; Anatoliy I. Masyuk; Patrick L. Splinter; Robert C. Huebert; Nicholas F. LaRusso

    2004-01-01

    AIM: We have previously demonstrated that cholangiocytes,the epithelial cells lining intrahepatic bile ducts, encode two functional bile acid transporters via alternative splicing of a single gene to facilitate bile acid vectorial transport.Cholangiocytes possess ASBT, an apical sodium-dependent bile acid transporter to take up bile acids, and t-ASBT, a basolateral alternatively spliced and truncated form of ASBT to efflux bile acids. Though hepatocyte and ileal bile acid transporters are in part regulated by the flux of bile acids,the effect of alterations in bile acid flux on the expression of t-ASBT in terminal ileocytes remains unclear. Thus, we tested the hypothesis that expression of ASBT and t-ASBT in cholangiocytes and ileocytes was regulated by bile acid flux. METHODS: Expression of ASBT and t-ASBT message and protein in cholangiocytes and ileocytes isolated from pairfed rats given control (C) and 1% taurocholate (TCA) or 5% cholestyramine (CY) enriched diets, were assessed by both quantitative RNase protection assays and quantitative immunoblotting. The data obtained from each of the control groups were pooled to reflect the changes observed following TCA and CY treatments with respect to the control diets.Cholangiocyte taurocholate uptake was determined using a novel microperfusion technique on intrahepatic bile duct units (IBDUs) derived from C, TCA and CY fed rats.RESULTS: In cholangiocytes, both ASBT and t-ASBT message RNA and protein were significantly decreased in response to TCA feeding compared to C diet. In contrast,message and protein of both bile acid transporters significantly increased following CY feeding compared to C diet. In the ileum, TCA feeding significantly up-regulated both ASBT and t-ASBT message and protein compared to C diet, while CY feeding significantly down-regulated message and protein of both bile acid transporters compared to C diet. As anticipated from alterations in cholangiocyte ASBT expression, the uptake of

  7. Role of Bile Acids and Bile Acid Receptors in Metabolic Regulation

    NARCIS (Netherlands)

    Lefebvre, Philippe; Cariou, Bertrand; Lien, Fleur; Kuipers, Folkert; Staels, Bart

    2009-01-01

    Lefebvre P, Cariou B, Lien F, Kuipers F, Staels B. Role of Bile Acids and Bile Acid Receptors in Metabolic Regulation. Physiol Rev 89: 147-191,2009; doi: 10.1152/physrev.00010.2008. - The incidence of the metabolic syndrome has taken epidemic proportions in the past decades, contributing to an incre

  8. Hepatic bile acids and bile acid-related gene expression in pregnant and lactating rats

    Directory of Open Access Journals (Sweden)

    Qiong N. Zhu

    2013-08-01

    Full Text Available Background. Significant physiological changes occur during pregnancy and lactation. Intrahepatic cholestasis of pregnancy (ICP is a liver disease closely related to disruption of bile acid homeostasis. The objective of this study was to examine the regulation of bile acid synthesis and transport in normal pregnant and lactating rats.Materials and Methods. Livers from timed pregnant SD rats were collected on gestational days (GD 10, 14 and 19, and postnatal days (PND 1, 7, 14 and 21. Total bile acids were determined by the enzymatic method, total RNA was isolated and subjected to real time RT-PCR analysis. Liver protein was extracted for western-blot analysis.Results. Under physiological conditions hepatic bile acids were not elevated during pregnancy but increased during lactation in rats. Bile acid synthesis rate-limiting enzyme Cyp7a1 was unchanged on gestational days, but increased on PND14 and 21 at mRNA and protein levels. Expression of Cyp8b1, Cyp27a1 and Cyp7b1 was also higher during lactation. The mRNA levels of small heterodimer partner (SHP and protein levels of farnesoid X receptor (FXR were increased during pregnancy and lactation. Bile acid transporters Ntcp, Bsep, Mrp3 and Mrp4 were lower at gestation, but increased during lactation. Hepatic Oatp transporters were decreased during pregnancy and lactation.Conclusion. Hepatic bile acid homeostasis is maintained during normal pregnancy in rats, probably through the FXR-SHP regulation. The expression of bile acid synthesis genes and liver bile acid accumulation were increased during lactation, together with increased expression of bile acid efflux transporter Bsep, Mrp3 and Mrp4.

  9. 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.

  10. Bile Acid-Induced Suicidal Erythrocyte Death

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    Elisabeth Lang

    2016-04-01

    Full Text Available Background/Aims: In nucleated cells, bile acids may activate cation channels subsequently leading to entry of Ca2+. In erythrocytes, increase of cytosolic Ca2+ activity triggers eryptosis, the suicidal death of erythrocytes characterized by phosphatidylserine exposure at the cell surface and cell shrinkage. Eryptosis is triggered by bile duct ligation, an effect partially attributed to conjugated bilirubin. The present study explored, whether bile acids may stimulate eryptosis. Methods: Phosphatidylserine exposing erythrocytes have been identified utilizing annexin V binding, cell volume estimated from forward scatter, cytosolic Ca2+ activity determined using Fluo-3 fluorescence, and ceramide abundance at the erythrocyte surface utilizing specific antibodies. Results: The exposure of human erythrocytes to glycochenodesoxycholic (GCDC and taurochenodesoxycholic (TCDC acid was followed by a significant decrease of forward scatter and significant increase of Fluo-3 fluorescence, ceramide abundance as well as annexin V binding. The effect on annexin V binding was significantly blunted, but not abolished by removal of extracellular Ca2+. Conclusion: Bile acids stimulate suicidal cell death, an effect paralleled by and in part due to Ca2+ entry and ceramide. The bile acid induced eryptosis may in turn lead to accelerated clearance of circulating erythrocytes and, thus, may contribute to anemia in cholestatic patients.

  11. Effect of bile acids on digestion

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    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

  12. Urine alkalization facilitates uric acid excretion

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    Seyama Issei

    2010-10-01

    Full Text Available Abstract Background Increase in the incidence of hyperuricemia associated with gout as well as hypertension, renal diseases and cardiovascular diseases has been a public health concern. We examined the possibility of facilitated excretion of uric acid by change in urine pH by managing food materials. Methods Within the framework of the Japanese government's health promotion program, we made recipes which consist of protein-rich and less vegetable-fruit food materials for H+-load (acid diet and others composed of less protein but vegetable-fruit rich food materials (alkali diet. Healthy female students were enrolled in this consecutive 5-day study for each test. From whole-day collected urine, total volume, pH, organic acid, creatinine, uric acid and all cations (Na+,K+,Ca2+,Mg2+,NH4+ and anions (Cl-,SO42-,PO4- necessary for the estimation of acid-base balance were measured. Results Urine pH reached a steady state 3 days after switching from ordinary daily diets to specified regimens. The amount of acid generated ([SO42-] +organic acid-gut alkai were linearly related with those of the excretion of acid (titratable acidity+ [NH4+] - [HCO3-], indicating that H+ in urine is generated by the metabolic degradation of food materials. Uric acid and excreted urine pH retained a linear relationship, where uric acid excretion increased from 302 mg/day at pH 5.9 to 413 mg/day at pH 6.5, despite the fact that the alkali diet contained a smaller purine load than the acid diet. Conclusion We conclude that alkalization of urine by eating nutritionally well-designed food is effective for removing uric acid from the body.

  13. Bile acids reduce endocytosis of high-density lipoprotein (HDL) in HepG2 cells.

    Science.gov (United States)

    Röhrl, Clemens; Eigner, Karin; Fruhwürth, Stefanie; Stangl, Herbert

    2014-01-01

    High-density lipoprotein (HDL) transports lipids to hepatic cells and the majority of HDL-associated cholesterol is destined for biliary excretion. Cholesterol is excreted into the bile directly or after conversion to bile acids, which are also present in the plasma as they are effectively reabsorbed through the enterohepatic cycle. Here, we provide evidence that bile acids affect HDL endocytosis. Using fluorescent and radiolabeled HDL, we show that HDL endocytosis was reduced in the presence of high concentrations of taurocholate, a natural non-cell-permeable bile acid, in human hepatic HepG2 and HuH7 cells. In contrast, selective cholesteryl-ester (CE) uptake was increased. Taurocholate exerted these effects extracellularly and independently of HDL modification, cell membrane perturbation or blocking of endocytic trafficking. Instead, this reduction of endocytosis and increase in selective uptake was dependent on SR-BI. In addition, cell-permeable bile acids reduced HDL endocytosis by farnesoid X receptor (FXR) activation: chenodeoxycholate and the non-steroidal FXR agonist GW4064 reduced HDL endocytosis, whereas selective CE uptake was unaltered. Reduced HDL endocytosis by FXR activation was independent of SR-BI and was likely mediated by impaired expression of the scavenger receptor cluster of differentiation 36 (CD36). Taken together we have shown that bile acids reduce HDL endocytosis by transcriptional and non-transcriptional mechanisms. Further, we suggest that HDL endocytosis and selective lipid uptake are not necessarily tightly linked to each other.

  14. 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...

  15. Depletion of hepatic uridine diphosphoglucuronic acid decreases the biliary excretion of drugs.

    Science.gov (United States)

    Gregus, Z; Watkins, J B; Thompson, T N; Klaassen, C D

    1983-05-01

    Hepatic levels of uridine diphosphoglucuronic acid (UDPGA) in rats decreased substantially (greater than 80%) 40 min after galactosamine (GAL) (600 mg/kg i.p.) or after 1 hr of diethyl ether (DE) narcosis. Biliary excretion of several cholephils requiring glucuronidation before excretion was reduced by GAL 76, 62, 92, 90 and 97% for bilirubin, diethylstilbestrol, iopanoic acid, phenolphthalein and valproic acid, respectively. GAL treatment caused delayed plasma clearances of the parent compounds and reductions in plasma concentrations and biliary excretions of glucuronide conjugates. The degree of this reduction was related to the maximal excretion rate of the individual compounds. For phenolphthalein glucuronide and phenol-3,6-dibromphthalein disulfonate, which do not undergo conjugation, GAL had no effect on their biliary excretion. DE-induced UDPGA depletion had no effect on phenolphthalein glucuronide excretion but reduced that of phenol-3,6-dibromphthalein disulfonate 25%. DE did not affect the plasma elimination or biliary secretion of phenolphthalein. Of the other cholephils requiring conjugation, DE reduced the excretion of bilirubin, diethylstilbestrol, iopanoic acid and valproic acid by 41, 29, 76 and 28%, respectively. DE decreased the plasma elimination of the parent compounds and the appearance of the conjugates in both plasma and bile. Reduction of glucuronide excretion into bile was less pronounced at higher doses of the cholephilic anions. Neither treatment reduced in vitro hepatic UDP-glucuronosyltransferase activity toward these substrates or substantially altered extrahepatic UDPGA concentrations. Thus, both GAL and DE decreased UDPGA to similar concentrations, but the biliary excretion of compounds requiring glucuronidation before secretion was depressed to a greater extent by GAL.

  16. [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.

  17. Herbert Falk: a vital force in the renaissance of bile acid research and bile acid therapy.

    Science.gov (United States)

    Hofmann, Alan F

    2011-01-01

    Herbert Falk died on August 8, 2008, after a long illness. It was his vision that initiated the Bile Acid Meetings and brought to market chenodeoxycholic acid and ursodeoxycholic acid for the dissolution of cholesterol gallstones as well as the successful treatment of cholestatic liver disease. The 1st Bile Acid Meeting was a small workshop held at the University Hospital of Freiburg in 1970. Great interest in the topic was evident at that small meeting and led to a larger meeting in 1972, whose scope included both the basic and clinical aspects of bile acids. These meetings have continued at biennial intervals, the 2010 meeting being the 21st. The program has always included discussions of the most fundamental aspects of bile acid biosynthesis and metabolism as well as clinical applications of bile acid therapy. The meetings featured brief presentations, ample time for discussion, and imaginative social programs. They have always been flawlessly organized. Social programs usually included a hike through the beautiful countryside of the Black Forest followed by dinner in a rustic restaurant. Herbert Falk took part in these programs, personally welcoming every participant. In the warm glow of the 'Badische' hospitality, friendships developed, and scientific collaborations were often arranged. From a scientific standpoint, there has been enormous progress in understanding the chemistry and biology of bile acids. Herbert Falk established the Windaus Prize in 1978, and the prize has been given to individuals whose contributions moved the field forward. These bile acid meetings have been marvelous, rewarding experiences. We must all be grateful to Herbert Falk's vision in establishing the Falk Foundation that has so generously sponsored these meetings. We also express our gratitude to his widow, Ursula Falk, who continues this worthy tradition.

  18. Beyond intestinal soap-bile acids in metabolic control

    NARCIS (Netherlands)

    Kuipers, Folkert; Bloks, Vincent W.; Groen, Albert K.

    2014-01-01

    Over the past decade, it has become apparent that bile acids are involved in a host of activities beyond their classic functions in bile formation and fat absorption. The identification of the farnesoid X receptor (FXR) as a nuclear receptor directly activated by bile acids and the discovery that bi

  19. Bile acids: Chemistry, physiology, and pathophysiology

    Institute of Scientific and Technical Information of China (English)

    Maria J Monte; Jose JG Marin; Alvaro Antelo; Jose Vazquez-Tato

    2009-01-01

    The family of bile acids includes a group of molecular species of acidic steroids with very peculiar physicalchemical and biological characteristics. They are synthesized by the liver from cholesterol through several complementary pathways that are controlled by mechanisms involving fine-tuning by the levels of certain bile acid species. Although their bestknown role is their participation in the digestion and absorption of fat, they also play an important role in several other physiological processes. Thus, genetic abnormalities accounting for alterations in their synthesis, biotransformation and/or transport may result in severe alterations, even leading to lethal situations for which the sole therapeutic option may be liver transplantation. Moreover, the increased levels of bile acids reached during cholestatic liver diseases are known to induce oxidative stress and apoptosis, resulting in damage to the liver parenchyma and, ventually, extrahepatic tissues. When this occurs during pregnancy, the outcome of gestation may be challenged. In contrast, the physical-chemical and biological properties of these compounds have been used as the bases for the development of drugs and as pharmaceutical tools for the delivery of active agents.

  20. Bile acid signaling in metabolic disease and drug therapy.

    Science.gov (United States)

    Li, Tiangang; Chiang, John Y L

    2014-10-01

    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.

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

    Science.gov (United States)

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

    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

  2. Fecal steroid excretion is increased in rats by oral administration of gymnemic acids contained in Gymnema sylvestre leaves.

    Science.gov (United States)

    Nakamura, Y; Tsumura, Y; Tonogai, Y; Shibata, T

    1999-06-01

    Gymnemic acids are the saponins with a triterpenoid structure contained in Gymnema sylvestre leaves and have the hypoglycemic effects. In spite of the cholesterol-binding properties of saponins, the effect of gymnemic acids on cholesterol metabolism has not been elucidated to date. We investigated the effects of gymnemic acids on fecal steroid excretion in rats. Three kinds of extracts from Gymnema sylvestre leaves, extract (GSE), acid precipitate (GSA) and column fractionate (GSF), of which the gymnemagenin (an aglycone of gymnemic acids) concentrations are 58.87, 161.6, and 363.3 mg/g respectively, were used for the experiments. These were administered to rats orally at the dose of 0.05-1.0 g/kg for 22 d. Rats were given free access to water and nonpurified diet without cholesterol, and the differences in fecal excretion of steroids and gymnemic acids were investigated. Although there were no significant effects of GSE, GSA and GSF decreased body weight gain and food intakes in a dose-dependent manner (P < 0.01). GSF (1.0 g/kg) significantly increased fecal excretion of neutral steroids and bile acids in a dose-dependent manner (P < 0.05), especially those of cholesterol and cholic acid (CA)-derived bile acids. The increases in fecal steroid excretion of cholesterol, total neutral steroids, total bile acids and CA-related bile acids were acute and significantly correlated with fecal gymnemagenin levels (r2 = 0.2316-0.9861, P < 0. 05). These results demonstrated for the first time that a high dose of gymnemic acids increases fecal cholesterol and CA-derived bile acid excretion. Further studies are needed to clarify the effect of gymnemic acids on cholesterol metabolism.

  3. The Adsorption Effect of Quaternized Chitosan Derivatives on Bile Acid

    Institute of Scientific and Technical Information of China (English)

    Shu Xian MENG; Ya Qing FENG; Wen Jin LI; Cai Xia YIN; Jin Ping DENG

    2006-01-01

    Three quaternized chitosan derivatives were synthesized and their adsorption performance of bile acid from aqueous solution was studied. The adsorption capacities and rates of bile acid onto quaternized chitosan derivatives were evaluated. The kinetic experimental data properly correlated with the second-order kinetic model, which indicated that the chemical sorption is the rate-limiting step. The results showed that the quaternized chitosan derivatives are favorable adsorbents for bile acid.

  4. 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....

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1988-09-01

    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.

  6. Effect of inducers and inhibitors of glucuronidation on the biliary excretion and choleretic action of valproic acid in the rat.

    Science.gov (United States)

    Watkins, J B; Klaassen, C D

    1982-02-01

    Valproic acid (VPA) induces an immediate choleresis in the rat which may be attributable to the osmotic properties of VPA-glucuronic acid conjugates in bile. The influence of inducers and inhibitors of glucuronidation of VPA on the biliary excretion and choleretic effect of VPA was studied. Hepatic UDP-glucuronyltransferase activity toward VPA was determined in vitro. Pretreatment with phenobarbital (75 mg/kg/day for 4 days) enhanced VPA glucuronidation; borneol (750 mg/kg) decreased VPA conjugation; 3-methylcholanthrene (20 mg/kg/day for 4 days) and galactosamine (600 mg/kg) had no effect on glucuronidation of VPA in vitro. Hepatic UDP-glucuronic acid content was decreased by borneol and galactosamine administration and was enhanced by phenobarbital and 3-methylcholanthrene pretreatment. The enzyme inducers increased the plasma disappearance of VPA in vivo but did not augment its biliary excretion or choleretic effect. Borneol and galactosamine, which inhibited the conjugation and plasma disappearance of VPA, decreased its biliary excretion and inhibited the VPA-induced increase in bile flow. Thus, the bile flow rate after VPA administration is closely related to the excretion of VPA-glucuronic acid. These data support the conclusion that the choleretic effect of VPA is due to the osmotic activity of VPA conjugates in bile.

  7. 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 recept

  8. Differential diagnosis in patients with suspected bile acid synthesis defects

    Institute of Scientific and Technical Information of China (English)

    Dorothea Haas; Hongying Gan-Schreier; Claus-Dieter Langhans; Tilman Rohrer; Guido Engelmann; Maura Heverin; David W Russell

    2012-01-01

    AIM:To investigate the clinical presentations associated with bile acid synthesis defects and to describe identification of individual disorders and diagnostic pitfalls.METHODS:Authors describe semiquantitative determination of 16 urinary bile acid metabolites by electrospray ionization-tandem mass spectrometry.Sample preparation was performed by solid-phase extraction.The total analysis time was 2 min per sample.Authors determined bile acid metabolites in 363 patients with suspected defects in bile acid metabolism.RESULTS:Abnormal bile acid metabolites were found in 36 patients.Two patients had bile acid synthesis defects but presented with atypical presentations.In 2 other patients who were later shown to be affected by biliary atresia and cystic fibrosis the profile of bile acid metabolites was initially suggestive of a bile acid synthesis defect.Three adult patients suffered from cerebrotendinous xanthomatosis.Nineteen patients had peroxisomal disorders,and 10 patients had cholestatic hepatopathy of other cause.CONCLUSION:Screening for urinary cholanoids should be done in every infant with cholestatic hepatopathy as well as in children with progressive neurological disease to provide specific therapy.

  9. Bile acids, farnesoid X receptor, atherosclerosis and metabolic control

    NARCIS (Netherlands)

    Kuipers, Folkert; Stroeve, Johanna H. M.; Caron, Sandrine; Staels, Bart

    2007-01-01

    Purpose of review Bile acids are amphiphilic molecules synthesized from cholesterol exclusively in the liver that are essential for effective absorption of dietary fat. In addition to this classical role', bile acids act as signalling molecules that control their own metabolism by activating the nuc

  10. Impaired Bile Acid Homeostasis in Children with Severe Acute Malnutrition.

    Directory of Open Access Journals (Sweden)

    Ling Zhang

    Full Text Available Severe acute malnutrition (SAM is a major cause of mortality in children under 5 years and is associated with hepatic steatosis. Bile acids are synthesized in the liver and participate in dietary fat digestion, regulation of energy expenditure, and immune responses. The aim of this work was to investigate whether SAM is associated with clinically relevant changes in bile acid homeostasis.An initial discovery cohort with 5 healthy controls and 22 SAM-patients was used to identify altered bile acid homeostasis. A follow up cohort of 40 SAM-patients were then studied on admission and 3 days after clinical stabilization to assess recovery in bile acid metabolism. Recruited children were 6-60 months old and admitted for SAM in Malawi. Clinical characteristics, feces and blood were collected on admission and prior to discharge. Bile acids, 7α-hydroxy-4-cholesten-3-one (C4 and FGF-19 were quantified.On admission, total serum bile acids were higher in children with SAM than in healthy controls and glycine-conjugates accounted for most of this accumulation with median and interquartile range (IQR of 24.6 μmol/L [8.6-47.7] compared to 1.9 μmol/L [1.7-3.3] (p = 0.01 in controls. Total serum bile acid concentrations did not decrease prior to discharge. On admission, fecal conjugated bile acids were lower and secondary bile acids higher at admission compared to pre- discharge, suggesting increased bacterial conversion. FGF19 (Fibroblast growth factor 19, a marker of intestinal bile acid signaling, was higher on admission and was associated with decreased C4 concentrations as a marker of bile acid synthesis. Upon recovery, fecal calprotectin, a marker of intestinal inflammation, was lower.SAM is associated with increased serum bile acid levels despite reduced synthesis rates. In SAM, there tends to be increased deconjugation of bile acids and conversion from primary to secondary bile acids, which may contribute to the development of liver disease.

  11. Promotion of PDT efficacy by bile acids

    Science.gov (United States)

    Castelli, Michelle; Reiners, John, Jr.; Kessel, David

    2003-06-01

    We had previously described the use of relatively hydrophobic bile acids, notably UDCA (ursodeoxycholate) for the promotion of the apoptotic response to photodynamic therapy. Further study revealed that this effect occurred only when the target for photodamage was the anti-apoptotic protein Bcl-2. The efficacy of lysosomal photodamage, leading to a cleavage of the protein Bid, was not influenced by UDCA. Moreover, the apoptotic cell death resulting from treatment of cells with the non-peptidic Bcl-2 inhibitor HA 14-1 was also promoted by UDCA. These results are consistent with the proposal that the pro-apoptotic effects of UDCA are directed against Bcl-2, promoting inactivation by HA 14-1 or photodamage.

  12. Intestinal bile acid physiology and pathophysiology

    Institute of Scientific and Technical Information of China (English)

    Olga Mart(I)nez-Augustin; Ferm(I)n Sánchez de Medina

    2008-01-01

    Bile acids (Bas) have a long established role in fat digestion in the intestine by acting as tensioactives,due to their amphipatic characteristics.Bas are reabsorbed very efficiently by the intestinal epithelium and recycled back to the liver v/a transport mechanisms that have been largely elucidated.The transport and synthesis of Bas are tightly regulated in part by specific plasma membrane receptors and nuclear receptors.In addition to their primary effect,Bas have been claimed to play a role in gastrointestinal cancer,intestinal inflammation and intestinal ionic transport.Bas are not equivalent in any of these biological activities,and structural requirements have been generally identified.In particular,some Bas may be useful for cancer chemoprevention and perhaps in inflammatory bowel disease,although further research is necessary in this field.This review covers the most recent developments in these aspects of BA intestinal biology.

  13. Bile Acid Determination after Standardized Glucose Load in Pregnant Women

    Science.gov (United States)

    Adams, April; Jacobs, Katherine; Vogel, Rachel Isaksson; Lupo, Virginia

    2015-01-01

    Objective Intrahepatic cholestasis of pregnancy (ICP) is a rare liver disorder, usually manifesting in the third trimester and associated with increased perinatal morbidity and mortality. The hallmark laboratory abnormality in ICP is elevated fasting serum bile acids; however, there are limited data on whether a nonfasting state affects a pregnant woman's total bile acids. This study assesses fasting and nonfasting bile acid levels in 10 healthy pregnant women after a standardized glucose load to provide insight into the effects of a glucose load on bile acid profiles. Study Design Pilot prospective cohort analysis of serum bile acids in pregnant women. A total of 10 healthy pregnant women from 28 to 32 weeks' gestation were recruited for the study before undergoing a glucose tolerance test. Total serum bile acids were collected for each subject in the overnight fasting state, and 1 and 3 hours after the 100-g glucose load. Results There was a statistically significant difference between fasting versus 3-hour values. There was no statistically significant difference between fasting versus 1-hour and 1-hour versus 3-hour values. Conclusion There is a difference between fasting and nonfasting total serum bile acids after a 100-g glucose load in healthy pregnant women. PMID:26495178

  14. [Functional status of the bile excretion system and upper gastrointestinal tract in patients with duodenal ulcer].

    Science.gov (United States)

    Razarenova, T G; Koshel', A P; Klokov, S S; Dibina, T V

    2010-01-01

    The research of functional condition of biliary tract in 35 patients suffered from gastroduodenal ulcers compared with 30 almost healthy patients was conducted. Disorders of motor function were found out in 13.2% patients in control group. The motor-evacuative function of biliary tract conformed to average scores of healthy patients group in only 8.6% cases. The accelerated gallbladder empting (11.4%), the hypermotoric biliary dyskinesia with the absence of latent period of biliary excretion (17.1%), the hypomotoric dysfunction of biliary tract (34.3%) were found out in the rest cases. The separate group of patients were patients with distortion of biliary excretion that was consisted in periodic increase and decrease of gall bladder volume during the contraction. We concluded that motor-evacuative function of biliary tract doesn't depend on the type of pathological process in the stomach or duodenum but correlates with gastric evacuation contents, the rate of cholagogic meal advancement along the duodenum and acid-productive function of the stomach.

  15. Exploitation of Bile Acid Transport Systems in Prodrug Design

    Directory of Open Access Journals (Sweden)

    Elina Sievänen

    2007-08-01

    Full Text Available The enterohepatic circulation of bile acids is one of the most efficient recycling routes in the human body. It is a complex process involving numerous transport proteins, which serve to transport bile acids from the small intestine into portal circulation, from the portal circulation into the hepatocyte, from the hepatocyte into the bile, and from the gall bladder to the small intestine. The tremendous transport capacity and organ specificity of enterohepatic circulation combined with versatile derivatization possibilities, rigid steroidal backbone, enantiomeric purity, availability, and low cost have made bile acids attractive tools in designing pharmacological hybrid molecules and prodrugs with the view of improving intestinal absorption, increasing the metabolic stability of pharmaceuticals, specifically targeting drugs to organs involved in enterohepatic circulation, as well as sustaining therapeutically reasonable systemic concentrations of active agents. This article briefly describes bile acid transport proteins involved in enterohepatic circulation, summarizes the key factors affecting on the transport by these proteins, and reviews the use of bile acids and their derivatives in designing prodrugs capable of exploiting the bile acid transport system.

  16. Ursodeoxycholic acid treatment of vanishing bile duct syndromes

    Institute of Scientific and Technical Information of China (English)

    Thomas Pusl; Ulrich Beuers

    2006-01-01

    Vanishing bile duct syndromes (VBDS) are characterized by progressive loss of small intrahepatic ducts caused by a variety of different diseases leading to chronic cholestasis, cirrhosis, and premature death from liver failure. The majority of adult patients with VBDS suffer from primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Ursodeoxycholic acid (UDCA), a hydrophilic dihydroxy bile acid, is the only drug currently approved for the treatment of patients with PBC, and anticholestatic effects have been reported for several other cholestatic syndromes. Several potential mechanisms of action of UDCA have been proposed including stimulation of hepatobiliary secretion, inhibition of apoptosis and protection of cholangiocytes against toxic effects of hydrophobic bile acids.

  17. Ursodeoxycholic acid in the Ursidae: biliary bile acids of bears, pandas, and related carnivores.

    Science.gov (United States)

    Hagey, L R; Crombie, D L; Espinosa, E; Carey, M C; Igimi, H; Hofmann, A F

    1993-11-01

    The biliary bile acid composition of gallbladder bile obtained from six species of bears (Ursidae), the Giant panda, the Red panda, and 11 related carnivores were determined by reversed phase liquid chromatography and gas chromatography-mass spectrometry. Bile acids were conjugated solely with taurine (in N-acyl linkage) in all species. Ursodeoxycholic acid (3 alpha, 7 beta-dihydroxy-5 beta-cholan-24-oic acid) was present in all Ursidae, averaging 1-39% of biliary bile acids depending on the species; it was not detected or present as a trace constituent (bears, and its proportion averaged 34% (range 0-62%). Ursodeoxycholic acid averaged 17% of biliary bile acids in the Polar bear (n = 4) and 18% in the Brown bear (n = 6). Lower proportions (1-8%) were present in the Sun bear (n = 2), Ceylon Sloth bear (n = 1), and the Spectacled bear (n = 1). Bile of all species contained taurine-conjugated chenodeoxycholic acid and cholic acid. In some related carnivores, deoxycholic acid, the 7-dehydroxylation product of cholic acid, was also present. To determine whether the 7 beta hydroxy group of ursodeoxycholic acid was formed by hepatic or bacterial enzymes, bile acids were determined in hepatic bile obtained from bears with chronic biliary fistulae. Fistula bile samples contained ursodeoxycholic acid, chenodeoxycholic acid, and a trace amount of cholic acid, all as taurine conjugates, indicating that ursodeoxycholic acid is a primary bile acid formed in the liver in Ursidae.(ABSTRACT TRUNCATED AT 250 WORDS)

  18. Bile Acid Pool Dynamics in Progressive Familial lntrahepatic Cholestasis With Partial External Bile Diversion

    NARCIS (Netherlands)

    Jericho, Hilary S.; Kaurs, Elizabeth; Boverhof, Renze; Knisely, Alex; Shneider, Benjamin L.; Verkade, Henkjan J.; Whitington, Peter F.

    2015-01-01

    Objectives: Partial external bile diversion (PEBD) is an established therapy for low-gamma-glutamyl transferase (GGT) progressive familial intrahepatic cholestasis (PFIC). This study sought to determine whether the dynamics of the cholic acid (CA) and chenodeoxycholic acid (CDCA) pools in subjects w

  19. 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

    varying in taurine and glycine contents alter BA metabolism, and thereby modulate the recently discovered systemic effects of BAs. Here we show that rats fed a diet containing saithe fish protein hydrolysate (saithe FPH), rich in taurine and glycine, for 26 days had markedly elevated fasting plasma BA......Conjugation of bile acids (BAs) to the amino acids taurine or glycine increases their solubility and promotes liver BA secretion. Supplementing diets with taurine or glycine modulates BA metabolism and enhances fecal BA excretion in rats. However, it is still unclear whether dietary proteins...

  20. Antibacterial drug treatment increases intestinal bile acid absorption via elevated levels of ileal apical sodium-dependent bile acid transporter but not organic solute transporter α protein.

    Science.gov (United States)

    Miyata, Masaaki; Hayashi, Kenjiro; Yamakawa, Hiroki; Yamazoe, Yasushi; Yoshinari, Kouichi

    2015-01-01

    Antibacterial drug treatment increases the bile acid pool size and hepatic bile acid concentration through the elevation of hepatic bile acid synthesis. However, the involvement of intestinal bile acid absorption in the increased bile acid pool size remains unclear. To determine whether intestinal bile acid absorption contributes to the increased bile acid pool in mice treated with antibacterial drugs, we evaluated the levels of bile acid transporter proteins and the capacity of intestinal bile acid absorption. Ileal apical sodium-dependent bile acid transporter (ASBT) mRNA and protein levels were significantly increased in ampicillin (ABPC)-treated mice, whereas organic solute transporter α (OSTα) mRNA levels, but not protein levels, significantly decreased in mice. Similar alterations in the expression levels of bile acid transporters were observed in mice treated with bacitracin/neomycin/streptomycin. The capacity for intestinal bile acid absorption was evaluated by an in situ loop method. Increased ileal absorption of taurochenodeoxycholic acid was observed in mice treated with ABPC. These results suggest that intestinal bile acid absorption is elevated in an ASBT-dependent manner in mice treated with antibacterial drugs.

  1. Determination of conjugated bile acids in human bile and duodenal fluid by reverse-phase high-performance liquid chromatography.

    Science.gov (United States)

    Bloch, C A; Watkins, J B

    1978-05-01

    A simple mehtod using reverse-phase liquid chromatography is presented for resolution and quantitation of the major conjugated bile acids of man, including the glycine and taurine conjugates of the dihydroxy bile acids, chenodeoxycholic and deoxycholic acid. Using modern, high-performance chromatographic equipment, analysis time is less than 30 minutes. The quantitative range of the method, with detection by refractive index, is 0.05 to 0.1 mumol of bile acid and the limit of detection for an injection sample is 0.01 mumol. This provides a sensitivity sufficient for analysis of dilute duodenal and gallbladder bile with minimal sample preparation.

  2. Methods for diagnosis of bile acid malabsorption in clinical practice.

    Science.gov (United States)

    Vijayvargiya, Priya; Camilleri, Michael; Shin, Andrea; Saenger, Amy

    2013-10-01

    Altered concentrations of bile acid (BA) in the colon can cause diarrhea or constipation. More than 25% of patients with irritable bowel syndrome with diarrhea or chronic diarrhea in Western countries have BA malabsorption (BAM). As BAM is increasingly recognized, proper diagnostic methods are needed to help direct the most effective course of treatment for the chronic bowel dysfunction. We review the methodologies, advantages, and disadvantages of tools that directly measure BAM: the (14)C-glycocholate breath and stool test, the (75)selenium homotaurocholic acid test (SeHCAT), and measurements of 7 α-hydroxy-4-cholesten-3-one (C4) and fecal BAs. The (14)C-glycocholate test is laborious and no longer widely used. The (75)SeHCAT has been validated but is not available in the United States. Measurement of serum C4 is a simple and accurate method that can be used for most patients but requires further clinical validation. Assays to quantify fecal BA (total and individual levels) are technically cumbersome and not widely available. Regrettably, none of these tests are routinely available in the United States; assessment of the therapeutic effects of a BA binder is used as a surrogate for diagnosis of BAM. Recent data indicate the advantages to studying fecal excretion of individual BAs and their role in BAM; these could support the use of the fecal BA assay, compared with other tests. Measurement of fecal BA levels could become a routine addition to the measurement of fecal fat in patients with unexplained diarrhea. Availability ultimately determines whether the C4, SeHCAT, or fecal BA test is used; more widespread availability of such tests would enhance clinical management of these patients.

  3. Diagnostic Methods for Bile Acid Malabsorption in Clinical Practice

    Science.gov (United States)

    Vijayvargiya, Priya; Camilleri, Michael; Shin, Andrea; Saenger, Amy

    2013-01-01

    Altered bile acid (BA) concentrations in the colon may cause diarrhea or constipation. BA malabsorption (BAM) accounts for >25% of patients with irritable bowel syndrome (IBS) with diarrhea and chronic diarrhea in Western countries. As BAM is increasingly recognized, proper diagnostic methods are desired in clinical practice to help direct the most effective treatment course for the chronic bowel dysfunction. This review appraises the methodology, advantages and disadvantages of 4 tools that directly measure BAM: 14C-glycocholate breath and stool test, 75Selenium HomotauroCholic Acid Test (SeHCAT), 7 α-hydroxy-4-cholesten-3-one (C4) and fecal BAs. 14C-glycocholate is a laborious test no longer widely utilized. 75SeHCAT is validated, but not available in the United States. Serum C4 is a simple, accurate method that is applicable to a majority of patients, but requires further clinical validation. Fecal measurements to quantify total and individual fecal BAs are technically cumbersome and not widely available. Regrettably, none of these tests are routinely available in the U.S., and a therapeutic trial with a BA binder is used as a surrogate for diagnosis of BAM. Recent data suggest there is an advantage to studying fecal excretion of the individual BAs and their role in BAM; this may constitute a significant advantage of the fecal BA method over the other tests. Fecal BA test could become a routine addition to fecal fat measurement in patients with unexplained diarrhea. In summary, availability determines the choice of test among C4, SeHCAT and fecal BA; more widespread availability of such tests would enhance clinical management of these patients. PMID:23644387

  4. Effect of bile salts and bile acids on human gastric mucosal epithelial cells

    Institute of Scientific and Technical Information of China (English)

    Yinxue Song; Jun Gong

    2008-01-01

    Objective:To explore the effect of bile salt and bile acid on cultured eternalized human gastric mucosa epithelium GES-1 cells.Methods:Cultured eternalized human gastric mucosa epithelium GES-1 cells were treated with media containing 6 different kinds of bile salts and 3 different kinds of bile acids and their mixture with different concentrations: GCDC(glycochenodeoxycholate), GDC (glycodeoxycholate), GC(glycocholate), TCDC(taurochenodeoxycholate), TDC(taurodeoxycholate), TC (taurocholate), LCA (lithocholicacid), CA(cholic acid), DCA(deoxycholic acid)(50 μ mol/L,250 μ mol/L,500 μ mol/L, 1000 μ mol/L), DY(mixture of bile salts) and DS(mixture of bile acids)(250 μ mol/L,500 μ mol/L,1000 μ mol/L,1500 μ mol/L, 2000 μ mol/L), in comparison with thecontrol group(in normal media without bile salts and bile acids).Cell proliferation was assessed by MTT(3-[4,5-Dimethylthiaolyl]-2,5- diphenyl-tetrazolium bromide) assay for 72 hours with different concentrations and the apoptotic cells were assayed by flow cytometry (FCM) with Annex V-FITC conjugated with propidium iodide(PI) staining for 24 hours with different concentrations(1500,2000 μ mol/L).Results:There was no significant difference in morphology and cell proliferation in GC group after 24-72 h.Low concentration(50 μ mol/L) of GCDC, GDC, TCDC, TDC and TC accelerated gastric epithelial cell growth in a dosage-time dependent manner.At middle concentration (250-500 μ mol/L), it showed positive effect after 24-48 h, while negative effect after 72 h.At high concentration(1000 μ tool/L), it accelerated gastric epithelial cell growth after 24h and show consistent inhibition even leading to necrosis after 48-72 h.LCA and CA showed a positive effect on the concentration of 50 μ mol/L after 24-72 h, while 250-1000 It mol/L showed a trend towards apoptosis after 24-72 h.At 50-500 μ mol/L, DCA showed proliferation after 24 h and apoptosis after 48-72 h, but showed necrosis after 24-72 h at 1000 μ moiFL.DY and DS

  5. Independent repression of bile acid synthesis and activation of c-Jun N-terminal kinase (JNK) by activated hepatocyte fibroblast growth factor receptor 4 (FGFR4) and bile acids.

    Science.gov (United States)

    Yu, Chundong; Wang, Fen; Jin, Chengliu; Huang, Xinqiang; McKeehan, Wallace L

    2005-05-06

    The fibroblast growth factor (FGF) receptor complex is a regulator of adult organ homeostasis in addition to its central role in embryonic development and wound healing. FGF receptor 4 (FGFR4) is the sole FGFR receptor kinase that is significantly expressed in mature hepatocytes. Previously, we showed that mice lacking mouse FGFR4 (mR4(-/-)) exhibited elevated fecal bile acids, bile acid pool size, and expression of liver cholesterol 7alpha-hydroxylase (CYP7A1), the rate-limiting enzyme for canonical neutral bile acid synthesis. To prove that hepatocyte FGFR4 was a negative regulator of cholesterol metabolism and bile acid synthesis independent of background, we generated transgenic mice overexpressing a constitutively active human FGFR4 (CahR4) in hepatocytes and crossed them with the FGFR4-deficient mice to generate CahR4/mR4(-/-) mice. In mice expressing active FGFR4 in liver, fecal bile acid excretion was 64%, bile acid pool size was 47%, and Cyp7a1 expression was 10-30% of wild-type mice. The repressed level of Cyp7a1 expression was resistant to induction by a high cholesterol diet relative to wild-type mice. Expression of CahR4 in mR4(-/-) mouse livers depressed bile acid synthesis below wild-type levels from the elevated levels observed in mR4(-/-). Levels of phosphorylated c-Jun N-terminal kinase (JNK), which is part of a pathway implicated in bile acid-mediated repression of synthesis, was 30% of wild-type levels in mR4(-/-) livers, whereas CahR4 livers exhibited an average 2-fold increase. However, cholate still strongly induced phospho-JNK in mR4(-/-) livers. These results confirm that hepatocyte FGFR4 regulates bile acid synthesis by repression of Cyp7a1 expression. Hepatocyte FGFR4 may contribute to the repression of bile acid synthesis through JNK signaling but is not required for activation of JNK signaling by bile acids.

  6. Bile acid-induced virulence gene expression of Vibrio parahaemolyticus reveals a novel therapeutic potential for bile acid sequestrants.

    Directory of Open Access Journals (Sweden)

    Kazuyoshi Gotoh

    Full Text Available Vibrio parahaemolyticus, a bacterial pathogen, causes human gastroenteritis. A type III secretion system (T3SS2 encoded in pathogenicity island (Vp-PAI is the main contributor to enterotoxicity and expression of Vp-PAI encoded genes is regulated by two transcriptional regulators, VtrA and VtrB. However, a host-derived inducer for the Vp-PAI genes has not been identified. Here, we demonstrate that bile induces production of T3SS2-related proteins under osmotic conditions equivalent to those in the intestinal lumen. We also show that bile induces vtrA-mediated vtrB transcription. Transcriptome analysis of bile-responsive genes revealed that bile strongly induces expression of Vp-PAI genes in a vtrA-dependent manner. The inducing activity of bile was diminished by treatment with bile acid sequestrant cholestyramine. Finally, we demonstrate an in vivo protective effect of cholestyramine on enterotoxicity and show that similar protection is observed in infection with a different type of V. parahaemolyticus or with non-O1/non-O139 V. cholerae strains of vibrios carrying the same kind of T3SS. In summary, these results provide an insight into how bacteria, through the ingenious action of Vp-PAI genes, can take advantage of an otherwise hostile host environment. The results also reveal a new therapeutic potential for widely used bile acid sequestrants in enteric bacterial infections.

  7. Bile acids as endogenous etiologic agents in gastrointestinal cancer

    Institute of Scientific and Technical Information of China (English)

    Harris Bernstein; Carol Bernstein; Claire M Payne; Katerina Dvorak

    2009-01-01

    Bile acids are implicated as etiologic agents in cancer of the gastrointestinal (GI) tract, including cancer of the esophagus, stomach, small intestine, liver, biliary tract, pancreas and colon/rectum. Deleterious effects of bile acid exposure, likely related to carcinogenesis,include: induction of reactive oxygen and reactive nitrogen species; induction of DNA damage; stimulation of mutation; induction of apoptosis in the short term,and selection for apoptosis resistance in the long term.These deleterious effects have, so far, been reported most consistently in relation to esophageal and colorectal cancer, but also to some extent in relation to cancer of other organs. In addition, evidence is reviewed for an association of increased bile acid exposure with cancer risk in human populations, in specific human genetic conditions, and in animal experiments. A model for the role of bile acids in GI carcinogenesis is presented from a Darwinian perspective that offers an explanation for how the observed effects of bile acids on cells contribute to cancer development.

  8. Bile acid nuclear receptor FXR and digestive system diseases

    Directory of Open Access Journals (Sweden)

    Lili Ding

    2015-03-01

    Full Text Available Bile acids (BAs are not only digestive surfactants but also important cell signaling molecules, which stimulate several signaling pathways to regulate some important biological processes. The bile-acid-activated nuclear receptor, farnesoid X receptor (FXR, plays a pivotal role in regulating bile acid, lipid and glucose homeostasis as well as in regulating the inflammatory responses, barrier function and prevention of bacterial translocation in the intestinal tract. As expected, FXR is involved in the pathophysiology of a wide range of diseases of gastrointestinal tract, including inflammatory bowel disease, colorectal cancer and type 2 diabetes. In this review, we discuss current knowledge of the roles of FXR in physiology of the digestive system and the related diseases. Better understanding of the roles of FXR in digestive system will accelerate the development of FXR ligands/modulators for the treatment of digestive system diseases.

  9. Episodic hypoglycemia with psi-hydroxy fatty acid excretion.

    Science.gov (United States)

    Colle, E; Mamer, O A; Montgomery, J A; Miller, J D

    1983-02-01

    We present case histories of two young children with episodes of hypoglycemia, elevation of SGOT, low insulin levels, increased urinary excretion of psi-hydroxy fatty acids (5-hydroxyhexanoic, 7-hydroxyoctanoic and 9-hydroxydecanoic), traces of the corresponding psi-ketoacids and elevations of urinary adipic, suberic, and sebacic acids. The ratio of psi-hydroxy fatty acids to 3-hydroxybutyric in the urine of these patients is higher than in patients of similar ages with similar illnesses. These acids persisted while the patients were well. Increased urinary psi-hydroxy fatty acids could be reproduced by a load of medium chain triglycerides without precipitating other clinical symptoms. Three children with hypoglycemia were found not to excrete measurable amounts of these unusual acids while ill. A medium chain triglyceride load in one of these children after recovery failed to elicit psi-hydroxy acid excretion. Small amounts of urinary 5-hydroxyhexanoic acid only were found in two patients with acute Reye's syndrome and in three of five severely ill children with starvation ketonuria. In this last group, no urinary psi-hydroxyacids could be detected after recovery. Normal children do not excrete measurable amounts (less than 1 mg/g creatinine) of these psi-hydroxyacids.

  10. Increased Renal Clearance of Rocuronium Compensates for Chronic Loss of Bile Excretion, via upregulation of Oatp2

    Science.gov (United States)

    Wang, Long; Zhou, Mai-Tao; Chen, Cai-Yang; Yin, Wen; Wen, Da-Xiang; Cheung, Chi-Wai; Yang, Li-Qun; Yu, Wei-Feng

    2017-01-01

    Requirement for rocuronium upon surgery changes only minimally in patients with end-stage liver diseases. Our study consisted of both human and rat studies to explore the reason. The reduction rate of rocuronium infusion required to maintain neuromuscular blockade during the anhepatic phase (relative to paleohepatic phase) was examined in 16 children with congenital biliary atresia receiving orthotopic liver transplantation. Pharmacodynamics and pharmacokinetics of rocuronium were studied based on BDL rats. The role of increased Oatp2 and decrease Oatp1 expressions in renal compensation were explored. The reduction of rocuronium requirements significantly decreased in obstructively jaundiced children (24 ± 9 vs. 39 ± 11%). TOF50 in BDL rats was increased by functional removal of the kidneys but not the liver, and the percentage of rocuronium excretion through urine increased (20.3 ± 6.9 vs. 8.6 ± 1.8%), while that decreased through bile in 28d-BDL compared with control group. However, this enhanced renal secretion for rocuronium was eliminated by Oatp2 knock-down, rather than Oatp1 overexpression (28-d BDL vs. Oatp1-ShRNA or Oatp2-ShRNA, 20.3 ± 6.9 vs. 17.0 ± 6.6 or 9.3 ± 3.2%). Upon chronic/sub-chronic loss of bile excretion, rocuronium clearance via the kidneys is enhanced, by Oatp2 up-regulation. PMID:28084414

  11. Effects of essential fatty acid deficiency on enterohepatic circulation of bile salts in mice.

    NARCIS (Netherlands)

    Lukovac, S.; Los, L.; Stellaard, F.; Rings, E.H.; Verkade, H.J.

    2009-01-01

    Essential fatty acid (EFA) deficiency in mice has been associated with increased bile production, which is mainly determined by the enterohepatic circulation (EHC) of bile salts. To establish the mechanism underlying the increased bile production, we characterized in detail the EHC of bile salts in

  12. The ileal lipid binding protein is required for efficient absorption and transport of bile acids in the distal portion of the murine small intestine.

    Directory of Open Access Journals (Sweden)

    Dana Praslickova

    Full Text Available The ileal lipid binding protein (ilbp is a cytoplasmic protein that binds bile acids with high affinity. However evidence demonstrating the role of this protein in bile acid transport and homeostasis is missing. We created a mouse strain lacking ilbp (Fabp6(-/- mice and assessed the impact of ilbp deficiency on bile acid homeostasis and transport in vivo. Elimination of ilbp increased fecal bile acid excretion (54.2%, P<0.05 in female but not male Fabp6(-/- mice. The activity of cholesterol 7α-hydroxylase (cyp7a1, the rate-controlling enzyme of the classical bile acid biosynthetic pathway, was significantly increased in female (63.5%, P<0.05 but not in male Fabp6(-/- mice. The amount of [(3H]taurocholic acid (TCA excreted by 24 h after oral administration was 102% (P<0.025 higher for female Fabp6(-/- mice whereas it was 57.3% (P<0.01 lower for male Fabp6(-/- mice, compared to wild-type mice. The retained fraction of the [(3H]TCA localized in the small and large intestines was increased by 22% (P<0.02 and decreased by 62.7% (P<0.01, respectively, in male Fabp6(-/- mice relative wild-type mice, whereas no changes were seen in female Fabp6(-/- mice. Mucosal to serosal bile acid transport using everted distal gut sacs was decreased by 74% (P<0.03 in both sexes of Fabp6(-/- mice as compared to wild-type mice. The results demonstrate that ilbp is involved in the apical to basolateral transport of bile acids in ileal enterocytes, and is vital for the maintenance of bile acid homeostasis in the enterohepatic circulation (EHC in mice.

  13. The ileal lipid binding protein is required for efficient absorption and transport of bile acids in the distal portion of the murine small intestine.

    Science.gov (United States)

    Praslickova, Dana; Torchia, Enrique C; Sugiyama, Michael G; Magrane, Elijah J; Zwicker, Brittnee L; Kolodzieyski, Lev; Agellon, Luis B

    2012-01-01

    The ileal lipid binding protein (ilbp) is a cytoplasmic protein that binds bile acids with high affinity. However evidence demonstrating the role of this protein in bile acid transport and homeostasis is missing. We created a mouse strain lacking ilbp (Fabp6(-/-) mice) and assessed the impact of ilbp deficiency on bile acid homeostasis and transport in vivo. Elimination of ilbp increased fecal bile acid excretion (54.2%, Pexcreted by 24 h after oral administration was 102% (Psmall and large intestines was increased by 22% (P<0.02) and decreased by 62.7% (P<0.01), respectively, in male Fabp6(-/-) mice relative wild-type mice, whereas no changes were seen in female Fabp6(-/-) mice. Mucosal to serosal bile acid transport using everted distal gut sacs was decreased by 74% (P<0.03) in both sexes of Fabp6(-/-) mice as compared to wild-type mice. The results demonstrate that ilbp is involved in the apical to basolateral transport of bile acids in ileal enterocytes, and is vital for the maintenance of bile acid homeostasis in the enterohepatic circulation (EHC) in mice.

  14. An in vivo microdialysis measurement of harpagoside in rat blood and bile for predicting hepatobiliary excretion and its interaction with cyclosporin A and verapamil.

    Science.gov (United States)

    Wu, Qian; Wen, Xiao-Dong; Qi, Lian-Wen; Wang, Wei; Yi, Ling; Bi, Zhi-Ming; Li, Ping

    2009-03-15

    Harpagoside, a major bioactive iridoid glucoside in genus Scrophularia, has been widely used in clinical practice for the treatment of pain in the joints and lower back for its neuroprotective and anti-inflammation activities. To investigate the pharmacokinetics and hepatobiliary excretion, an in vivo microdialysis method coupled with high performance liquid chromatography was developed to monitor the concentration of harpagoside in blood and bile. The harpagoside bile-to-blood distribution ratio (AUC(bile)/AUC(blood)) up to 986.28+/-78.46 significantly decreased to 6.41+/-0.56 or 221.20+/-18.92 after co-administration of cyclosporin A or verapamil. The results indicated that harpagoside went through concentrative elimination from the bile which was probably regulated by P-glucoprotein, providing possible clinical trials of co-administration of transporter inhibitors to decrease drug efflux, thus to enhance the curative effects.

  15. Gut microbiota inhibit Asbt-dependent intestinal bile acid reabsorption via Gata4

    NARCIS (Netherlands)

    Out, Carolien; Patankar, Jay V.; Doktorova, Marcela; Boesjes, Marije; Bos, Trijnie; de Boer, Sanna; Havinga, Rick; Wolters, Henk; Boverhof, Renze; van Dijk, Theo H.; Smoczek, Anna; Bleich, Andre; Sachdev, Vinay; Kratky, Dagmar; Kuipers, Folkert; Verkade, Henkjan J.; Groen, Albert K.

    2015-01-01

    Background & Aims: Regulation of bile acid homeostasis in mammals is a complex process regulated via extensive cross-talk between liver, intestine and intestinal microbiota. Here we studied the effects of gut microbiota on bile acid homeostasis in mice. Methods: Bile acid homeostasis was assessed in

  16. Alteration of bile acid metabolism in the rat induced by chronic ethanol consumption

    Science.gov (United States)

    Xie, Guoxiang; Zhong, Wei; Li, Houkai; Li, Qiong; Qiu, Yunping; Zheng, Xiaojiao; Chen, Huiyuan; Zhao, Xueqing; Zhang, Shucha; Zhou, Zhanxiang; Zeisel, Steven H.; Jia, Wei

    2013-01-01

    Our understanding of the bile acid metabolism is limited by the fact that previous analyses have primarily focused on a selected few circulating bile acids; the bile acid profiles of the liver and gastrointestinal tract pools are rarely investigated. Here, we determined how chronic ethanol consumption altered the bile acids in multiple body compartments (liver, gastrointestinal tract, and serum) of rats. Rats were fed a modified Lieber-DeCarli liquid diet with 38% of calories as ethanol (the amount equivalent of 4–5 drinks in humans). While conjugated bile acids predominated in the liver (98.3%), duodenum (97.8%), and ileum (89.7%), unconjugated bile acids comprised the largest proportion of measured bile acids in serum (81.2%), the cecum (97.7%), and the rectum (97.5%). In particular, taurine-conjugated bile acids were significantly decreased in the liver and gastrointestinal tract of ethanol-treated rats, while unconjugated and glycine-conjugated species increased. Ethanol consumption caused increased expression of genes involved in bile acid biosynthesis, efflux transport, and reduced expression of genes regulating bile acid influx transport in the liver. These results provide an improved understanding of the systemic modulations of bile acid metabolism in mammals through the gut-liver axis.—Xie, G., Zhong, W., Li, H., Li, Q., Qiu, Y., Zheng, X., Chen, H., Zhao, X., Zhang, S., Zhou, Z., Zeisel, S. H., Jia, W. Alteration of bile acid metabolism in the rat induced by chronic ethanol consumption. PMID:23709616

  17. Altered amino acid excretion in children with autism.

    Science.gov (United States)

    Evans, Craig; Dunstan, R Hugh; Rothkirch, Tony; Roberts, Tim K; Reichelt, Karl L; Cosford, Robyn; Deed, Gary; Ellis, Libby B; Sparkes, Diane L

    2008-02-01

    Autism is a complex and life-long behavioural disorder of unknown aetiology. Recent reports have indicated the involvement of digestive tract dysfunction and possible complications from inadequate nutrition. In this study, 34 autistic children (12 untreated and 22 receiving therapeutic treatments related to digestive function and nutritional uptake) and 29 control subjects (all 5-15 years of age) were investigated to determine whether there were any anomalies in the urinary excretion of amino acids, glucose, sucrose, arabinose and tartaric acid using GC/FID and GC/MS analysis techniques. Significantly lower relative urinary levels of essential amino acids were revealed for both the untreated (mean +/- SEM, 32.53 +/- 3.09%) and treated (31.98 +/- 2.87%) autistic children compared with the controls (37.87 +/- 1.50%). There were no significant differences in measured excretions of sugars or tartaric acid. It was concluded that the untreated autistic children had evidence of altered metabolic homeostasis.

  18. 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

  19. 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

  20. Differentiation of various traditional Chinese medicines derived from animal bile and gallstone: simultaneous determination of bile acids by liquid chromatography coupled with triple quadrupole mass spectrometry.

    Science.gov (United States)

    Qiao, Xue; Ye, Min; Pan, De-lin; Miao, Wen-juan; Xiang, Cheng; Han, Jian; Guo, De-an

    2011-01-01

    Animal biles and gallstones are popularly used in traditional Chinese medicines, and bile acids are their major bioactive constituents. Some of these medicines, like cow-bezoar, are very expensive, and may be adulterated or even replaced by less expensive but similar species. Due to poor ultraviolet absorbance and structural similarity of bile acids, effective technology for species differentiation and quality control of bile-based Chinese medicines is still lacking. In this study, a rapid and reliable method was established for the simultaneous qualitative and quantitative analysis of 18 bile acids, including 6 free steroids (cholic acid, chenodeoxycholic acid, deoxycholic acid, lithocholic acid, hyodeoxycholic acid, and ursodeoxycholic acid) and their corresponding glycine conjugates and taurine conjugates, by using liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS). This method was used to analyze six bile-based Chinese medicines: bear bile, cattle bile, pig bile, snake bile, cow-bezoar, and artificial cow-bezoar. Samples were separated on an Atlantis dC₁₈ column and were eluted with methanol-acetonitrile-water containing ammonium acetate. The mass spectrometer was monitored in the negative electrospray ionization mode. Total ion currents of the samples were compared for species differentiation, and the contents of bile acids were determined by monitoring specific ion pairs in a selected reaction monitoring program. All 18 bile acids showed good linearity (r² > 0.993) in a wide dynamic range of up to 2000-fold, using dehydrocholic acid as the internal standard. Different animal biles could be explicitly distinguished by their major characteristic bile acids: tauroursodeoxycholic acid and taurochenodeoxycholic acid for bear bile, glycocholic acid, cholic acid and taurocholic acid for cattle bile, glycohyodeoxycholic acid and glycochenodeoxycholic acid for pig bile, and taurocholic acid for snake bile. Furthermore, cattle bile, cow

  1. Diagnosis in bile acid-CoA: Amino acid N-acyltransferase deficiency

    Institute of Scientific and Technical Information of China (English)

    Nedim Had(z)i(c); Laura N Bull; Peter T Clayton; AS Knisely

    2012-01-01

    Cholate-CoA ligase (CCL) and bile acid-CoA:amino acid N-acyltransferase (BAAT) sequentially mediate bile-acid amidation.Defects can cause intrahepatic cholestasis.Distinction has required gene sequencing.We assessed potential clinical utility of immunostaining of liver for CCL and BAAT.Using commercially available antibodies against BAAT and CCL,we immunostained liver from an infant with jaundice,deficiency of amidated bile acids,and transcription-terminating mutation in BAAT.CCL was normally expressed.BAAT expression was not detected.Immunostaining may facilitate diagnosis in bileacid amidation defects.

  2. Potency of individual bile acids to regulate bile acid synthesis and transport genes in primary human hepatocyte cultures.

    Science.gov (United States)

    Liu, Jie; Lu, Hong; Lu, Yuan-Fu; Lei, Xiaohong; Cui, Julia Yue; Ellis, Ewa; Strom, Stephen C; Klaassen, Curtis D

    2014-10-01

    Bile acids (BAs) are known to regulate their own homeostasis, but the potency of individual bile acids is not known. This study examined the effects of cholic acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA) and ursodeoxycholic acid (UDCA) on expression of BA synthesis and transport genes in human primary hepatocyte cultures. Hepatocytes were treated with the individual BAs at 10, 30, and 100μM for 48 h, and RNA was extracted for real-time PCR analysis. For the classic pathway of BA synthesis, BAs except for UDCA markedly suppressed CYP7A1 (70-95%), the rate-limiting enzyme of bile acid synthesis, but only moderately (35%) down-regulated CYP8B1 at a high concentration of 100μM. BAs had minimal effects on mRNA of two enzymes of the alternative pathway of BA synthesis, namely CYP27A1 and CYP7B1. BAs increased the two major target genes of the farnesoid X receptor (FXR), namely the small heterodimer partner (SHP) by fourfold, and markedly induced fibroblast growth factor 19 (FGF19) over 100-fold. The BA uptake transporter Na(+)-taurocholate co-transporting polypeptide was unaffected, whereas the efflux transporter bile salt export pump was increased 15-fold and OSTα/β were increased 10-100-fold by BAs. The expression of the organic anion transporting polypeptide 1B3 (OATP1B3; sixfold), ATP-binding cassette (ABC) transporter G5 (ABCG5; sixfold), multidrug associated protein-2 (MRP2; twofold), and MRP3 (threefold) were also increased, albeit to lesser degrees. In general, CDCA was the most potent and effective BA in regulating these genes important for BA homeostasis, whereas DCA and CA were intermediate, LCA the least, and UDCA ineffective.

  3. The Farnesoid X receptor - A molecular link between bile acid and lipid and glucose metabolism

    NARCIS (Netherlands)

    Claudel, T; Staels, B; Kuipers, F

    2005-01-01

    Bile acids are the end products of cholesterol metabolism. They are synthesized in the liver and secreted via bile into the intestine, where they aid in the absorption of fat-soluble vitamins and dietary fat. Subsequently, bile acids return to the liver to complete their enterohepatic circulation. T

  4. Bile acid receptors and nonalcoholic fatty liver disease

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    With the high prevalence of obesity, diabetes, and otherfeatures of the metabolic syndrome in United States,nonalcoholic fatty liver disease (NAFLD) has inevitablybecome a very prevalent chronic liver disease and isnow emerging as one of the leading indications for livertransplantation. Insulin resistance and derangementof lipid metabolism, accompanied by activation ofthe pro-inflammatory response and fibrogenesis, areessential pathways in the development of the moreclinically significant form of NAFLD, known as nonalcoholicsteatohepatitis (NASH). Recent advances inthe functional characterization of bile acid receptors,such as farnesoid X receptor (FXR) and transmembraneG protein-coupled receptor (TGR) 5, have providedfurther insight in the pathophysiology of NASH andhave led to the development of potential therapeutictargets for NAFLD and NASH. Beyond maintaining bileacid metabolism, FXR and TGR5 also regulate lipidmetabolism, maintain glucose homeostasis, increaseenergy expenditure, and ameliorate hepatic inflammation.These intriguing features have been exploitedto develop bile acid analogues to target pathways inNAFLD and NASH pathogenesis. This review providesa brief overview of the pathogenesis of NAFLD andNASH, and then delves into the biological functions ofbile acid receptors, particularly with respect to NASHpathogenesis, with a description of the associatedexperimental data, and, finally, we discuss the prospectsof bile acid analogues in the treatment of NAFLD andNASH.

  5. Analysis of ileal sodium/bile acid cotransporter and related nuclear receptor genes in a family with multiple cases of idiopathic bile acid malabsorption

    Institute of Scientific and Technical Information of China (English)

    Marco Montagnani; Anna Abrahamsson; Cecilia G(a)lman; G(o)sta Eggertsen; Hanns-Ulrich Marschall; Elisa Ravaioli; Curt Einarsson; Paul A Dawson

    2006-01-01

    The etiology of most cases of idiopathic bile acid malabsorption (TBAM) is unknown. Tn this study, a Swedish family with bile acid malabsorption in three consecutive generations was screened for mutations in the ileal apical sodium-bile acid cotransporter gene (ASBT; gene symbol, SLC10A2) and in the genes for several of the nuclear receptors known to be important for ASBT expression: the farnesoid X receptor (FXR)and peroxisome proliferator activated receptor alpha (PPARα). The patients presented with a clinical history of idiopathic chronic watery diarrhea, which was responsive to cholestyramine treatment and consistent with IBAM. Bile acid absorption was determined using 75Se-homocholic acid taurine(SeHCAT); bile acid synthesis was estimated by measuring the plasma levels of 7α-hydroxy-4-cholesten-3-one (C4). The ASBT,FXR, and PPARα genes in the affected and unaffected family members were analyzed using single stranded conformation polymorphism (SSCP), denaturing HPLC,and direct sequencing. No ASBT mutations were identified and the ASBT gene did not segregate with the bile acid malabsorption phenotype. Similarly, no mutations or polymorphisms were identified in the FXR or PPARα genes associated with the bile acid malabsorption phenotype. These studies indicate that the intestinal bile acid malabsorption in these patients cannot be attributed to defects in ASBT. In the absence of apparent ileal disease, alternative explanations such as accelerated transit through the small intestine may be responsible for the IBAM.

  6. EFFECT OF CASEIN-BASED SEMISYNTHETIC FOOD ON RENAL ACID EXCRETION AND ACID-BASE STATE OF BLOOD IN DOGS

    NARCIS (Netherlands)

    ZIJLSTRA, WG; LANGBROEK, AJM; KRAAN, J; RISPENS, P; NIJMEIJER, A

    1995-01-01

    Urinary acid excretion and blood acid-base stare were determined in dogs fed a casein-based semi-synthetic food (SSF), to which different amounts of salts had been added, in comparison with feeding normal dog food. Net acid excretion (NAE) and inorganic acid excretion (IAE) increased during SSF feed

  7. Raisin dietary fiber composition and in vitro bile acid binding.

    Science.gov (United States)

    Camire, Mary E; Dougherty, Michael P

    2003-01-29

    Raisins are dried grapes that are popular shelf-stable snacks. Three commercially important types of raisins were studied: sun-dried (natural), artificially dried (dipped), and sulfur dioxide-treated (golden) raisins. Dietary fiber composition was analyzed by AACC method 32-25. Polysaccharides were hydrolyzed, and the resulting sugars were analyzed by colorimetric and gas chomatographic methods. Fructans were measured with a colorimetric kit assay. Total dietary fiber values agreed with published values, with pectins and neutral polysaccharides of mannose and glucose residues predominating. Dipped raisins had over 8% fructans. No fructans were found in fresh grapes. Raisin types varied in their ability to bind bile acids in vitro. Coarsely chopped raisins bound more bile than did finely chopped or whole raisins.

  8. Bile Acid Responses in Methane and Non-Methane Producers to Standard Breakfast Meals

    Science.gov (United States)

    Bile acids and their conjugates are important regulators of glucose homeostasis. Previous research has revealed the ratio of cholic acid to deoxycholic acid to affect insulin resistance in humans. Bile acid de-conjugation and intestinal metabolism depend on gut microbes which may be affected by hos...

  9. Microbiota transplantation restores normal fecal bile acid composition in recurrent Clostridium difficile infection.

    Science.gov (United States)

    Weingarden, Alexa R; Chen, Chi; Bobr, Aleh; Yao, Dan; Lu, Yuwei; Nelson, Valerie M; Sadowsky, Michael J; Khoruts, Alexander

    2014-02-15

    Fecal microbiota transplantation (FMT) has emerged as a highly effective therapy for refractory, recurrent Clostridium difficile infection (CDI), which develops following antibiotic treatments. Intestinal microbiota play a critical role in the metabolism of bile acids in the colon, which in turn have major effects on the lifecycle of C. difficile bacteria. We hypothesized that fecal bile acid composition is altered in patients with recurrent CDI and that FMT results in its normalization. General metabolomics and targeted bile acid analyses were performed on fecal extracts from patients with recurrent CDI treated with FMT and their donors. In addition, 16S rRNA gene sequencing was used to determine the bacterial composition of pre- and post-FMT fecal samples. Taxonomic bacterial composition of fecal samples from FMT recipients showed rapid change and became similar to the donor after the procedure. Pre-FMT fecal samples contained high concentrations of primary bile acids and bile salts, while secondary bile acids were nearly undetectable. In contrast, post-FMT fecal samples contained mostly secondary bile acids, as did non-CDI donor samples. Therefore, our analysis showed that FMT resulted in normalization of fecal bacterial community structure and metabolic composition. Importantly, metabolism of bile salts and primary bile acids to secondary bile acids is disrupted in patients with recurrent CDI, and FMT corrects this abnormality. Since individual bile salts and bile acids have pro-germinant and inhibitory activities, the changes suggest that correction of bile acid metabolism is likely a major mechanism by which FMT results in a cure and prevents recurrence of CDI.

  10. The Peculiar Existence of Protein-Bound Unconjugated Bile Acid in the Cytoplasmic Fraction of Rat Brain%与蛋白结合的非共轭胆汁酸在小鼠大脑细胞浆中的独特存在

    Institute of Scientific and Technical Information of China (English)

    MANO Nariyasu; GOTO Takaaki; GOTO Junichi

    2004-01-01

    Bile acids are synthesized in the liver from cholesterol by the action of hepatic enzymes and excreted into the small intestine via the bile duct. In the intestinal lumen, they assist lipolysis and the absorption of fats by forming mixed micelles, and then return to the liver upon absorption in the

  11. Suppression of the HPA Axis During Cholestasis Can Be Attributed to Hypothalamic Bile Acid Signaling.

    Science.gov (United States)

    McMillin, Matthew; Frampton, Gabriel; Quinn, Matthew; Divan, Ali; Grant, Stephanie; Patel, Nisha; Newell-Rogers, Karen; DeMorrow, Sharon

    2015-12-01

    Suppression of the hypothalamic-pituitary-adrenal (HPA) axis has been shown to occur during cholestatic liver injury. Furthermore, we have demonstrated that in a model of cholestasis, serum bile acids gain entry into the brain via a leaky blood brain barrier and that hypothalamic bile acid content is increased. Therefore, the aim of the current study was to determine the effects of bile acid signaling on the HPA axis. The data presented show that HPA axis suppression during cholestatic liver injury, specifically circulating corticosterone levels and hypothalamic corticotropin releasing hormone (CRH) expression, can be attenuated by administration of the bile acid sequestrant cholestyramine. Secondly, treatment of hypothalamic neurons with various bile acids suppressed CRH expression and secretion in vitro. However, in vivo HPA axis suppression was only evident after the central injection of the bile acids taurocholic acid or glycochenodeoxycholic acid but not the other bile acids studied. Furthermore, we demonstrate that taurocholic acid and glycochenodeoxycholic acid are exerting their effects on hypothalamic CRH expression after their uptake through the apical sodium-dependent bile acid transporter and subsequent activation of the glucocorticoid receptor. Taken together with previous studies, our data support the hypothesis that during cholestatic liver injury, bile acids gain entry into the brain, are transported into neurons through the apical sodium-dependent bile acid transporter and can activate the glucocorticoid receptor to suppress the HPA axis. These data also lend themselves to the broader hypothesis that bile acids may act as central modulators of hypothalamic peptides that may be altered during liver disease.

  12. Effect of bile acid sequestrants on glycaemic control

    DEFF Research Database (Denmark)

    Hansen, Morten; Sonne, David Peick; Mikkelsen, Kristian Hallundbæk;

    2012-01-01

    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...... 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...

  13. Evaluation of a semiquantitative SNAP test for measurement of bile acids in dogs

    OpenAIRE

    Rachel L. Seibert; Tobias, Karen M.; Ann Reed; Karl R. Snyder

    2014-01-01

    Background. Serum bile acids (SBA) are used as a routine screening tool of liver function in dogs. Serum samples are usually shipped to a referral laboratory for quantitative analysis with an enzymatic chemistry analyzer. The canine SNAP Bile Acids Test (SNAP-BAT) provides an immediate, semi-quantitative measurement of bile acid concentrations in-house. With the SNAP-BAT, bile acids concentrations of 5–30 µmol/L are quantified, and results outside of that range are classified as 30 µmol/L. Ag...

  14. Effects of bile acids on proliferation and ultrastructural alteration of pancreatic cancer cell lines

    Institute of Scientific and Technical Information of China (English)

    Zheng Wu; Yi Lüi; Bo Wang; Chang Liu; Zuo-Ren Wang,

    2003-01-01

    AIM: Pancreatic cancer in the head is frequently accompanied by jaundice and high bile acid level in serum. This study focused on the direct effects of bile acids on proliferation and ultrastructural alteration of pancreatic cancer.METHODS: Pancreatic cancer cell lines PANC-1, MIA PaCa2 and PGHAM-1 were explored in this study. The cell lines were cultured in media supplemented with certain bile acids,CA, DCA, LCA, TCDC, TDCA and GCA. Their influence on cell growth was measured with MTT assay after 72 h of incubation. Cell cycles of PANC-1 cells in 40 μM of bile acids media were analyzed by flow cytometry. Ultrastructural alteration of PANC-1 cells induced by DCA was observed using scanning and transmission electron microscope (SEM and TEM).RESULTS: At various concentrations of bile acids and incubation time, no enhanced effects of bile acids on cell proliferation were observed. Significant inhibitory effects were obtained in almost all media with bile acids. DCA and CA increased the percentage of G0+G1 phase cells, while GCA and TDCA elevated the S phase cell number. After 48 h of incubation in DCA medium, PANC-1 cells showed some structural damages such as loss of their microvilli and vacuolization of organelles in cytoplasm.CONCLUSION: Bile acids can reduce proliferation of pancreatic cancer cells due to their direct cytotoxicity. This result implies that elevation of bile acids in jaundiced serum may inhibit pancreatic cancer progression.

  15. 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.

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

    Science.gov (United States)

    James, Laura; Yan, Ke; Pence, Lisa; Simpson, Pippa; Bhattacharyya, Sudeepa; Gill, Pritmohinder; Letzig, Lynda; Kearns, Gregory; Beger, Richard

    2015-01-01

    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; pacetaminophen 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.

  17. Changes of gastrointestinal myoelectric activity and bile acid pool size after cholecystectomy in guinea pigs

    Institute of Scientific and Technical Information of China (English)

    Xue-Mei Zhang; Lei Dong; Li-Na Liu; Bi-Xia Chang; Qian He; Qian Li

    2005-01-01

    AIM: To investigate the bile acid pool size after cholecystectomy whether or not correlated to the gastrointestinal migrating myoelectric complex (MMC) in guinea pigs.METHODS: Gallbladder motilities were assessed before cholecystectomy. Furthermore, we continuously monitored interdigestive gastrointestinal motilities using bipolar electrodes in conscious guinea pigs before and after surgery at 4 wk in standard diet group and high cholesterol diet (cholesterol gallstone) group. Total bile acid pool sizes were measured by isotope dilution method at meantime.RESULTS: After cholecystectomy, there were parallel falls in duration of phase Ⅰ, Ⅱ, Ⅲ and MMC cycle duration but increase in amplitude in the guinea pigs with normal gallbladder function, and in the guinea pigs with cholesterol stones. However, There were not significantly differences. On the other hand, the bile acid pool was definitely small in the GS guinea pigs compared to normal guinea pigs and became slightly smaller after cholecystectomy. Similarly, bile acid in gallbladder bile, fecal bile acid was slightly increased in GS guinea pigs after cholecystectomy, to the same degree as normal. These differences, however, were not significant.CONCLUSION: It is concluded that in the guinea pigs with normal gallbladder function, and in the guinea pigs with cholesterol stones: (1) Cholecystectomy produce a similar but less marked trend in bile acid pool; and (2) MMC are linked to enterohepatic circulation of bile acids, rather than surgery, which is consistent with changes of the bile acid pool size. As a result, gastrointestinal dyskinesia is not involved in occurrence of postcholecystectomy syndrome.

  18. Hepatic bile acid metabolism in the neonatal hamster: expansion of the bile acid pool parallels increased Cyp7a1 expression levels.

    Science.gov (United States)

    Burke, Katie T; Horn, Paul S; Tso, Patrick; Heubi, James E; Woollett, Laura A

    2009-07-01

    Intraluminal concentrations of bile acids are low in newborn infants and increase rapidly after birth, at least partly owing to increased bile acid synthesis rates. The expansion of the bile acid pool is critical since bile acids are required to stimulate bile flow and absorb lipids, a major component of newborn diets. The purpose of the present studies was to determine the mechanism responsible for the increase in bile acid synthesis rates and the subsequent enlargement of bile acid pool sizes (BAPS) during the neonatal period, and how changes in circulating hormone levels might affect BAPS. In the hamster, pool size was low just after birth and increased modestly until 10.5 days postpartum (dpp). BAPS increased more significantly ( approximately 3-fold) between 10.5 and 15.5 dpp. An increase in mRNA and protein levels of cholesterol 7alpha-hydroxylase (Cyp7a1), the rate-limiting step in classical bile acid synthesis, immediately preceded an increase in BAPS. In contrast, levels of oxysterol 7alpha-hydroxylase (Cyp7b1), a key enzyme in bile acid synthesis by the alternative pathway, were relatively elevated by 1.5 dpp. farnesyl X receptor (FXR) and short heterodimeric partner (SHP) mRNA levels remained relatively constant at a time when Cyp7a1 levels increased. Finally, although simultaneous increases in circulating cortisol and Cyp7a1 levels occurred, precocious expression of Cyp7a1 could not be induced in neonatal hamsters with dexamethasone. Thus the significant increase in Cyp7a1 levels in neonatal hamsters is due to mechanisms independent of the FXR and SHP pathway and cortisol.

  19. Gut microbiota, cirrhosis and alcohol regulate bile acid metabolism in the gut

    Science.gov (United States)

    Ridlon, Jason M.; Kang, Dae-Joong; Hylemon, Phillip B.; Bajaj, Jasmohan S

    2015-01-01

    The understanding of the complex role of the bile acid-gut microbiome axis in health and disease processes is evolving rapidly. Our focus revolves around the interaction of the gut microbiota with liver diseases, especially cirrhosis. The bile acid pool size has recently been shown to be a function of microbial metabolism of bile acid and regulation of the microbiota by bile acids is important in the development and progression of several liver diseases. Humans produce a large, conjugated hydrophilic bile acid pool, maintained through positive-feedback antagonism of FXR in intestine and liver. Microbes use bile acids, and via FXR signaling this results in a smaller, unconjugated hydrophobic bile acid pool. This equilibrium is critical to maintain health. The challenge is to examine the manifold functions of gut bile acids as modulators of antibiotic, probiotic and disease progression in cirrhosis, metabolic syndrome and alcohol use. Recent studies have shown potential mechanisms explaining how perturbations in the microbiome affect bile acid pool size and composition. With advancing liver disease and cirrhosis, there is dysbiosis in the fecal, ileal and colonic mucosa, in addition to a decrease in bile acid concentration in the intestine due to the liver problems. This results in a dramatic shift toward the Firmicutes, particularly Clostridium cluster XIVa and increasing production of deoxycholic acid (DCA). Alcohol intake speeds up these processes in the subjects with and without cirrhosis without significant FXR feedback. Taken together, these pathways can impact intestinal and systemic inflammation while worsening dysbiosis. The interaction between bile acids, alcohol, cirrhosis and dysbiosis is an important relationship that influences intestinal and systemic inflammation, which in turn determines progression of the overall disease process. These interactions and the impact of commonly used therapies for liver disease can provide insight into the pathogenesis

  20. Metabolic Effects of Bile Acids in the Gut in Health and Disease

    NARCIS (Netherlands)

    Boesjes, Marije; Brufau Dones, Gemma

    2014-01-01

    In the last decade, it became clear that bile acids, in addition to their role in intestinal absorption of lipids and fat-soluble vitamins, are major regulators of metabolism. They activate signal transduction pathways through binding to the specific bile acid receptors TGR5 and FXR. Indirectly, bil

  1. 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 5beta-reductase....

  2. Effects of bile acids and the bile acid receptor FXR agonist on the respiratory rhythm in the in vitro brainstem medulla slice of neonatal Sprague-Dawley rats.

    Directory of Open Access Journals (Sweden)

    Cong Zhao

    Full Text Available Intrahepatic cholestasis of pregnancy is always accompanied by adverse fetal outcomes such as malfunctions of respiration. Farnesoid X receptor (FXR plays a critical role in the homeostasis of bile acids. Thus, we are determined to explore the effects of farnesoid X receptor (FXR and five bile acids on respiratory rhythm generation and modulation of neonatal rats. Spontaneous periodic respiratory-related rhythmical discharge activity (RRDA was recorded from hypoglossal nerves during the perfusion of modified Krebs solution. Group 1-6 was each given GW4064 and five bile acids of chenodeoxycholic acid (CDCA, deoxycholic acid (DCA, lithocholic acid (LCA, cholic acid (CA as well as ursodeoxycholic acid (UDCA at different concentrations to identify their specific functions on respiratory rhythm modulations. Group 7 was applied to receive FXR blocker Z-guggulsterone and Z-guggulsterone with the above bile acids separately to explore the role of FXR in the respiratory rhythm modulation. Group 8 was given dimethyl sulfoxide (DMSO as controls. Apart from UDCA, CDCA, DCA LCA and CA all exerted effects on RRDA recorded from hypoglossal nerves in a concentration-dependent manner. Respiratory cycle (RC, Inspiratory time (TI, Expiratory Time (TE and Integral Amplitude (IA were influenced and such effects could be reversed by Z-guggulsterone. FXR may contribute to the effects on the modulation of respiratory rhythm exerted by bile acids.

  3. Structural basis of the alternating-access mechanism in a bile acid transporter

    Science.gov (United States)

    Zhou, Xiaoming; Levin, Elena J.; Pan, Yaping; McCoy, Jason G.; Sharma, Ruchika; Kloss, Brian; Bruni, Renato; Quick, Matthias; Zhou, Ming

    2014-01-01

    Bile acids are synthesized from cholesterol in hepatocytes and secreted through the biliary tract into the small intestine, where they aid in absorption of lipids and fat-soluble vitamins. Through a process known as enterohepatic recirculation, more than 90% of secreted bile acids are then retrieved from the intestine and returned to the liver for resecretion. In humans, there are two Na+-dependent bile acid transporters involved in enterohepatic recirculation, the Na+-taurocholate co-transporting polypeptide (NTCP; also known as SLC10A1) expressed in hepatocytes, and the apical sodium-dependent bile acid transporter (ASBT; also known as SLC10A2) expressed on enterocytes in the terminal ileum. In recent years, ASBT has attracted much interest as a potential drug target for treatment of hypercholesterolaemia, because inhibition of ASBT reduces reabsorption of bile acids, thus increasing bile acid synthesis and consequently cholesterol consumption. However, a lack of three-dimensional structures of bile acid transporters hampers our ability to understand the molecular mechanisms of substrate selectivity and transport, and to interpret the wealth of existing functional data. The crystal structure of an ASBT homologue from Neisseria meningitidis (ASBTNM) in detergent was reported recently, showing the protein in an inward-open conformation bound to two Na+ and a taurocholic acid. However, the structural changes that bring bile acid and Na+ across the membrane are difficult to infer from a single structure. To understand the structural changes associated with the coupled transport of Na+ and bile acids, here we solved two structures of an ASBT homologue from Yersinia frederiksenii (ASBTYf) in a lipid environment, which reveal that a large rigid-body rotation of a substrate-binding domain gives the conserved `crossover' region, where two discontinuous helices cross each other, alternating accessibility from either side of the cell membrane. This result has implications

  4. 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.

  5. Use of Omega-3 Polyunsaturated Fatty Acids to Treat Inspissated Bile Syndrome: A Case Report

    Science.gov (United States)

    Jun, Woo Young; Cho, Min Jeng; Han, Hye Seung

    2016-01-01

    Inspissated bile syndrome (IBS) is a rare condition in which thick intraluminal bile, including bile plugs, sludge, or stones, blocks the extrahepatic bile ducts in an infant. A 5-week-old female infant was admitted for evaluation of jaundice and acholic stool. Diagnostic tests, including ultrasound sonography, magnetic resonance cholangiopancreatography, and a hepatobiliary scan, were not conclusive. Although the diagnosis was unclear, the clinical and laboratory findings improved gradually on administration of urodeoxycholic acid and lipid emulsion containing omega-3 polyunsaturated fatty acids (PUFAs) for 3 weeks. However, a liver biopsy was suggestive of biliary atresia. This finding forced us to perform intraoperative cholangiography, which revealed a patent common bile duct with impacted thick bile. We performed normal saline irrigation and the symptom was improved, the final diagnosis was IBS. Thus, we herein report that IBS can be treated with omega-3 PUFAs as an alternative to surgical intervention. PMID:28090475

  6. Net acid excretion during first week of life.

    Science.gov (United States)

    Chan, L L; Balfe, J W; Exeni, R; Cifuentes, R F; Bryan, M H; Atkinson, S A

    1981-03-01

    Metabolic acidosis occurs frequently in newborns. Net acid excretion (NAE) in 34 preterm and 12 term infants was measured during the first week of life. Twenty preterm infants received breast milk or formula; the remaining infants received total parenteral nutrition (TPN) -- synthetic amino acids or casein hydrolysate solution. NAE for breast milk vs formula fed infants was 5.4 +/- 0.4 and 7.8 +/- 0.6 muEq/min/m2 (mean +/- SEM). The corresponding values for the two TPN solutions in preterm infants were significantly higher at 12.5 +/- 1.4 and 19.4 +/- 3.5 muEq/min/m2. Term infants produced even greater amount of net acid, 20.6 +/- 2.9 and 35 +/- 3.7 muEq/min/m2 respectively for the two TPN solutions. Milk fed infants are less prone to acidosis because of base generated from milk consumption. Due to its inherent acidogenic effect, TPN solutions induce acidosis more readily. Infants receiving TPN are therefore required to generate a higher NAE rate to maintain acid-base homeostasis compared to milk fed infants.

  7. Dysfunction of organic anion transporting polypeptide 1a1 alters intestinal bacteria and bile acid metabolism in mice.

    Directory of Open Access Journals (Sweden)

    Youcai Zhang

    Full Text Available Organic anion transporting polypeptide 1a1 (Oatp1a1 is predominantly expressed in liver and is able to transport bile acids (BAs in vitro. Male Oatp1a1-null mice have increased concentrations of taurodeoxycholic acid (TDCA, a secondary BA generated by intestinal bacteria, in both serum and livers. Therefore, in the present study, BA concentrations and intestinal bacteria in wild-type (WT and Oatp1a1-null mice were quantified to investigate whether the increase of secondary BAs in Oatp1a1-null mice is due to alterations in intestinal bacteria. The data demonstrate that Oatp1a1-null mice : (1 have similar bile flow and BA concentrations in bile as WT mice; (2 have a markedly different BA composition in the intestinal contents, with a decrease in conjugated BAs and an increase in unconjugated BAs; (3 have BAs in the feces that are more deconjugated, desulfated, 7-dehydroxylated, 3-epimerized, and oxidized, but less 7-epimerized; (4 have 10-fold more bacteria in the small intestine, and 2-fold more bacteria in the large intestine which is majorly due to a 200% increase in Bacteroides and a 30% reduction in Firmicutes; and (5 have a different urinary excretion of bacteria-related metabolites than WT mice. In conclusion, the present study for the first time established that lack of a liver transporter (Oatp1a1 markedly alters the intestinal environment in mice, namely the bacteria composition.

  8. Bile Acids, FXR, and Metabolic Effects of Bariatric Surgery

    Directory of Open Access Journals (Sweden)

    Olivier F. Noel

    2016-01-01

    Full Text Available Overweight and obesity represent major risk factors for diabetes and related metabolic diseases. Obesity is associated with a chronic and progressive inflammatory response leading to the development of insulin resistance and type 2 diabetes (T2D mellitus, although the precise mechanism mediating this inflammatory process remains poorly understood. The most effective intervention for the treatment of obesity, bariatric surgery, leads to glucose normalization and remission of T2D. Recent work in both clinical studies and animal models supports bile acids (BAs as key mediators of these effects. BAs are involved in lipid and glucose homeostasis primarily via the farnesoid X receptor (FXR transcription factor. BAs are also involved in regulating genes involved in inflammation, obesity, and lipid metabolism. Here, we review the novel role of BAs in bariatric surgery and the intersection between BAs and immune, obesity, weight loss, and lipid metabolism genes.

  9. Bile-acid-induced cell injury and protection

    Institute of Scientific and Technical Information of China (English)

    Maria J Perez; Oscar Briz

    2009-01-01

    Several studies have characterized the cellular and molecular mechanisms of hepatocyte injury caused by the retention of hydrophobic bile acids (BAs) in cholestatic diseases. BAs may disrupt cell membranes through their detergent action on lipid components and can promote the generation of reactive oxygen species that, in turn, oxidatively modify lipids, proteins, and nucleic acids, and eventually cause hepatocyte necrosis and apoptosis. Several pathways are involved in triggering hepatocyte apoptosis. Toxic BAs can activate hepatocyte death receptors directly and induce oxidative damage, thereby causing mitochondrial dysfunction, and induce endoplasmic reticulum stress. When these compounds are taken up and accumulate inside biliary cells, they can also cause apoptosis. Regarding extrahepatic tissues, the accumulation of BAs in the systemic circulation may contribute to endothelial injury in the kidney and lungs. In gastrointestinal cells, BAs may behave as cancer promoters through an indirect mechanism involving oxidative stress and DNA damage, as well as acting as selection agents for apoptosis-resistant cells. The accumulation of BAs may have also deleterious effects on placental and fetal cells. However, other BAs, such as ursodeoxycholic acid, have been shown to modulate BA-induced injury in hepatocytes. The major beneficial effects of treatment with ursodeoxycholic acid are protection against cytotoxicity due to more toxic BAs; the stimulation of hepatobiliary secretion; antioxidant activity, due in part to an enhancement in glutathione levels; and the inhibition of liver cell apoptosis. Other natural BAs or their derivatives, such as cholyl-Nmethylglycine or cholylsarcosine, have also aroused pharmacological interest owing to their protective properties.

  10. Deconjugation of Bile Acids with Immobilized Genetically Engineered Lactobacillus plantarum 80(pCBH1

    Directory of Open Access Journals (Sweden)

    M. L. Jones

    2005-01-01

    Full Text Available Bile acids are important to normal human physiology. However, bile acids can be toxic when produced in pathologically high concentrations in hepatobileary and other diseases. This study shows that immobilized genetically engineered Lactobacillus plantarum 80 (pCBH1 (LP80 (pCBH1 can efficiently hydrolyze bile acids and establishes a basis for their use. Results show that immobilized LP80 (pCBH1 is able to effectively break down the conjugated bile acids into glycodeoxycholic acid (GDCA and taurodeoxycholic acid (TDCA with bile salt hydrolase (BSH activities of 0.17 and 0.07 μmol DCA/mg CDW/h, respectively. The deconjugation product, deoxycholic acid (DCA, was diminished by LP80 (pCBH1 within 4 h of initial BSH activity. This in-vitro study suggests that immobilized genetically engineered bacterial cells have important potential for deconjugation of bile acids for lowering of high levels of bile acids for therapy.

  11. Reduced fecal sterol excretion in subjects with familial hypoalphalipoproteinemia

    NARCIS (Netherlands)

    El Harchaoui, Karim; Franssen, Remco; Hovingh, G. Kees; Bisoendial, Radjesh J.; Stellaard, Frans; Kuipers, Folkert; Kastelein, John J. P.; Kuivenhoven, Jan Albert; Stroes, Erik S. G.; Groen, Albert K.

    2009-01-01

    BACKGROUND: Fecal bile acid and neutral sterol excretion are the obligate endpoints of the reverse cholesterol transport pathway (RCT). In studies in mice, no evidence was found for a relation between HDL-cholesterol (HDL-c) levels and fecal sterol excretion. In this study, we have evaluated this re

  12. Iron-regulated excretion of alpha-keto acids by Salmonella typhimurium.

    OpenAIRE

    Reissbrodt, R.; Kingsley, R; Rabsch, W.; Beer, W.; Roberts, M.; Williams, P H

    1997-01-01

    Excretion of alpha-keto acids by clinical isolates and laboratory strains of Salmonella typhimurium was determined by high-performance liquid chromatography analysis of culture supernatants. The levels of excretion increased markedly with increasing iron stress imposed by the presence of alpha,alpha'-dipyridyl or conalbumin in the medium. The major product was pyruvic acid, but significant concentrations of alpha-ketoglutaric acid, alpha-ketoisovaleric acid, and alpha-ketoisocaproic acid were...

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

    Energy Technology Data Exchange (ETDEWEB)

    Scanff, P.; Souidi, M.; Grison, S.; Griffiths, N.M.; Gourmelon, P. [Inst. de Radioprotection et de Surete Nucleaire, (IRSN), Direction de la RadioProtection de l' Homme, Service de Radiobiologie et d' Epidemiologie, Fontenay-aux-Roses, CEDEX (France)]. E-mail: pascale.scanff@irsn.fr

    2004-02-01

    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)

  14. 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...

  15. Bile Acid Scaffolds in Supramolecular Chemistry: The Interplay of Design and Synthesis

    Directory of Open Access Journals (Sweden)

    Anthony P. Davis

    2007-08-01

    Full Text Available Since early work in the 1980s, the bile acids have become well established as building blocks for supramolecular chemistry. The author’s laboratory has specialised in converting cholic acid, the archetypal bile acid, into macrocyclic and acyclic receptors for anions and carbohydrates. This review highlights the synthetic aspects of this work, especially the use of modern synthetic methodology to perform less obvious structural transformations.

  16. Hydrogen-Abstraction, Energy Transfer and Exciplex Formation in Photoactive Systems Based on Bile Acids

    OpenAIRE

    Miró Richart, Paula

    2016-01-01

    [EN] Bile acids are a family of amphiphilic steroids that play a pivotal role in physiological functions such as elimination of cholesterol or solubilization of lipids. Chemically, they share a steroidal skeleton with an unusual cis fusion between rings A and B, a short lateral chain ending in a carboxylic acid moiety and different number of hydroxyl groups on the alpha-face. Hence, bile acids offer a versatile architecture that can be used to investigate photophysical processes of interest ...

  17. Inhibition of ileal bile acid transporter: An emerging therapeutic strategy for chronic idiopathic constipation.

    Science.gov (United States)

    Mosińska, Paula; Fichna, Jakub; Storr, Martin

    2015-06-28

    Chronic idiopathic constipation is a common disorder of the gastrointestinal tract that encompasses a wide profile of symptoms. Current treatment options for chronic idiopathic constipation are of limited value; therefore, a novel strategy is necessary with an increased effectiveness and safety. Recently, the inhibition of the ileal bile acid transporter has become a promising target for constipation-associated diseases. Enhanced delivery of bile acids into the colon achieves an accelerated colonic transit, increased stool frequency, and relief of constipation-related symptoms. This article provides insight into the mechanism of action of ileal bile acid transporter inhibitors and discusses their potential clinical use for pharmacotherapy of constipation in chronic idiopathic constipation.

  18. Adsorption of bile acid by chitosan salts prepared with cinnamic acid and analogue compounds.

    Science.gov (United States)

    Murata, Yoshifumi; Nagaki, Kumiko; Kofuji, Kyouko; Sanae, Fujiko; Kontani, Hitoshi; Kawashima, Susumu

    2006-01-01

    A chitosan (CS) powder treated with cinnamic acid and an analogue compound (CN) was prepared as CS-CN. Using it, bile acid adsorption by CS-CN and the release of CN were investigated in vitro. When CS-CN was soaked in a taurocholate solution, it released CN and simultaneously adsorbed the bile acid. For CS-CN prepared with cinnamic acid, the amount of CN released was 0.286 +/- 0.001 mmol/g CS-CN; the amount of taurocholate adsorbed was 0.284 +/- 0.003 mmol/g CS-CN. These two functions were recognized on alginate or pectin gel beads containing CS-CN. The amount of released CN was altered extensively by the species of CN used for gel-bead preparation. Results suggest that CS-CN is a candidate for complementary medicine to prevent lifestyle-related diseases.

  19. 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.

  20. Steam Cooking Significantly Improves in Vitro Bile Acid Binding of Beets, Eggplant, Asparagus, Carrots, Green Beans and Cauliflower

    Science.gov (United States)

    The relative healthful potential of cooked beets, okra, eggplant, asparagus, carrots, green beans, cauliflower and turnips was evaluated by determining their in vitro bile acid binding using a mixture of bile acids secreted in human bile at a duodenal physiological pH of 6.3. Six treatments and two...

  1. Reference standard for serum bile acids in pregnancy.

    LENUS (Irish Health Repository)

    2012-01-31

    Please cite this paper as: Egan N, Bartels A, Khashan A, Broadhurst D, Joyce C, O\\'Mullane J, O\\'Donoghue K. Reference standard for serum bile acids in pregnancy. BJOG 2012;00:000-000. DOI: 10.1111\\/j.1471-0528.2011.03245.x. Objective Obstetric cholestasis (OC) is a liver disorder characterised by pruritus and elevated serum bile acids (SBA) that affects one in 200 pregnant women. It is associated with adverse perinatal outcomes such as premature delivery and stillbirth. Mild OC is defined as SBA levels of 10-39 mumol\\/l, and severe OC is defined by levels >40 mumol\\/l. SBA levels in normal pregnancy have not been investigated. We aimed to establish reference values for SBA in healthy pregnant women across different trimesters of pregnancy. Design Cross-sectional analysis of SBA levels. Setting A large tertiary referral university teaching maternity hospital. Population Healthy pregnant women with a singleton pregnancy and a body mass index (BMI) < 40, excluding women with significant alcohol intake, history of liver disease, prior cholecystectomy and OC. Methods Cross-sectional analysis of SBA levels at 12, 20, 28 and 36 weeks of gestation, and on days 1-3 postpartum. Main outcome measures SBA levels in mumol\\/l. Results A total of 219 women attending for antenatal care were recruited, and SBA levels were assayed at 12, 20, 28 and 36 weeks of gestation, and up to 72 hours postpartum (n = 44-49 cases at each stage). The majority were white European women, with a median age of 30 years (range 17-46 years) and median BMI of 25 (range 18-38). Values of SBA ranged from 0.3 to 9.8 mumol\\/l in 216 women, with only three measurements outside this range. There were no significant changes throughout pregnancy. Conclusions SBA values in uncomplicated pregnancies are consistent, regardless of gestation, and are not elevated in pregnancy. The current reference values for the diagnosis of OC appear to be appropriate.

  2. Organic acid excretion in Penicillium ochrochloron increases with ambient pH

    Directory of Open Access Journals (Sweden)

    Pamela eVrabl

    2012-04-01

    Full Text Available Despite being of high biotechnological relevance, many aspects of organic acid excretion in filamentous fungi like the influence of ambient pH are still insufficiently understood. While the excretion of an individual organic acid may peak at a certain pH value, the few available studies investigating a broader range of organic acids indicate that total organic acid excretion rises with increasing external pH.We hypothesized that this phenomenon might be a general response of filamentous fungi to increased ambient pH. If this is the case, the observation should be widely independent of the organism, growth conditions or experimental design and might therefore be a crucial key point in understanding the function and mechanisms of organic acid excretion in filamentous fungi.In this study we explored this hypothesis using ammonium limited chemostat cultivations (pH 2-7, and ammonium or phosphate limited bioreactor batch cultivations (pH 5 and 7. Two strains of Penicillium ochrochloron were investigated differing in the spectrum of excreted organic acids.Confirming our hypothesis, the main result demonstrated that organic acid excretion in P. ochrochloron was enhanced at high external pH levels compared to low pH levels independent of the tested strain, nutrient limitation and cultivation method. We discuss these findings against the background of three hypotheses explaining organic acid excretion in filamentous fungi, i.e. overflow metabolism, charge balance and aggressive acidification hypothesis.

  3. 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.

  4. Alteration of bile acid metabolism in pseudo germ-free rats [corrected].

    Science.gov (United States)

    Bhowmik, Salil Kumar; An, Ji Hye; Lee, Soo Hyun; Jung, Byung Hwa

    2012-11-01

    To characterize the impact of gut microbiota on host bile acid metabolism, we investigated the metabolic profiles of oxysterols and bile acids (BAs) in a conventional rat model (SD) (n=5) and its pseudo germ-free (GF) equivalent (n=5). GF rats were developed by the oral administration of bacitracin, neomycin and streptomycin (200 mg/kg, each) twice a day for 6 days. Urinary levels of oxysterols and bile acid metabolites were quantified using gas chromatography-mass spectrometry (GC-MS). The activity levels of enzymes involved in the bile acid metabolic pathway were determined through urinary concentration ratio between product to precursor. Cholic acid (CA) and α-/β-muricholic acid (α-/β-MCA) were significantly elevated at pseudo germ-free condition. An increase of hydroxylase (cholesterol 7α-hydroxylase, oxysterol 7α-hydroxylase and cytochrome P450 scc) and a significant decrease of 7α-dehydroxylase were observed. The urinary concentration ratio of primary bile acids, a marker for hepatotoxicity, increased in pseudo germfree conditions. Therefore, it was found that gut microbiota could play a significant role in the bile acids homeostasis and metabolism.

  5. Bile salt recognition by human liver fatty acid binding protein.

    Science.gov (United States)

    Favretto, Filippo; Santambrogio, Carlo; D'Onofrio, Mariapina; Molinari, Henriette; Grandori, Rita; Assfalg, Michael

    2015-04-01

    Fatty acid binding proteins (FABPs) act as intracellular carriers of lipid molecules, and play a role in global metabolism regulation. Liver FABP (L-FABP) is prominent among FABPs for its wide ligand repertoire, which includes long-chain fatty acids as well as bile acids (BAs). In this work, we performed a detailed molecular- and atomic-level analysis of the interactions established by human L-FABP with nine BAs to understand the binding specificity for this important class of cholesterol-derived metabolites. Protein-ligand complex formation was monitored using heteronuclear NMR, steady-state fluorescence spectroscopy, and mass spectrometry. BAs were found to interact with L-FABP with dissociation constants in the narrow range of 0.6-7 μm; however, the diverse substitution patterns of the sterol nucleus and the presence of side-chain conjugation resulted in complexes endowed with various degrees of conformational heterogeneity. Trihydroxylated BAs formed monomeric complexes in which single ligand molecules occupied similar internal binding sites, based on chemical-shift perturbation data. Analysis of NMR line shapes upon progressive addition of taurocholate indicated that the binding mechanism departed from a simple binary association equilibrium, and instead involved intermediates along the binding path. The co-linear chemical shift behavior observed for L-FABP complexes with cholate derivatives added insight into conformational dynamics in the presence of ligands. The observed spectroscopic features of L-FABP/BA complexes, discussed in relation to ligand chemistry, suggest possible molecular determinants of recognition, with implications regarding intracellular BA transport. Our findings suggest that human L-FABP is a poorly selective, universal BA binder.

  6. 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 hepatocytes

  7. Cholesterol absorption and excretion in ileostomy subjects on high- and low-dietary-cholesterol intakes.

    Science.gov (United States)

    Ellegård, L; Bosaeus, I

    1994-01-01

    Six healthy ileostomy subjects were given [3H]cholesterol and [14C]beta-sitosterol in a single meal together with two controlled diets containing 150 or 450 mg cholesterol/d. Each diet was eaten for 3 d. Cholesterol absorption and excretion of cholesterol, bile acids, fat, energy, and nitrogen were analyzed. Fractional cholesterol absorption increased from 44 +/- 2.6% (mean +/- SE) to 61 +/- 3.4% (P effluent, or excretion of energy, nitrogen, fat, and bile acids did not differ between periods. Endogenous cholesterol excretion remained unchanged whereas net cholesterol excretion (output minus intake) was 37% higher (P < 0.05) on low compared with high cholesterol intake.

  8. 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

    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 be implic......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...... be implicated in postprandial glucose metabolism. OBJECTIVE: To describe postprandial plasma concentrations of 12 individual bile acids and FGF-19 in patients with type 2 diabetes (T2D) and healthy controls. DESIGN AND SETTING: Descriptive study, performed at the Center for Diabetes Research, Gentofte Hospital...... and FGF-19 concentrations. RESULTS: Postprandial total bile acid concentrations increased with increasing meal fat content (P

  9. Xenobiotic, bile acid, and cholesterol transporters: function and regulation.

    Science.gov (United States)

    Klaassen, Curtis D; Aleksunes, Lauren M

    2010-03-01

    Transporters influence the disposition of chemicals within the body by participating in absorption, distribution, and elimination. Transporters of the solute carrier family (SLC) comprise a variety of proteins, including organic cation transporters (OCT) 1 to 3, organic cation/carnitine transporters (OCTN) 1 to 3, organic anion transporters (OAT) 1 to 7, various organic anion transporting polypeptide isoforms, sodium taurocholate cotransporting polypeptide, apical sodium-dependent bile acid transporter, peptide transporters (PEPT) 1 and 2, concentrative nucleoside transporters (CNT) 1 to 3, equilibrative nucleoside transporter (ENT) 1 to 3, and multidrug and toxin extrusion transporters (MATE) 1 and 2, which mediate the uptake (except MATEs) of organic anions and cations as well as peptides and nucleosides. Efflux transporters of the ATP-binding cassette superfamily, such as ATP-binding cassette transporter A1 (ABCA1), multidrug resistance proteins (MDR) 1 and 2, bile salt export pump, multidrug resistance-associated proteins (MRP) 1 to 9, breast cancer resistance protein, and ATP-binding cassette subfamily G members 5 and 8, are responsible for the unidirectional export of endogenous and exogenous substances. Other efflux transporters [ATPase copper-transporting beta polypeptide (ATP7B) and ATPase class I type 8B member 1 (ATP8B1) as well as organic solute transporters (OST) alpha and beta] also play major roles in the transport of some endogenous chemicals across biological membranes. This review article provides a comprehensive overview of these transporters (both rodent and human) with regard to tissue distribution, subcellular localization, and substrate preferences. Because uptake and efflux transporters are expressed in multiple cell types, the roles of transporters in a variety of tissues, including the liver, kidneys, intestine, brain, heart, placenta, mammary glands, immune cells, and testes are discussed. Attention is also placed upon a variety of

  10. Bile acid diarrhoea and FGF19: new views on diagnosis, pathogenesis and therapy.

    Science.gov (United States)

    Walters, Julian R F

    2014-07-01

    Chronic diarrhoea induced by bile acids is common and the underlying mechanisms are linked to homeostatic regulation of hepatic bile acid synthesis by fibroblast growth factor 19 (FGF19). Increasing evidence, including that from several large case series using SeHCAT (selenium homocholic acid taurine) tests for diagnosis, indicates that bile acid diarrhoea (BAD) accounts for a sizeable proportion of patients who would otherwise be diagnosed with IBS. Studies of other approaches for diagnosis of BAD have shown increased bile acid synthesis, increased faecal levels of primary bile acids, dysbiosis and different urinary volatile organic compounds when compared with healthy controls or with other diseases. The role of the ileal hormone FGF19 in BAD has been strengthened: a prospective clinical study has confirmed low FGF19 levels in BAD, and so a test to measure these levels could be developed for diagnosis. In animal models, FGF19 depletion by antibodies produces severe diarrhoea. Bile acids affect colonic function through farnesoid X receptor (FXR) and TGR5 receptors. As well as these effects in the colon, FXR-dependent stimulation of ileal FGF19 production could be a logical mechanism to provide therapeutic benefit in BAD. Further studies of FGF19 in humans hold promise in providing novel treatments for this cause of chronic diarrhoea.

  11. Review: Mechanisms of How the Intestinal Microbiota Alters the Effects of Drugs and Bile Acids.

    Science.gov (United States)

    Klaassen, Curtis D; Cui, Julia Yue

    2015-10-01

    Information on the intestinal microbiota has increased exponentially this century because of technical advancements in genomics and metabolomics. Although information on the synthesis of bile acids by the liver and their transformation to secondary bile acids by the intestinal microbiota was the first example of the importance of the intestinal microbiota in biotransforming chemicals, this review will discuss numerous examples of the mechanisms by which the intestinal microbiota alters the pharmacology and toxicology of drugs and other chemicals. More specifically, the altered pharmacology and toxicology of salicylazosulfapridine, digoxin, l-dopa, acetaminophen, caffeic acid, phosphatidyl choline, carnitine, sorivudine, irinotecan, nonsteroidal anti-inflammatory drugs, heterocyclic amines, melamine, nitrazepam, and lovastatin will be reviewed. In addition, recent data that the intestinal microbiota alters drug metabolism of the host, especially Cyp3a, as well as the significance and potential mechanisms of this phenomenon are summarized. The review will conclude with an update of bile acid research, emphasizing the bile acid receptors (FXR and TGR5) that regulate not only bile acid synthesis and transport but also energy metabolism. Recent data indicate that by altering the intestinal microbiota, either by diet or drugs, one may be able to minimize the adverse effects of the Western diet by altering the composition of bile acids in the intestine that are agonists or antagonists of FXR and TGR5. Therefore, it may be possible to consider the intestinal microbiota as another drug target.

  12. Reconstitution of bile acid transport in the rat hepatoma McArdle RH-7777 cell line.

    Science.gov (United States)

    Torchia, E C; Shapiro, R J; Agellon, L B

    1996-07-01

    The liver recovers bile acids from the portal circulation primarily via an active process that is dependent on sodium ions. Hepatocytes lose the ability to transport bile acids in culture, and, in liver-derived permanent cell lines, this ability is severely reduced or absent. To study the importance of bile acids in regulating liver-specific functions (e.g., cellular bile acid and cholesterol metabolism), we have re-established active bile acid transport in cultured cells. The complementary DNA (cDNA) encoding the rat sodium/taurocholate cotransporting polypeptide (ntcp) was placed under the control of a cytomegalovirus promoter and transfected into the rat hepatoma cell line, McArdle RH-7777. Transfected cells were screened for the ability to take up [3H]-taurocholate. Clones that displayed the ability to take up taurocholate were expanded (designated McNtcp) and further characterized. The apparent Michaelis constant (Km) for taurocholate uptake was similar among the different clones. The observed maximum velocity (Vmax), however, differed and was positively correlated with the abundance of recombinant ntcp messenger RNA (mRNA). The highest level of taurocholate uptake activity observed in McNtcp cells was comparable with that of freshly isolated hepatocytes. Efflux of accumulated taurocholate from McNtcp cells proceeded in a manner similar to primary hepatocytes, indicating that McArdle RH-7777 cells have retained the ability to secrete bile acids. Moreover, taurocholate uptake in McNtcp cells was inhibited by other bile acid species. Based on the observed kinetic parameters, the reconstituted McArdle RH-7777 cells mimic the ability of primary hepatocytes to transport bile acids.

  13. Amino acid-bile acid based molecules: extremely narrow surfactant nanotubes formed by a phenylalanine-substituted cholic acid.

    Science.gov (United States)

    Travaglini, Leana; D'Annibale, Andrea; Schillén, Karin; Olsson, Ulf; Sennato, Simona; Pavel, Nicolae V; Galantini, Luciano

    2012-12-21

    An amino acid-substituted bile acid forms tubular aggregates with inner and outer diameters of about 3 and 6 nm. The diameters are unusually small for surfactant self-assembled tubes. The results enhance the spectrum of applications of supramolecular tubules and open up possibilities for investigating a novel class of biological amphiphiles.

  14. Long-term effect of wholemeal bread on stool weight, transit time, fecal bile acids, fats, and neutral sterols.

    Science.gov (United States)

    Eastwood, M A; Elton, R A; Smith, J H

    1986-03-01

    Stool weight, fecal constituents, bile acids, fat, neutral sterols, and intestinal transit time were recorded in 28 subjects over 18 mo. During the first 12 mo the subjects ate white bread. They were studied for an initial period of 7 days, and after 6 mo (study period 1). For the first 6 mo they ate their usual intake of bread, they then increased their white bread intake by 62 g/day for 6 mo (study period 2). The subjects ate a self-selected diet throughout the 18 mo study. During the last 6 mo (study period 3) the subjects replaced white bread by the same amount of wholemeal bread as in study period 2. No increase in stool weight occurred until study period 3 when there was an increase of 20%. There developed a linear relationship between stool weight and intestinal transit time which was not found during the initial first and second study periods. A seasonal influence on serum cholesterol was not observed during the wholemeal bread period. Fecal bile acid excretion was unchanged throughout the experiment.

  15. Renal excretion of vanillylmandelic acid and homovanillic acid in rats with paw edema or adjuvant arthritis.

    Science.gov (United States)

    Krause, E; Horn, M

    1982-01-01

    1. Urinary excretion of unconjugated vanillylmandelic acid (VMA) and homovanillic acid (HVA) was found to be decreased in adjuvant arthritic rats. The decrease is apparently not due to impaired animal activity, but it could be explained by the reduction of catecholamine biosynthesis and/or release induced by E prostaglandins the biosynthesis of which is increased in the inflammation. It could also be caused by an increased "consumption" of catecholamines during prostaglandin biosynthesis. 2. Both the reduction of biosynthesis or release and an increased "consumption" of catecholamines would mean that inflammation is characterized by deficiency of the anti-inflammatory catecholamines. 3. The investigations failed to demonstrate an adequate decrease of the urinary excretion of VMA and HVA in rats with edemas induced by carrageenin, serotonin, formaline, silver nitrate, kaolin, dextran and baker's yeast, respectively. The experiments should be repeated with other catecholamine metabolites.

  16. Reliability of Urinary Excretion Rate Adjustment in Measurements of Hippuric Acid in Urine

    Directory of Open Access Journals (Sweden)

    Annamaria Nicolli

    2014-07-01

    Full Text Available The urinary excretion rate is calculated based on short-term, defined time sample collections with a known sample mass, and this measurement can be used to remove the variability in urine concentrations due to urine dilution. Adjustment to the urinary excretion rate of hippuric acid was evaluated in 31 healthy volunteers (14 males and 17 females. Urine was collected as short-term or spot samples and tested for specific gravity, creatinine and hippuric acid. Hippuric acid values were unadjusted or adjusted to measurements of specific gravity, creatinine or urinary excretion rate. Hippuric acid levels were partially independent of urinary volume and urinary flow rate, in contrast to specific gravity and creatinine, which were both highly dependent on the hippuric acid level. Accordingly, hippuric acid was independent on urinary specific gravity and creatinine excretion. Unadjusted and adjusted values for specific gravity or creatinine were generally closely correlated, especially in spot samples. Values adjusted to the urinary excretion rate appeared well correlated to those unadjusted and adjusted to specific gravity or creatinine values. Thus, adjustment of crude hippuric acid values to the urinary excretion rate is a valid procedure but is difficult to apply in the field of occupational medicine and does not improve the information derived from values determined in spot urine samples, either unadjusted or adjusted to specific gravity and creatinine.

  17. Dexamethasone exposure of neonatal rats modulates biliary lipid secretion and hepatic expression of genes controlling bile acid metabolism in adulthood without interfering with primary bile acid kinetics

    NARCIS (Netherlands)

    Liu, Yan; Havinga, Rick; Van der Leij, Feike R.; Boverhof, Renze; Sauer, Pieter J. J.; Kuipers, Folkert; Stellaard, Frans

    2008-01-01

    Literature suggests that glucocorticoid (GC) exposure during early life may have long-term consequences into adult life. GCs are known to influence hepatic bile acid synthesis and their transport within the enterohepatic circulation. This study addresses effects of early postnatal exposure to GC on

  18. Cholesterol excretion and colon cancer.

    Science.gov (United States)

    Broitman, S A

    1981-09-01

    Populations consuming diets high in fat and cholesterol exhibit a greater incidence of colon cancer than those consuming less fat and cholesterol. Lowering elevated serum cholesterol levels experimentally or clinically is associated with increased large-bowel tumorigenesis. Thus, cholesterol lost to the gut, either dietary or endogenously synthesized, appears to have a role in large-bowel cancer. Whether the effect(s) is mediated by increases in fecal bile acid excretion or some other mechanism is not clear.

  19. Influence of acid and bile acid on ERK activity, PPARY expression and cell proliferation in normal human esophageal epithelial cells

    Institute of Scientific and Technical Information of China (English)

    Zhi-Ru Jiang; Jun Gong; Zhen-Ni Zhang; Zhe Qiao

    2006-01-01

    AIM: To observe the effects of acid and bile acid exposure on cell proliferation and the expression of extracellular signal-regulated protein kinase (ERK) and peroxisome proliferator-activated receptor Y (PPARy) in normal human esophageal epithelial cells in vitro.METHODS: In vitro cultured normal human esophageal epithelial cells were exposed to acidic media (pH 4.0-6.5), media containing different bile acid (250 μmol/L), media containing acid and bile acid, respectively.Cell proliferation was assessed using MTT and flow cytometry. The expressions of phosphorylated ERK1/2 and PPARy protein were determined by the immunoblotting technique.RESULTS: Acid-exposed (3 min) esophageal cells exhibited a significant increase in proliferation ratio,S phase of the cell cycle (P<0.05) and the level of phosphorylated ERK1/2 protein. When the acid-exposure period exceeded 6 min, we observed a decrease in proliferation ratio and S phase of the cell cycle, with an increased apoptosis ratio (P<0.05). Bile acid exposure (3-12 min) also produced an increase in proliferation ratio, S phase of the cell cycle (P<0.05)and phosphorylated ERK1/2 expression. On the contrary,deoxycholic acid (DCA) exposure (>20 min) decreased proliferation ratio. Compared with bile acid exposure (pH 7.4), bile acid exposure (pH 6.5, 4) significantly decreased proliferation ratio (P<0.05). There was no expression of PPARY in normal human esophageal epithelial cells.CONCLUSION: The rapid stimuli of acid or bile acid increase proliferation in normal human esophageal epithelial cells by activating the ERK pathway.

  20. Importance of Large Intestine in Regulating Bile Acids and Glucagon-Like Peptide-1 in Germ-Free Mice.

    Science.gov (United States)

    Selwyn, Felcy Pavithra; Csanaky, Iván L; Zhang, Youcai; Klaassen, Curtis D

    2015-10-01

    It is known that 1) elevated serum bile acids (BAs) are associated with decreased body weight, 2) elevated glucagon-like peptide-1 (GLP-1) levels can decrease body weight, and 3) germ-free (GF) mice are resistant to diet-induced obesity. The purpose of this study was to test the hypothesis that a lack of intestinal microbiota results in more BAs in the body, resulting in increased BA-mediated transmembrane G protein-coupled receptor 5 (TGR5) signaling and increased serum GLP-1 as a mechanism of resistance of GF mice to diet-induced obesity. GF mice had 2- to 4-fold increased total BAs in the serum, liver, bile, and ileum. Fecal excretion of BAs was 63% less in GF mice. GF mice had decreased secondary BAs and increased taurine-conjugated BAs, as anticipated. Surprisingly, there was an increase in non-12α-OH BAs, namely, β-muricholic acid, ursodeoxycholic acid (UDCA), and their taurine conjugates, in GF mice. Further, in vitro experiments confirmed that UDCA is a primary BA in mice. There were minimal changes in the mRNA of farnesoid X receptor target genes in the ileum (Fibroblast growth factor 15, small heterodimer protein, and ileal bile acid-binding protein), in the liver (small heterodimer protein, liver receptor homolog-1, and cytochrome P450 7a1), and BA transporters (apical sodium dependent bile acid transporter, organic solute transporter α, and organic solute transporter β) in the ileum of GF mice. Surprisingly, there were marked increases in BA transporters in the large intestine. Increased GLP-1 levels and gallbladder size were observed in GF mice, suggesting activation of TGR5 signaling. In summary, the GF condition results in increased expression of BA transporters in the colon, resulting in 1) an increase in total BA concentrations in tissues, 2) a change in BA composition to favor an increase in non-12α-OH BAs, and 3) activation of TGR5 signaling with increased gallbladder size and GLP-1.

  1. Ileal mucosal bile acid absorption is increased in Cftr knockout mice

    Directory of Open Access Journals (Sweden)

    Somasundaram Sivagurunathan

    2001-10-01

    Full Text Available Abstract Background Excessive loss of bile acids in stool has been reported in patients with cystic fibrosis. Some data suggest that a defect in mucosal bile acid transport may be the mechanism of bile acid malabsorption in these individuals. However, the molecular basis of this defect is unknown. This study examines the expression of the ileal bile acid transporter protein (IBAT and rates of diffusional (sodium independent and active (sodium dependent uptake of the radiolabeled bile acid taurocholate in mice with targeted disruption of the cftr gene. Methods Wild-type, heterozygous cftr (+/- and homozygous cftr (-/- mice were studied. Five one-cm segments of terminal ileum were excised, everted and mounted onto thin stainless steel rods and incubated in buffer containing tracer 3H-taurocholate. Simultaneously, adjacent segments of terminal ileum were taken and processed for immunohistochemistry and Western blots using an antibody against the IBAT protein. Results In all ileal segments, taurocholate uptake rates were fourfold higher in cftr (-/- and two-fold higher in cftr (+/- mice compared to wild-type mice. Passive uptake was not significantly higher in cftr (-/- mice than in controls. IBAT protein was comparably increased. Immuno-staining revealed that the greatest increases occurred in the crypts of cftr (-/- animals. Conclusions In the ileum, IBAT protein densities and taurocholate uptake rates are elevated in cftr (-/- mice > cftr (+/- > wild-type mice. These findings indicate that bile acid malabsorption in cystic fibrosis is not caused by a decrease in IBAT activity at the brush border. Alternative mechanisms are proposed, such as impaired bile acid uptake caused by the thick mucus barrier in the distal small bowel, coupled with a direct negative regulatory role for cftr in IBAT function.

  2. High level of deoxycholic acid in human bile does not promote cholesterol gallstone formation

    Institute of Scientific and Technical Information of China (English)

    Ulf Gustafsson; Staffan Sahlin; Curt Einarsson

    2003-01-01

    AIM: To study whether patients with excess deoxycholic acid (DCA) differ from those with normal percentage of DCA with respect to biliary lipid composition and cholesterol saturation of gallbladder bile.METHODS: Bile was collected during operation through puncturing into the gallbladder from 122 cholesterol gallstone patients and 46 gallstone-free subjects undergoing cholecystectomy. Clinical data, biliary lipids, bile acid composition,presence of crystals and nucleation time were analyzed.RESULTS: A subgroup of gallstone patients displayeda higher proportion of DCA in bile than gallstone free subjects.By choosing a cut-off level of the 90th percentile, a group of 13 gallstone patients with high DCA levels (mean 50percent of total bile acids) and a large group of 109 patients with normal DCA levels (mean 21 percent of total bile acids)were obtained. The mean age of the patients with high DCA levels was higher than that of the group with normal levels (mean age: 62 years vs45 years) and so was the mean BMI (28.3 vs. 24.7). Plasma levels of cholesterol and triglycerides were slightly higher in the DCA excess groups compared with those in the normal DCA group. There was no difference in biliary lipid composition, cholesterol saturation, nucleation time or occurrence of cholesterol crystals in bile between patients with high and normal levels of DCA.CONCLUSION: Gallstone patients with excess DCA were of older age and had higher BMI than patients with normal DCA. The two groups of patients did not differ with respect to biliary lipid composition, cholesterol saturation, nucleation time or occurrence of cholesterol crystals. It is concluded that DCA in bile does not seem to contribute to gallstone formation in cholesterol gallstone patients.

  3. Biliary lipid, bile acid composition, and dietary correlations in Micmac Indian women. A population study.

    Science.gov (United States)

    Williams, C N; Johnston, J L; McCarthy, S; Field, C A

    1981-01-01

    The precursor state for cholesterol gallstone formation is cholesterol-saturated bile. We studied a high-risk group for cholesterol gallstones to determine whether dietary variables affect bile cholesterol. Bile samples were analyzed from 46 Micmac Indian women without gallstones and 13 with gallstones for molar percentage cholesterol (MPC) and bile acid composition. The data were analyzed by multiple regression analysis with MPC as the dependent variable and the dietary variables, obtained from four consecutive-day food records, and biliary bile acid composition as the independent variables. In the 46 women without gallstones, obesity, calorie range/calorie intake, and iron and calcium intake were, in their order of importance, significant factors. In normal weight subjects (ponderal index > 12.5) relative obesity was still a significant correlate. Obesity and iron intake were positive correlates while calorie range/calorie intake and calcium intake varied inversely. When the effect of obesity was controlled, these factors were still significant in this group, as they were in the gallstone group. In addition, the duration of overnight fast obtained by history, together with the proportions of deoxycholic and chenodeoxycholic acids in bile were correlates of the biliary molar percentage cholesterol.

  4. RELEASE OF INTROGENOUS SUBSTANCES BY BREWER'S YEAST. 3. SHOCK EXCRETION OF AMINO ACIDS.

    Science.gov (United States)

    LEWIS, M J; PHAFF, H J

    1964-06-01

    Lewis, M. J. (University of California, Davis), and H. J. Phaff. Release of nitrogenous substances by brewers' yeast. III. Shock excretion of amino acids. J. Bacteriol. 87:1389-1396. 1964.-When Saccharomyces carlsbergensis (two strains) and S. cerevisiae (one strain) were grown in static culture and the harvested, washed cells were suspended in a solution of glucose, amino acids were suddenly released and then rapidly reabsorbed in a space of about 2 hr. The phenomenon of amino acid release, which was termed shock excretion, varied in intensity with the strain of yeast and was shown to be dependent on the size of the pool of free amino acids within the cells. Shock excretion was independent of osmotic pressure of the suspending medium, but required the presence of a fermentable sugar. d-Galactose and maltose caused shock excretion only when yeast was previously adapted to these sugars. Limiting glucose concentrations prevented reabsorption of amino acids, and a further decrease in glucose concentration also limited excretion. Shock excretion was strikingly reduced when the temperature of the suspending medium was lowered.

  5. Bile acid and immunosuppressive therapy in primary biliary cirrhosis

    NARCIS (Netherlands)

    F.H.J. Wolfhagen (Franciscus)

    1995-01-01

    textabstractPrimary Biliary Cirrhosis (PBC) is a chronic, cholestatic liver disease characterized by non-suppurative destruction of interlobular and septal bile ducts, with subsequent liver damage and eventually development of cirrhosis. The disease is relatively rare with an estimated annual incide

  6. Between peptides and bile acids: self-assembly of phenylalanine substituted cholic acids.

    Science.gov (United States)

    Travaglini, Leana; D'Annibale, Andrea; di Gregorio, Maria Chiara; Schillén, Karin; Olsson, Ulf; Sennato, Simona; Pavel, Nicolae V; Galantini, Luciano

    2013-08-01

    Biocompatible molecules that undergo self-assembly are of high importance in biological and medical applications of nanoscience. Peptides and bile acids are among the most investigated due to their ability to self-organize into many different, often stimuli-sensitive, supramolecular structures. With the aim of preparing molecules mixing the aggregation properties of bile acid and amino acid-based molecules, we report on the synthesis and self-association behavior of two diastereomers obtained by substituting a hydroxyl group of cholic acid with a l-phenylalanine residue. The obtained molecules are amphoteric, and we demonstrate that they show a pH-dependent self-assembly. Both molecules aggregate in globular micelles at high pH, whereas they form tubular superstructures under acid conditions. Unusual narrow nanotubes with outer and inner cross-section diameters of about 6 and 3 nm are formed by the derivatives. The diasteroisomer with α orientation of the substituent forms in addition a wider tubule (17 nm cross-section diameter). The ability to pack in supramolecular tubules is explained in terms of a wedge-shaped bola-form structure of the derivatives. Parallel or antiparallel face-to-face dimers are hypothesized as fundamental building blocks for the formation of the narrow and wide nanotubes, respectively.

  7. Effects of chronic lithium administration on renal acid excretion in humans and rats.

    Science.gov (United States)

    Weiner, I David; Leader, John P; Bedford, Jennifer J; Verlander, Jill W; Ellis, Gaye; Kalita, Priyakshi; Vos, Frederiek; de Jong, Sylvia; Walker, Robert J

    2014-12-01

    Lithium therapy's most common side effects affecting the kidney are nephrogenic diabetes insipidus (NDI) and chronic kidney disease. Lithium may also induce a distal renal tubular acidosis. This study investigated the effect of chronic lithium exposure on renal acid-base homeostasis, with emphasis on ammonia and citrate excretion. We compared 11 individuals on long-term lithium therapy with six healthy individuals. Under basal conditions, lithium-treated individuals excreted significantly more urinary ammonia than did control subjects. Following an acute acid load, urinary ammonia excretion increased approximately twofold above basal rates in both lithium-treated and control humans. There were no significant differences between lithium-treated and control subjects in urinary pH or urinary citrate excretion. To elucidate possible mechanisms, rats were randomized to diets containing lithium or regular diet for 6 months. Similar to humans, basal ammonia excretion was significantly higher in lithium-treated rats; in addition, urinary citrate excretion was also significantly greater. There were no differences in urinary pH. Expression of the critical ammonia transporter, Rhesus C Glycoprotein (Rhcg), was substantially greater in lithium-treated rats than in control rats. We conclude that chronic lithium exposure increases renal ammonia excretion through mechanisms independent of urinary pH and likely to involve increased collecting duct ammonia secretion via the ammonia transporter, Rhcg.

  8. Investigation of antibacterial, acid and bile tolerance properties of lactobacilli isolated from Koozeh cheese

    Directory of Open Access Journals (Sweden)

    Hassan Hassanzadazar

    2012-09-01

    Full Text Available Lactobacillus strains are a major part of the probiotics, microflora of the intestine and of fermented dairy products, and are found in a variety of environments. The aim of this study was to find out the ability of bile and acid tolerance and antibacterial properties of the twenty eight isolates of three group lactobacilli namely Lactobacillus plantarum, Lactobacillus casei and Lactobacillus delbruki. For this purpose Twenty eight different Lactobacillus strains that isolated from Koozeh cheese as a traditional cheese were screened. The acid tolerance test was studied under pH 2.0 and 3.0 with 7.5 as control. The cell count for the acid tolerance test was obtained at an interval of 0, 1, 2 and 3 hours respectively and was pour plated on Man, Rogosa, and Sharpe (MRS agar to be incubated at 37 °C for 24 hours. All cells were selected for bile tolerance test in MRS broth containing bile concentrations of 0% as control and 0.3% as test. Then cell counts were enumerated after 24 hours of incubation on MRS agar. Results showed twenty seven isolates did not have ability to tolerate acid and bile salts and antimicrobial activity against four indicator bacteria included Eshirichia coli, Listeria monocytogenesis, bacillus cereus, Salmonella entritidis. Only one Isolate namely Lactobacillus casei could tolerate acid and bile salt and had antibacterial activity against of L. monocytogenesis. Therefore we can consider this strain as a native probiotic but extra examinations was required.

  9. Chemoprotective effects of curcumin in esophageal epithelial cells exposed to bile acids

    Institute of Scientific and Technical Information of China (English)

    Matthew; R; Bower; Harini; S; Aiyer; Robert; CG; Martin

    2010-01-01

    AIM:To investigate the ability of curcumin to counteract the impact of bile acids on gene expression of esophageal epithelial cells.METHODS:An esophageal epithelial cell line(HET1A)was treated with curcumin in the presence of deoxycholic acid.Cell proliferation and viability assays were used to establish an appropriate dose range for curcumin.The combined and individual effects of curcumin and bile acid on cyclooxygenase-2(COX-2)and superoxide dismutase(SOD-1 and SOD-2)gene expression were also assessed.RES...

  10. 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.

  11. Effects of essential fatty acid deficiency on enterohepatic circulation of bile salts in mice

    NARCIS (Netherlands)

    Lukovac, S.; Los, E. L.; Stellaard, F.; Rings, E. H. H. M.; Verkade, H. J.

    2009-01-01

    Lukovac S, Los EL, Stellaard F, Rings EH, Verkade HJ. Effects of essential fatty acid deficiency on enterohepatic circulation of bile salts in mice. Am J Physiol Gastrointest Liver Physiol 297: G520-G531, 2009. First published July 16, 2009; doi: 10.1152/ajpgi.00091.2009.-Essential fatty acid (EFA)

  12. Bile Acids in Polycystic Liver Diseases: Triggers of Disease Progression and Potential Solution for Treatment.

    Science.gov (United States)

    Perugorria, Maria J; Labiano, Ibone; Esparza-Baquer, Aitor; Marzioni, Marco; Marin, Jose J G; Bujanda, Luis; Banales, Jesús M

    2017-01-01

    Polycystic liver diseases (PLDs) are a group of genetic hereditary cholangiopathies characterized by the development and progressive growth of cysts in the liver, which are the main cause of morbidity. Current therapies are based on surgical procedures and pharmacological strategies, which show short-term and modest beneficial effects. Therefore, the determination of the molecular mechanisms of pathogenesis appears to be crucial in order to find new potential targets for pharmacological therapy. Ductal plate malformation during embryogenesis and abnormal cystic cholangiocyte growth and secretion are some of the key mechanisms involved in the pathogenesis of PLDs. However, the discovery of the presence of bile acids in the fluid collected from human cysts and the intrahepatic accumulation of cytotoxic bile acids in an animal model of PLD (i.e. polycystic kidney (PCK) rat) suggest a potential role of impaired bile acid homeostasis in the pathogenesis of these diseases. On the other hand, ursodeoxycholic acid (UDCA) has emerged as a new potential therapeutic tool for PLDs by promoting the inhibition of cystic cholangiocyte growth in both PCK rats and highly symptomatic patients with autosomal dominant polycystic kidney disease (ADPKD: most common type of PLD), and improving symptoms. Chronic treatment with UDCA normalizes the decreased intracellular calcium levels in ADPKD human cholangiocytes in vitro, which results in the reduction of their baseline-stimulated proliferation. Moreover, UDCA decreases the liver concentration of cytotoxic bile acids in PCK rats and the bile acid-dependent enhanced proliferation of cystic cholangiocytes. Here, the role of bile acids in the pathogenesis of PLDs and the potential therapeutic value of UDCA for the treatment of these diseases are reviewed and future lines of investigation in this field are proposed.

  13. 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.

  14. INHIBITION OF BILE ACID ACCUMULATION DECREASED THE EXCESSIVE HEPATOCYTE APOPTOSIS AND IMPROVED THE LIVER SECRETION FUNCTIONS ON OBSTRUCTIVE JAUNDICE PATIENTS

    Directory of Open Access Journals (Sweden)

    Akmal Taher

    2011-06-01

    Full Text Available Excessive hepatocyte apoptosis induced by bile acid accumulation occurred in severe obstructive jaundice, and impair the liver secretion function. The objective of this study is to determine whether the inhibition of bile acid accumulation through bile duct decompression affect the excessive hepatocyte apoptosis and caused improvement the liver secretion functions on human model. In this study we use a before and after study on severe obstructive jaundice patients due to extra hepatic bile duct tumor was decompressed. Bile duct decompression was performed as a model of the role of inhibition of bile acid accumulation inhibition bile acid accumulation and excessive hepatocyte apoptosis. Bile acid and marker of liver secretion functions were serially measured. Liver biopsy pre and post decompression was performed for Hepatocyte apoptosis pathologic examination by TUNEL fluorescing, which measured by 2 people in double blinded system. Total bile acid, and liver secretion functions were measured by automated chemistry analyzer. The result of this study shows that twenty one severe obstructive jaundice patients were included. After decompression the hepatocyte apoptosis index decreased from an average of 53.1 (SD 105 to 11.7 (SD 13.6 (p < 0.05. Average of bile acid serum decreased from 96.4 (SD 53.8 to 19.9 (SD 39.5 until 13.0 (SD 12.6 μmol/L (p < 0.05 Total ilirubin decreased from 20.0 (SD 8.9 to 13.3 (SD 5.0 until 6.2 (SD 4.0 mg/dL (p < 0.05, while the phosphates alkaline (ALP and γ-glutamil transpeptidase (γ-GT activities also decreased ignificantly. In conclusion, bile acids accumulation and excessive hepatocyte poptosis through bile duct decompression improve the liver secretion functions by inhibition mechanism.

  15. 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

  16. Bile components and amino acids affect survival of the newly excysted juvenile Clonorchis sinensis in maintaining media.

    Science.gov (United States)

    Li, Shunyu; Kim, Tae Im; Yoo, Won Gi; Cho, Pyo Yun; Kim, Tong-Soo; Hong, Sung-Jong

    2008-10-01

    Clonorchis sinensis thrives on bile juice. The effects of bile and bile acids on newly excysted juvenile C. sinensis (CsNEJ) were studied in terms of survival. Survival of CsNEJs maintained in 1x Locke's solution, Dulbecco's modified Eagle's medium, NCTC 109, Eagle's, RPMI 1640, and 0.1% glucose was high, but dropped rapidly in 2x Locke's, 0.85% NaCl, and phosphate-buffered saline. Most amino acids in the media favored CsNEJ survival; however, aspartic and glutamic acids and adenine reduced survival. Survival was also significantly lower in media containing more than 0.1% bile. CsNEJs preconditioned in low bile media survived longer in higher bile media. All bile acids and conjugated bile salts were found to favor CsNEJ survival, except for lithocholic acid (LCA) which was toxic. NCTC 109 medium was found to be optimal for the in vitro maintenance of CsNEJs and 1x Locke's solution to be suitable for analyzing the biological effects of bioactive compounds and molecules. Based on these results, we propose that bile acids enhance activity of CsNEJs, but LCA deteriorate CsNEJs.

  17. 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

    in humans would affect fecal microbiota composition and subsequently bile acid and glucose metabolism. METHODS: In this single blinded randomized controlled trial, 20 male obese subjects with metabolic syndrome were randomized to 7 days of amoxicillin 500 mg t.i.d. or 7 days of vancomycin 500 mg t.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...

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

    DEFF Research Database (Denmark)

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

    2016-01-01

    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...

  19. Investigation on bile acid receptor regulators. Discovery of cholanoic acid derivatives with dual G-protein coupled bile acid receptor 1 (GPBAR1) antagonistic and farnesoid X receptor (FXR) modulatory activity.

    Science.gov (United States)

    Sepe, Valentina; Renga, Barbara; Festa, Carmen; Finamore, Claudia; Masullo, Dario; Carino, Adriana; Cipriani, Sabrina; Distrutti, Eleonora; Fiorucci, Stefano; Zampella, Angela

    2016-01-01

    Bile acids, the end products of cholesterol metabolism, activate multiple mechanisms through the interaction with membrane G-protein coupled receptors including the bile acid receptor GPBAR1 and nuclear receptors such as the bile acid sensor, farnesoid X receptor (FXR). Even if dual FXR/GPBAR1 agonists are largely considered a novel opportunity in the treatment of several liver and metabolic diseases, selective targeting of one of these receptors represents an attractive therapeutic approach for a wide range of disorders in which dual modulation is associated to severe side effects. In the present study we have investigated around the structure of LCA generating a small library of cholane derivatives, endowed with dual FXR agonism/GPBAR1 antagonism. To the best of our knowledge, this is the first report of bile acid derivatives able to antagonize GPBAR1.

  20. Detection of atypical bile acids in disease states and their identification by gas chromatography-mass spectrometry-computer techniques

    Energy Technology Data Exchange (ETDEWEB)

    Szczepanik-Van Leeuwen, P. A.; Stellaard, F.

    1978-01-01

    The study of the bile acid constituents of serum, bile, urine, and stool of patients exhibiting liver disease has increased in importance with the availability of newer methods for their detection and identification. A cogent question for study has been whether specific bile acids are toxic and thus are the cause of liver disease, or whether they accumulate as a result of disease-induced alteration in metabolism. Examining a wide variety of clinical samples, we have observed that many patients with diagnosed cholestasis show the presence of atypical bile acids due to metabolic aberrations in either the side chain or in the steroid ring. Because cholestasis represents a spectrum of diseases with differing metabolic and/or anatomic defects and because our studies cover a variety of cholestatic states, we have sought to establish a correlation between the presence of these atypical bile acids and the disease state. The complexity of the bile acid mixtures to be examined requires that gas chromatographic-mass spectrometric-computer techniques be used to provide a reliable analysis. It is believed that atypical bile acids can be readily identified by GC/CI mass spectrometry with great sensitivity. It is also believed that such bile acid analysis may prove useful to the study and diagnosis of liver disease. Present data suggest that the identification of atypical bile acids in biological samples may enable differentiation between different types of intrahepatic cholestasis. Such analyses may prove useful to distinguish specific diseases, such as Byler's disease (and Byler's-like cholestasis) from other types of cholestasis and may distinguish diseases involving mitochondrial defects. Finally, the presence of atypical bile acids may indicate, by the particular compounds formed, where and what kind of damage occurs in a disease and may ultimately establish if these atypical bile acids are a cause or effect of the liver damage.

  1. Pyrene appended bile acid conjugates: Synthesis and a structure-gelation property study

    Indian Academy of Sciences (India)

    Shreedhar Bhat; Arto Valkonen; Juha Koivukorpi; Anupama Ambika; Erkki Kolehmainen; Uday Maitra; Kari Rissanen

    2011-07-01

    A wide variety of novel compounds obtained by combining two types of known organogelators, viz., bile acid alkyl amides and pyrene alkanoic acids, were synthesized and screened for their gelation ability. The 3 esters of 1-pyrene butyric acid (PBA) of alkylamides of deoxycholic acid (DCA) turned out to be effective in the gel formation with many organic solvents although the gelation has to be triggered by the addition of a charge transfer (CT) agent 2,4,7-trinitrofluorenone (TNF). The special feature of these molecules is that the organogelation is achieved only after derivatizing the acid moiety of the 1-pyrenealkanoic acids. Additionally, the gelation properties can be fine-tuned by inserting different functional groups at the bile acid side chain. The gels obtained are deep red in colour and optically transparent up to 2% w/v. The SEM studies of the obtained xerogels revealed bundled rod-like morphology without specialized branching.

  2. Altered systemic bile acid homeostasis contributes to liver disease in pediatric patients with intestinal failure

    Science.gov (United States)

    Xiao, Yong-Tao; Cao, Yi; Zhou, Ke-Jun; Lu, Li-Na; Cai, Wei

    2016-01-01

    Intestinal failure (IF)-associated liver disease (IFALD), as a major complication, contributes to significant morbidity in pediatric IF patients. However, the pathogenesis of IFALD is still uncertain. We here investigate the roles of bile acid (BA) dysmetabolism in the unclear pathogenesis of IFALD. It found that the histological evidence of pediatric IF patients exhibited liver injury, which was characterized by liver bile duct proliferation, inflammatory infiltration, hepatocyte apoptosis and different stages of fibrosis. The BA compositions were altered in serum and liver of pediatric IF patients, as reflected by a primary BA dominant composition. In IF patients, the serum FGF19 levels decreased significantly, and were conversely correlated with ileal inflammation grades (r = −0.50, p CYP7A1) increased evidently. In conclusion, ileum inflammation decreases FXR expression corresponding to reduce serum FGF19 concentration, along with increased hepatic bile acid synthesis, leading to liver damages in IF patients. PMID:27976737

  3. Intestinal FXR-mediated FGF15 production contributes to diurnal control of hepatic bile acid synthesis in mice

    NARCIS (Netherlands)

    Stroeve, Johanna H. M.; Brufau, Gemma; Stellaard, Frans; Gonzalez, Frank J.; Staels, Bart; Kuipers, Folkert

    2010-01-01

    Hepatic bile acid synthesis is subject to complex modes of transcriptional control, in which the bile acid-activated nuclear receptor farnesoid X receptor (FXR) in liver and intestine-derived, FXR-controlled fibroblast growth factor 15 (Fgf15) are involved. The Fgf15 pathway is assumed to contribute

  4. 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...

  5. 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' ro

  6. Is biliary bile acid a good predictor for acute cellular rejection in living donor liver transplantation?

    Institute of Scientific and Technical Information of China (English)

    Mohammed Saied Hedaya; Walid M. El Moghazy; YamamotoYasutomo; Tomioka Kiyoshi; Toshimi Kaido; Hiroto Egawa; Shinji Uemoto; Yasutsugu Takada

    2009-01-01

    BACKGROUND: In liver transplantation, acute cellular rejection (ACR) is still a major complication that can lead to mortality. Bile secretion has been considered as a marker of early graft function. METHODS: The study included 41 adults who received living donor liver transplantation (LDLT) at Kyoto University Hospital between April 2007 and February 2008. The patients were stratified according to the presence or absence of ACR. Bile samples were collected from donors once and from recipients every other day for the first 2 weeks after transplantation. Total bile acid (BA) and taurine-conjugated bile acid (TCBA) in bile were measured by magnetic resonance spectroscopy. The recipient/donor (R/D) BA ratio and R/D TCBA ratio were calculated. RESULTS: The ACR group (n=12) showed a greater decrease in BA post-transplantation than the non-ACR group, but this difference was not statistically significant. On both day 7 and day 9 post-transplantation the R/D TCBA was significantly different between the two groups (P=0.038 on day 7 and P=0.036 on day 9). The R/D TCBA ratio ≥0.5 on days 7 and 9, and ≥0.38 on day 11 post-transplantation were associated with better ACR-free survival. CONCLUSION: The recipient/donor TCBA ratio can be a predictor for ACR after LDLT as early as post-transplantation day 7.

  7. Biofilm Formation and Detachment in Gram-Negative Pathogens Is Modulated by Select Bile Acids.

    Directory of Open Access Journals (Sweden)

    Laura M Sanchez

    Full Text Available Biofilms are a ubiquitous feature of microbial community structure in both natural and host environments; they enhance transmission and infectivity of pathogens and provide protection from human defense mechanisms and antibiotics. However, few natural products are known that impact biofilm formation or persistence for either environmental or pathogenic bacteria. Using the combination of a novel natural products library from the fish microbiome and an image-based screen for biofilm inhibition, we describe the identification of taurine-conjugated bile acids as inhibitors of biofilm formation against both Vibrio cholerae and Pseudomonas aeruginosa. Taurocholic acid (1 was isolated from the fermentation broth of the fish microbiome-derived strain of Rhodococcus erythropolis and identified using standard NMR and MS methods. Screening of the twelve predominant human steroidal bile acid components revealed that a subset of these compounds can inhibit biofilm formation, induce detachment of preformed biofilms under static conditions, and that these compounds display distinct structure-activity relationships against V. cholerae and P. aeruginosa. Our findings highlight the significance of distinct bile acid components in the regulation of biofilm formation and dispersion in two different clinically relevant bacterial pathogens, and suggest that the bile acids, which are endogenous mammalian metabolites used to solubilize dietary fats, may also play a role in maintaining host health against bacterial infection.

  8. Lipid binding protein response to a bile acid library: a combined NMR and statistical approach.

    Science.gov (United States)

    Tomaselli, Simona; Pagano, Katiuscia; Boulton, Stephen; Zanzoni, Serena; Melacini, Giuseppe; Molinari, Henriette; Ragona, Laura

    2015-11-01

    Primary bile acids, differing in hydroxylation pattern, are synthesized from cholesterol in the liver and, once formed, can undergo extensive enzyme-catalysed glycine/taurine conjugation, giving rise to a complex mixture, the bile acid pool. Composition and concentration of the bile acid pool may be altered in diseases, posing a general question on the response of the carrier (bile acid binding protein) to the binding of ligands with different hydrophobic and steric profiles. A collection of NMR experiments (H/D exchange, HET-SOFAST, ePHOGSY NOESY/ROESY and (15) N relaxation measurements) was thus performed on apo and five different holo proteins, to monitor the binding pocket accessibility and dynamics. The ensemble of obtained data could be rationalized by a statistical approach, based on chemical shift covariance analysis, in terms of residue-specific correlations and collective protein response to ligand binding. The results indicate that the same residues are influenced by diverse chemical stresses: ligand binding always induces silencing of motions at the protein portal with a concomitant conformational rearrangement of a network of residues, located at the protein anti-portal region. This network of amino acids, which do not belong to the binding site, forms a contiguous surface, sensing the presence of the bound lipids, with a signalling role in switching protein-membrane interactions on and off.

  9. Biofilm Formation and Detachment in Gram-Negative Pathogens Is Modulated by Select Bile Acids.

    Science.gov (United States)

    Sanchez, Laura M; Cheng, Andrew T; Warner, Christopher J A; Townsley, Loni; Peach, Kelly C; Navarro, Gabriel; Shikuma, Nicholas J; Bray, Walter M; Riener, Romina M; Yildiz, Fitnat H; Linington, Roger G

    2016-01-01

    Biofilms are a ubiquitous feature of microbial community structure in both natural and host environments; they enhance transmission and infectivity of pathogens and provide protection from human defense mechanisms and antibiotics. However, few natural products are known that impact biofilm formation or persistence for either environmental or pathogenic bacteria. Using the combination of a novel natural products library from the fish microbiome and an image-based screen for biofilm inhibition, we describe the identification of taurine-conjugated bile acids as inhibitors of biofilm formation against both Vibrio cholerae and Pseudomonas aeruginosa. Taurocholic acid (1) was isolated from the fermentation broth of the fish microbiome-derived strain of Rhodococcus erythropolis and identified using standard NMR and MS methods. Screening of the twelve predominant human steroidal bile acid components revealed that a subset of these compounds can inhibit biofilm formation, induce detachment of preformed biofilms under static conditions, and that these compounds display distinct structure-activity relationships against V. cholerae and P. aeruginosa. Our findings highlight the significance of distinct bile acid components in the regulation of biofilm formation and dispersion in two different clinically relevant bacterial pathogens, and suggest that the bile acids, which are endogenous mammalian metabolites used to solubilize dietary fats, may also play a role in maintaining host health against bacterial infection.

  10. Bile acids are "homeotrophic" sensors of the functional hepatic capacity and regulate adaptive growth during liver regeneration.

    Science.gov (United States)

    Geier, Andreas; Trautwein, Christian

    2007-01-01

    Liver mass depends on one or more unidentified humoral signals that drive regeneration when liver functional capacity is diminished. Bile acids are important liver products, and their levels are tightly regulated. Here, we identify a role for nuclear receptor-dependent bile acid signaling in normal liver regeneration. Elevated bile acid levels accelerate regeneration, and decreased levels inhibit liver regrowth, as does the absence of the primary nuclear bile acid receptor FXR. We propose that FXR activation by increased bile acid flux is a signal of decreased functional capacity of the liver. FXR, and possibly other nuclear receptors, may promote homeostasis not only by regulating expression of appropriate metabolic target genes but also by driving homeotrophic liver growth.

  11. Suppression of bile acid synthesis by thyroid hormone in primary human hepatocytes

    Institute of Scientific and Technical Information of China (English)

    Ewa Cristine Siljevik Ellis

    2006-01-01

    AIM: It is known that thyroid hormones alter the bile acid metabolism in humans, however the effect on individual enzymes has been difficult to elucidate.This is mainly due to the lack of human liver cell lines producing bile acids. We used cultures of primary human hepatocytes to study the effects of triiodothyronine (T3) on bile acid synthesis.METHODS: Primary hepatocytes were isolated from liver tissue obtained from three different patients undergoing liver resection due to underlying malignancy. The hepatocytes were cultured under serum-free conditions and treated from d 1 to d 5 with culture containing 0.1-1000 nmol/L of T3. Bile acid formation and mRNA levels of key enzymes were analysed.RESULTS: The lowest concentration of T3 decreased cholic acid (CA) formation to 43%-53% of controls and chenodeoxycholic acid (CDCA) to 52%-75% of controls on d 5. The highest dose further decreased CA formation to 16%-48% of controls while CDCA formation remained at 50%-117% of controls. Expression of mRNA levels of cholesterol 7α-hydroxylase (CYP7A1) and sterol 12α-hydroxylase (CYP8B1) dose-dependently decreased.Sterol 27-hydroxylase (CYP27A1) levels also decreased,but not to the same extent.CONCLUSION: T3 dose-dependently decreased total bile acid formation in parallel with decreased expression of CYP7A1 and CYP8B1. CA formation is inhibited to a higher degree than CDCA, resulting in a marked decrease in the CA/CDCA ratio.

  12. The clinical significance of disordered renal excretion of xanthurenic acid in depressive patients.

    Science.gov (United States)

    Hoes, M J; Sijben, N

    1981-01-01

    Xanthurenic acid is a metabolite of L-tryptophanicotinic acid ribonucleotide biosynthesis. The excretion of xanthurenic acid from urine 24 h after ingestion of 5 g L-tryptophan is increased in depressive patients, and 17-hydroxycorticosteroids are considered of primary importance to this disorder. However, in this study, the excretion of xanthurenic acid and 17-hydroxycorticosteroids did not correlate with the scores of the Raskin depression scale, Hamilton depression scale, Zung depression scale, or the Zung anxiety scale in depressive patients. The patients were treated with either pyridoxine plus L-tryptophan, a presumably serotonin-enhancing treatment (n = 10) or maprotiline, a noradrenaline-enhancing drug (n = 10). Repeated measurements showed no differences between treatments after 2 or 4 weeks of treatment. The improvement in xanthurenic acid excretion precedes clinical improvements in depression. The excretion of xanthurenic acid only at 2 weeks correlated significantly with the anxiety and depression scores at 4 weeks, making prediction of clinical improvement possible. The neurobiological mode of action on noradrenergic or serotonergic neurons of antidepressant medication is of questionable significance to their therapeutic effect.

  13. In vivo multiphoton imaging of bile duct ligation

    Science.gov (United States)

    Liu, Yuan; Li, Feng-Chieh; Chen, Hsiao-Chin; Chang, Po-shou; Yang, Shu-Mei; Lee, Hsuan-Shu; Dong, Chen-Yuan

    2008-02-01

    Bile is the exocrine secretion of liver and synthesized by hepatocytes. It is drained into duodenum for the function of digestion or drained into gallbladder for of storage. Bile duct obstruction is a blockage in the tubes that carry bile to the gallbladder and small intestine. However, Bile duct ligation results in the changes of bile acids in serum, liver, urine, and feces1, 2. In this work, we demonstrate a novel technique to image this pathological condition by using a newly developed in vivo imaging system, which includes multiphoton microscopy and intravital hepatic imaging chamber. The images we acquired demonstrate the uptake, processing of 6-CFDA in hepatocytes and excretion of CF in the bile canaliculi. In addition to imaging, we can also measure kinetics of the green fluorescence intensity.

  14. Investigation of side chain liquid crystal polymers bearing cholesterol and bile acid derivatives

    Institute of Scientific and Technical Information of China (English)

    Zhang Junhua; Stephen Freiberg; Francois Brisse; C.Géraldine Bazuin; Zhu Xiaoxia

    2004-01-01

    Cholic acid (or 3a,7a,12a-trihydoxyl-5a-cholan-24-oic acid) and lithocholic acid (or 3a-hydroxyl-5a-cholanic-24-oic acid) are commonly occurring bile acids synthesized from cholesterol in the liver in mammals. They all possess a steroid skeleton containing four rings, three with six carbons and one with five carbons. The transformation of cholesterol to cholic acid results in two major structural changes that affect the steroid skeleton. The first is the hydrogenation of the double bond between C5 and C6 and the second is a conformational flip of ring A from the 5a-position to the 5a-position. In addition, one or more hydroxyl groups are added to the steroid skeleton. Outside of the ring system, C24 is converted from a saturated alkyl to a carboxylic acid group.Side chain polymers based on cholesterol moiety have been made as reported in the literature.Since bile acids and cholesterol are all in the family of steroid molecules, it is of interest to investigate whether bile acids may also act as mesogenic groups.Therefore, flexible spacer groups with 10 carbons are introduced between bile acid skeleton and the poymerizable double bonds. The monomers and polymers are compared with cholesterol and dihydrocholesterol monomers and polymers with the same spacers. Dihydrocholesterol is chosen to investigate the influence of the double bond in the formation of LC, given that both cholesterol and dihydrocholesterol have a planar structure but there is no double bond in the latter. These monomers and their corresponding polymers were characterized for their liquid crystalline (LC) properties by differential scanning calorimetry (DSC), polarizing optical microscopy (POM) and X-ray diffraction.It was found that only the compounds bearing the planar cholesterol moieties possess LC phases. It is concluded that the 5a-configuration between the first and second cycles on the steroid skeleton of bile acids does not favor proper alignment of the rigid part of the bile acid moieties

  15. Regulation of bile acid synthesis by the nuclear receptor Rev-erb alpha

    NARCIS (Netherlands)

    Duez, Helene; Van Der Veen, Jelske N.; Duhem, Christian; Pourcet, Benoit; Touvier, Thierry; Fontaine, Coralie; Derudas, Bruno; Bauge, Eric; Havinga, Rick; Bloks, Vincent W.; Wolters, Henk; Van Der Sluijs, Fjodor H.; Vennstrom, Bjorn; Kuipers, Folkert; Staels, Bart

    2008-01-01

    Background & Aims: Conversion into bile acids represents an important route to remove excess cholesterol from the body. Rev-erb alpha is a nuclear receptor that participates as one of the clock genes in the control of circadian rhythmicity and plays a regulatory role in lipid metabolism and adipogen

  16. Effect of cholecystectomy on bile acid synthesis and circulating levels of fibroblast growth factor 19

    NARCIS (Netherlands)

    Barrera, Francisco; Azocar, Lorena; Molina, Hector; Schalper, Kurt A.; Ocares, Marcia; Liberona, Jessica; Villarroel, Luis; Pimentel, Fernando; Perez-Ayuso, Rosa M.; Nervi, Flavio; Groen, Albert K.; Miquel, Juan F.

    2015-01-01

    Background and rationale for the study. FGF19/15 is a gut-derived hormone presumably governing bile acid (BA) synthesis and gallbladder (GB) refilling. FGF19 mRNA is present in human GB cholangiocytes (hGBECs); however, the physiological significance of GB-derived FGF19 remains unknown. We investiga

  17. Analysis of fecal bile acids and neutral steroids using gas-liquid chromatography

    NARCIS (Netherlands)

    Srikumar, T.S.; Wezendonk, B.; Dokkum, W. van

    1998-01-01

    In the present pilot study, for investigating the physiological effects of different types of nondigestible oligosaccharides, we have validated the application of methodologies for the analysis of bile acids and neutral steroids in feces of human subjects. The accuracy of the extraction and chromato

  18. Bile acids and bariatric surgery%胆汁酸与减重手术

    Institute of Scientific and Technical Information of China (English)

    刘光耀; 王群伟; 刘威

    2015-01-01

    As an essential metabolic molecule, bile acids regulate triglyceride, cholesterol, energy metabolism. Bariatric surgery offers a treatment that can reduce weight and induce metabolic syndrome, but the mechanism is still unclear. New researches reveal that serum bile acids are elevated after surgery, as well as the improvement of metabolic disease. The surgery changes gastrointestinal tract, resulting in a short circuiting of the enterohepatic circulation of bile acids. Here we review the bile acids metabolism and their effect after bariatric surgery.%胆汁酸作为机体的重要代谢信号分子,参与了糖类、脂肪及能量的代谢。减重手术目前是治疗治疗肥胖症和代谢综合征有效途径之一,但其机制尚不明确。研究发现,减重手术后胆汁酸水平明显升高,并且与代谢综合征改善正相关。由于减重手术后胃肠道生理结构发生变化,必然会对胆汁酸代谢产生影响。本文对胆汁酸对代谢和对减重手术的影响作一综述。

  19. Transmembrane domain II of the human bile acid transporter SLC10A2 coordinates sodium translocation.

    Science.gov (United States)

    Sabit, Hairat; Mallajosyula, Sairam S; MacKerell, Alexander D; Swaan, Peter W

    2013-11-01

    Human apical sodium-dependent bile acid transporter (hASBT, SLC10A2) is responsible for intestinal reabsorption of bile acids and plays a key role in cholesterol homeostasis. We used a targeted and systematic approach to delineate the role of highly conserved transmembrane helix 2 on the expression and function of hASBT. Cysteine mutation significantly depressed transport activity for >60% of mutants without affecting cell surface localization of the transporter. All mutants were inaccessible toward chemical modification by membrane-impermeant MTSET reagent, strongly suggesting that transmembrane 2 (TM2) plays an indirect role in bile acid substrate translocation. Both bile acid uptake and sodium dependence of TM2 mutants revealed a distinct α-helical periodicity. Kinetic studies with conservative and non-conservative mutants of sodium sensitive residues further underscored the importance of Gln(75), Phe(76), Met(79), Gly(83), Leu(86), Phe(90), and Asp(91) in hASBT function. Computational analysis indicated that Asp(91) may coordinate with sodium during the transport cycle. Combined, our data propose that a consortium of sodium-sensitive residues along with previously reported residues (Thr(134), Leu(138), and Thr(149)) from TM3 may form the sodium binding and translocation pathway. Notably, residues Gln(75), Met(79), Thr(82), and Leu(86) from TM2 are highly conserved in TM3 of a putative remote bacterial homologue (ASBTNM), suggesting a universal mechanism for the SLC10A transporter family.

  20. 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 BMI-mat

  1. Bile acids induce hepatic stellate cell proliferation via activation of the epidermal growth factor receptor

    NARCIS (Netherlands)

    Svegliati-Baroni, G; Ridolfi, F; Hannivoort, R; Saccomanno, S; Homan, M; De Minicis, S; Jansen, PLM; Candelaresi, C; Benedetti, A; Moshage, H

    2005-01-01

    Background B Aims: Hepatic stellate cell (HSC) proliferation is a key event in the development of liver fibrosis. In many liver diseases, HSCs are exposed to inflammatory cytokines, reactive oxygen species, and bile acids. Although inflammatory cytokines and reactive oxygen species are known to prom

  2. 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 w...

  3. Spontaneous gallstone formation in deer mice: interaction of cholesterol, bile acids, and dietary fiber.

    Science.gov (United States)

    Ginnett, Dorothy A; Theis, Jerold H; Kaneko, J Jerry

    2003-01-01

    A study of the physiologic and ecologic factors involved in a spontaneous seasonal gallstone cycle of deer mice (Peromyscus maniculatus gambelii) was conducted at the Tulelake National Wildlife Refuge (California, USA) from March 1991 to June 1992. The specific hypothesis examined was whether or not seasonal increases in dietary fiber intake provides the necessary conditions for a solubility defect, or supersaturation mechanism, resulting in precipitation of cholesterol gallstones. Results indicated that in addition to the seasonal gallstone prevalence cycle, these deer mice exhibit significant seasonal cycling in serum cholesterol, serum bile acids, fecal bile acids, and diet composition. These physiologic and dietary cycles were phase-advanced 3 mo over the gallstone prevalence cycle, indicating an approximate 3 mo time period for gallstone formation under field conditions. Further, seasonal dietary fiber (plant material and seeds) was positively correlated with both serum cholesterol and the fecal bile acids. This suggests that in wild deer mice, variations in dietary fiber may significantly affect the resorption of bile acids, thereby providing a potential physiologic and nutritional mechanism for spontaneous cholesterol gallstone formation.

  4. Delineation of biochemical, molecular, and physiological changes accompanying bile acid pool size restoration in Cyp7a1(-/-) mice fed low levels of cholic acid.

    Science.gov (United States)

    Jones, Ryan D; Repa, Joyce J; Russell, David W; Dietschy, John M; Turley, Stephen D

    2012-07-15

    Cholesterol 7α-hydroxylase (CYP7A1) is the initiating and rate-limiting enzyme in the neutral pathway that converts cholesterol to primary bile acids (BA). CYP7A1-deficient (Cyp7a1(-/-)) mice have a depleted BA pool, diminished intestinal cholesterol absorption, accelerated fecal sterol loss, and increased intestinal cholesterol synthesis. To determine the molecular and physiological effects of restoring the BA pool in this model, adult female Cyp7a1(-/-) mice and matching Cyp7a1(+/+) controls were fed diets containing cholic acid (CA) at modest levels [0.015, 0.030, and 0.060% (wt/wt)] for 15-18 days. A level of just 0.03% provided a CA intake of ~12 μmol (4.8 mg) per day per 100 g body wt and was sufficient in the Cyp7a1(-/-) mice to normalize BA pool size, fecal BA excretion, fractional cholesterol absorption, and fecal sterol excretion but caused a significant rise in the cholesterol concentration in the small intestine and liver, as well as a marked inhibition of cholesterol synthesis in these organs. In parallel with these metabolic changes, there were marked shifts in intestinal and hepatic expression levels for many target genes of the BA sensor farnesoid X receptor, as well as genes involved in cholesterol transport, especially ATP-binding cassette (ABC) transporter A1 (ABCA1) and ABCG8. In Cyp7a1(+/+) mice, this level of CA supplementation did not significantly disrupt BA or cholesterol metabolism, except for an increase in fecal BA excretion and marginal changes in mRNA expression for some BA synthetic enzymes. These findings underscore the importance of using moderate dietary BA levels in studies with animal models.

  5. An optimized probucol microencapsulated formulation integrating a secondary bile acid (deoxycholic acid as a permeation enhancer

    Directory of Open Access Journals (Sweden)

    Mooranian A

    2014-09-01

    Full Text Available Armin Mooranian,1 Rebecca Negrulj,1 Nigel Chen-Tan,2 Gerald F Watts,3 Frank Arfuso,4 Hani Al-Salami11Biotechnology and Drug Development Research Laboratory, School of Pharmacy, Curtin Health Innovation Research Institute, Biosciences Research Precinct, Curtin University, 2Faculty of Science and Engineering, Curtin University, 3School of Medicine and Pharmacology, Royal Perth Hospital, University of Western Australia, 4School of Biomedical Science, Curtin Health Innovation Research Institute, Biosciences Research Precinct, Curtin University, Perth, AustraliaAbstract: The authors have previously designed, developed, and characterized a novel microencapsulated formulation as a platform for the targeted delivery of therapeutics in an animal model of type 2 diabetes, using the drug probucol (PB. The aim of this study was to optimize PB microcapsules by incorporating the bile acid deoxycholic acid (DCA, which has good permeation-enhancing properties, and to examine its effect on microcapsules’ morphology, rheology, structural and surface characteristics, and excipients’ chemical and thermal compatibilities. Microencapsulation was carried out using a BÜCHI-based microencapsulating system established in the authors’ laboratory. Using the polymer sodium alginate (SA, two microencapsulated formulations were prepared: PB-SA (control and PB-DCA-SA (test at a constant ratio (1:30 and 1:3:30, respectively. Complete characterization of the microcapsules was carried out. The incorporation of DCA resulted in better structural and surface characteristics, uniform morphology, and stable chemical and thermal profiles, while size and rheological parameters remained similar to control. In addition, PB-DCA-SA microcapsules showed good excipients’ compatibilities, which were supported by data from differential scanning calorimetry, Fourier transform infrared spectroscopy, scanning electron microscopy, and energy dispersive X-ray studies, suggesting

  6. 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.

  7. 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.

  8. Domoic acid excretion in dungeness crabs, razor clams and mussels.

    Science.gov (United States)

    Schultz, Irvin R; Skillman, Ann; Woodruff, Dana

    2008-07-01

    Domoic acid (DA) is a neurotoxic amino acid produced by several marine algal species of the Pseudo-nitzschia (PN) genus. We studied the elimination of DA from hemolymph after intravascular (IV) injection in razor clams (Siliqua patula), mussels (Mytilus edulis) and Dungeness crabs (Cancer magister). Crabs were also injected with two other organic acids, dichloroacetic acid (DCAA) and kainic acid (KA). For IV dosing, hemolymph was repetitively sampled and DA concentrations measured by HPLC-UV. Toxicokinetic analysis of DA in crabs suggested most of the injected dose remained within hemolymph compartment with little extravascular distribution. This observation is in sharp contrast to results obtained from clams and mussels which exhibited similarly large apparent volumes of distribution despite large differences in overall clearance. These findings suggest fundamentally different storage and elimination processes are occurring for DA between bivalves and crabs.

  9. Prospective evaluation of faecal fatty acid excretion in short bowel syndrome in newborns.

    NARCIS (Netherlands)

    Heineman, E.; Dejong, C.H.C.; Piena-Spoel, M.; Liefaard, G.; Molenaar, J.C.; Tibboel, D.

    1996-01-01

    Prospective evaluation of faecal fatty acid excretion in short bowel syndrome in newborns. Heineman E, Dejong CH, Piena-Spoel M, Liefaard G, Molenaar JC, Tibboel D. Department of Paediatric Surgery, Sophia Children's Hospital, Rotterdam, The Netherlands. Short bowel syndrome (SBS) in the newborn res

  10. Effect of bile acid perfusion on colonic motor function in patients with the irritable colon syndrome.

    OpenAIRE

    1980-01-01

    A study was performed to determine the effect of bile acid perfusion on motility in the sigmoid colon of patients with the irritable colon syndrome compared with normal subjects. Deoxycholic acid (15 mM) statistically significantly increased motility in normal subjects (control 25.0 +/- 6.4%, perfusion 71.4 +/- 7.2%, P < 0.05) but neither chenodeoxycholic acid nor cholic acid had any apparent effect. In patients with the irritable colon syndrome, however, deoxycholic acid at 5 mM concentratio...

  11. Chronic Over-expression of Fibroblast Growth Factor 21 Increases Bile Acid Biosynthesis by Opposing FGF15/19 Action

    Directory of Open Access Journals (Sweden)

    Jun Zhang

    2017-02-01

    Full Text Available Pharmacological doses of fibroblast growth factor (FGF 21 effectively normalize glucose, lipid and energy homeostasis in multiple animal models with many benefits translating to obese humans with type 2 diabetes. However, a role for FGF21 in the regulation of bile acid metabolism has not been reported. Herein, we demonstrate AAV-mediated FGF21 overexpression in mice increases liver expression of the key bile acid producing enzyme, Cyp7a1, resulting in an increased bile acid pool. Furthermore, in cholecystectomized mice, FGF21-mediated bile acid pool increase led to increased transit of bile acids into colon. We elucidate that the mechanism of FGF21 induced bile acid changes is mainly through antagonizing FGF15/19 function on liver βKlotho/FGFR4 receptor complex; thus inhibiting FGF15/19-mediated suppression of Cyp7a1 expression. In conclusion, these data reveal a previously unidentified role for FGF21 on bile acid metabolism and may be relevant to understand the effects of FGF21 analogs in clinical studies.

  12. Excretion of amino acids by humans during space flight

    Science.gov (United States)

    Stein, T. P.; Schluter, M. D.

    1998-01-01

    We measured the urine amino acid distribution patterns before, during and after space flight on the Space Shuttle. The urine samples were collected on two separate flights of the space shuttle. The first flight lasted 9.5 days and the second flight 15 days. Urine was collected continuously on 8 subjects for the period beginning 10 d before launch to 6 d after landing. Results: In contrast to the earlier Skylab missions where a pronounced amino aciduria was found, on shuttle the urinary amino acids showed little change with spaceflight except for a marked decrease in all of the amino acids on FD (flight day) 1 (pvaline on FD3 and FD4 (p<0.05). Conclusions: (i) Amino aciduria is not an inevitable consequence of space flight. (ii) The occurrence of amino aciduria, like muscle protein breakdown is a mission specific effect rather than part of the general human response to microgravity.

  13. Bile Acids Function Synergistically To Repress Invasion Gene Expression in Salmonella by Destabilizing the Invasion Regulator HilD.

    Science.gov (United States)

    Eade, Colleen R; Hung, Chien-Che; Bullard, Brian; Gonzalez-Escobedo, Geoffrey; Gunn, John S; Altier, Craig

    2016-08-01

    Salmonella spp. are carried by and can acutely infect agricultural animals and humans. After ingestion, salmonellae traverse the upper digestive tract and initiate tissue invasion of the distal ileum, a virulence process carried out by the type III secretion system encoded within Salmonella pathogenicity island 1 (SPI-1). Salmonellae coordinate SPI-1 expression with anatomical location via environmental cues, one of which is bile, a complex digestive fluid that causes potent repression of SPI-1 genes. The individual components of bile responsible for SPI-1 repression have not been previously characterized, nor have the bacterial signaling processes that modulate their effects been determined. Here, we characterize the mechanism by which bile represses SPI-1 expression. Individual bile acids exhibit repressive activity on SPI-1-regulated genes that requires neither passive diffusion nor OmpF-mediated entry. By using genetic methods, the effects of bile and bile acids were shown to require the invasion gene transcriptional activator hilD and to function independently of known upstream signaling pathways. Protein analysis techniques showed that SPI-1 repression by bile acids is mediated by posttranslational destabilization of HilD. Finally, we found that bile acids function synergistically to achieve the overall repressive activity of bile. These studies demonstrate a common mechanism by which diverse environmental cues (e.g., certain short-chain fatty acids and bile acids) inhibit SPI-1 expression. These data provide information relevant to Salmonella pathogenesis during acute infection in the intestine and during chronic infection of the gallbladder and inform the basis for development of therapeutics to inhibit invasion as a means of repressing Salmonella pathogenicity.

  14. Salmonella fecal excretion control in broiler chickens by organic acids and essential oils blend feed added

    Directory of Open Access Journals (Sweden)

    A Borsoi

    2011-03-01

    Full Text Available Salmonellosis is an important disease with economic impact as it may affect animal performance and may result in foodborne disease in humans through the eggs and carcass contamination. Regarding the Salmonella control, it is possible to decrease its fecal excretion and the contamination of chicken carcasses by adding organic acids to the feed or drinking water at appropriate times. The aim of this study was to test a blend of organic acids and essential oils in broilers challenged with Salmonella Enteritidis (SE, and to verify the fecal excretion of Salmonella. Sixty broilers were placed in four groups. One group was the negative control. Another group was orally inoculated at 1 day-old with 10(5 CFU/mL of SE as a positive SE control. Two groups (T3 and T4 were orally inoculated at 1 day-old with 10(5 CFU/mL of SE and their feed was separately treated with 0.5 and 1% of organic acids and essential oils, respectively. To assess the fecal excretion of SE, cloacal swabs were collected from all birds at 2, 6, 13 and 20 days after inoculation. The T3 and T4 groups showed a reduction in fecal excretion of SE at 6 and 20 days after inoculation.

  15. Urinary excretion of orally administered oxalic acid in saccharin and o-phenylphenol-fed NMRI mice.

    Science.gov (United States)

    Salminen, E; Salminen, S

    1986-01-01

    Both saccharin and o-phenylphenol have been suggested to be carcinogenic to the urinary bladder in experimental animals, but the mechanism has remained unclear. The aim of this study was to investigate the effects of dietary saccharin and o-phenylphenol on the urinary excretion of dietary oxalic acid. Male NMRI mice were gradually adapted to either 3% o-phenylphenol or 5% saccharin in their diet. Having being adapted to these diets for 1 week or after consuming them for 3 months, the animals were fasted for 6 h and given a 2.5-microCi oral dose of U-14C-oxalic acid. Dosed animals were kept in metabolism cages for 48 h to monitor urinary and fecal excretion of the label. Adaptation to dietary o-phenylphenol appeared to increase the urinary excretion of orally administered U-14C-oxalic acid when food and water were available during urinary and fecal collections. Adaptation to dietary saccharin had little effect on urinary oxalate levels when compared to control animals. These results indicate that changes in urinary oxalate levels should be more carefully studied in connection with potential urinary bladder carcinogens to avoid the possibility of bladder irritation by increased urinary oxalate excretion.

  16. Boldine enhances bile production in rats via osmotic and Farnesoid X receptor dependent mechanisms

    Energy Technology Data Exchange (ETDEWEB)

    Cermanova, Jolana [Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove (Czech Republic); Kadova, Zuzana [Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove (Czech Republic); Deparment of Pharmacology and Toxicology, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove (Czech Republic); Zagorova, Marie [Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove (Czech Republic); Hroch, Milos [Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove (Czech Republic); Department of Medical Biochemistry, Charles University in Prague, Faculty of Medicine in Hradec Kralove (Czech Republic); Tomsik, Pavel [Department of Medical Biochemistry, Charles University in Prague, Faculty of Medicine in Hradec Kralove (Czech Republic); Nachtigal, Petr; Kudlackova, Zdenka [Department of Biological and Medical Sciences, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove (Czech Republic); Pavek, Petr; Dubecka, Michaela; Ceckova, Martina; Staud, Frantisek [Deparment of Pharmacology and Toxicology, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove (Czech Republic); Laho, Tomas [Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove (Czech Republic); Micuda, Stanislav, E-mail: micuda@lfhk.cuni.cz [Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove (Czech Republic)

    2015-05-15

    Boldine, the major alkaloid from the Chilean Boldo tree, is used in traditional medicine to support bile production, but evidence to support this function is controversial. We analyzed the choleretic potential of boldine, including its molecular background. The acute- and long-term effects of boldine were evaluated in rats either during intravenous infusion or after 28-day oral treatment. Infusion of boldine instantly increased the bile flow 1.4-fold in healthy rats as well as in animals with Mrp2 deficiency or ethinylestradiol induced cholestasis. This effect was not associated with a corresponding increase in bile acid or glutathione biliary excretion, indicating that the effect is not related to stimulation of either bile acid dependent or independent mechanisms of bile formation and points to the osmotic activity of boldine itself. We subsequently analyzed bile production under conditions of changing biliary excretion of boldine after bolus intravenous administration and found strong correlations between both parameters. HPLC analysis showed that bile concentrations of boldine above 10 μM were required for induction of choleresis. Importantly, long-term pretreatment, when the bile collection study was performed 24-h after the last administration of boldine, also accelerated bile formation despite undetectable levels of the compound in bile. The effect paralleled upregulation of the Bsep transporter and increased biliary clearance of its substrates, bile acids. We consequently confirmed the ability of boldine to stimulate the Bsep transcriptional regulator, FXR receptor. In conclusion, our study clarified the mechanisms and circumstances surrounding the choleretic activity of boldine. - Highlights: • Boldine may increase bile production by direct as well as indirect mechanisms. • Biliary concentrations of boldine above 10 μM directly stimulate bile production. • Long-term oral boldine administration increases bile acid (BA) biliary secretion. • Boldine

  17. Mechanisms underlying the anti-aging and anti-tumor effects of lithocholic bile acid.

    Science.gov (United States)

    Arlia-Ciommo, Anthony; Piano, Amanda; Svistkova, Veronika; Mohtashami, Sadaf; Titorenko, Vladimir I

    2014-09-18

    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.

  18. 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

    .02) and peak glucagon-like peptide-1 (GLP-1) (r = 0.58, P lipid metabolism in patients......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...

  19. Coordinated induction of bile acid detoxification and alternative elimination in mice: role of FXR-regulated organic solute transporter-alpha/beta in the adaptive response to bile acids.

    Science.gov (United States)

    Zollner, Gernot; Wagner, Martin; Moustafa, Tarek; Fickert, Peter; Silbert, Dagmar; Gumhold, Judith; Fuchsbichler, Andrea; Halilbasic, Emina; Denk, Helmut; Marschall, Hanns-Ulrich; Trauner, Michael

    2006-05-01

    The bile acid receptor farnesoid X receptor (FXR) is a key regulator of hepatic defense mechanisms against bile acids. A comprehensive study addressing the role of FXR in the coordinated regulation of adaptive mechanisms including biosynthesis, metabolism, and alternative export together with their functional significance is lacking. We therefore fed FXR knockout (FXR(-/-)) mice with cholic acid (CA) and ursodeoxycholic acid (UDCA). Bile acid synthesis and hydroxylation were assessed by real-time RT-PCR for cytochrome P-450 (Cyp)7a1, Cyp3a11, and Cyp2b10 and mass spectrometry-gas chromatography for determination of bile acid composition. Expression of the export systems multidrug resistance proteins (Mrp)4-6 in the liver and kidney and the recently identified basoalteral bile acid transporter, organic solute transporter (Ost-alpha/Ost-beta), in the liver, kidney, and intestine was also investigated. CA and UDCA repressed Cyp7a1 in FXR(+/+) mice and to lesser extents in FXR(-/-) mice and induced Cyp3a11 and Cyp2b10 independent of FXR. CA and UDCA were hydroxylated in both genotypes. CA induced Ost-alpha/Ost-beta in the liver, kidney, and ileum in FXR(+/+) but not FXR(-/-) mice, whereas UDCA had only minor effects. Mrp4 induction in the liver and kidney correlated with bile acid levels and was observed in UDCA-fed and CA-fed FXR(-/-) animals but not in CA-fed FXR(+/+) animals. Mrp5/6 remained unaffected by bile acid treatment. In conclusion, we identified Ost-alpha/Ost-beta as a novel FXR target. Absent Ost-alpha/Ost-beta induction in CA-fed FXR(-/-) animals may contribute to increased liver injury in these animals. The induction of bile acid hydroxylation and Mrp4 was independent of FXR but could not counteract liver toxicity sufficiently. Limited effects of UDCA on Ost-alpha/Ost-beta may jeopardize its therapeutic efficacy.

  20. 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

  1. Hydrophobicity and Retention Coefficient of Selected Bile Acid Oxo Derivatives

    NARCIS (Netherlands)

    Posa, Mihalj; Pilipovic, Ana; Lalic, Mladena; Popovic, Jovan

    2010-01-01

    Retention coefficients (k) of cholic acid and its keto derivatives are determined by means of Reversed Phase High Pressure Liquid Chromatography at different temperatures (303K, 309K, and 313K). At each studied temperature, retention factor decreases if the hydroxyl group in the cholic acid molecule

  2. Unconjugated secondary bile acids activate the unfolded protein response and induce golgi fragmentation via a src-kinase-dependant mechanism

    Science.gov (United States)

    Sharma, Ruchika; Quilty, Francis; Gilmer, John F.; Long, Aideen; Byrne, Anne-Marie

    2017-01-01

    Bile acids are components of gastro-duodenal refluxate and regarded as causative agents in oesophageal disease but the precise mechanisms are unknown. Here we demonstrate that a specific subset of physiological bile acids affect the protein secretory pathway by inducing ER stress, activating the Unfolded Protein Response (UPR) and causing disassembly of the Golgi apparatus in oesophageal cells. Deoxycholic acid (DCA), Chemodeoxycholic acid (CDCA) and Lithocholic acid (LCA) activated the PERK arm of the UPR, via phosphorylation of eIF2α and up-regulation of ATF3, CHOP and BiP/GRP78. UPR activation by these bile acids is mechanistically linked with Golgi fragmentation, as modulating the UPR using a PERK inhibitor (GSK2606414) or salubrinal attenuated bile acid-induced effects on Golgi structure. Furthermore we demonstrate that DCA, CDCA and LA activate Src kinase and that inhibition of this kinase attenuated both bile acid-induced BiP/GRP78 expression and Golgi fragmentation. This study highlights a novel mechanism whereby environmental factors (bile acids) impact important cellular processes regulating cell homeostasis, including the UPR and Golgi structure, which may contribute to cancer progression in the oesophagus. PMID:27888615

  3. PGC-1alpha activates CYP7A1 and bile acid biosynthesis.

    Science.gov (United States)

    Shin, Dong-Ju; Campos, Jose A; Gil, Gregorio; Osborne, Timothy F

    2003-12-12

    Cholesterol 7-alpha-hydroxylase (CYP7A1) is the key enzyme that commits cholesterol to the neutral bile acid biosynthesis pathway and is highly regulated. In the current studies, we have uncovered a role for the transcriptional co-activator PGC-1alpha in CYP7A1 gene transcription. PGC-1alpha plays a vital role in adaptive thermogenesis in brown adipose tissue and stimulates genes important to mitochondrial function and oxidative metabolism. It is also involved in the activation of hepatic gluconeogenesic gene expression during fasting. Because the mRNA for CYP7A1 was also induced in mouse liver by fasting, we reasoned that PGC-1alpha might be an important co-activator for CYP7A1. Here we show that PGC-1alpha and CYP7A1 are also co-induced in livers of mice in response to streptozotocin induced diabetes. Additionally, infection of cultured HepG2 cells with a recombinant adenovirus expressing PGC-1alpha directly activates CYP7A1 gene expression and increases bile acid biosynthesis as well. Furthermore, we show that PGC-1alpha activates the CYP7A1 promoter directly in transient transfection assays in cultured cells. Thus, PGC-1alpha is a key activator of CYP7A1 and bile acid biosynthesis and is likely responsible for the fasting and diabetes dependent induction of CYP7A1. PGC-1alpha has already been shown to be a critical activator of several other oxidative processes including adaptive thermogenesis and fatty acid oxidation. Our studies provide further evidence of the fundamental role played by PGC-1alpha in oxidative metabolism and define PGC-1alpha as a link between diabetes and bile acid metabolism.

  4. Increased cholesterol 7α-hydroxylase expression and size of the bile acid pool in the lactating rat

    Science.gov (United States)

    Wooton-Kee, Clavia Ruth; Cohen, David E.; Vore, Mary

    2008-01-01

    Maximal bile acid secretory rates and expression of bile acid transporters in liver and ileum are increased in lactation, possibly to facilitate increased enterohepatic recirculation of bile acids. We determined changes in the size and composition of the bile acid pool and key enzymes of the bile acid synthetic pathway [cholesterol 7α-hydroxylase (Cyp7a1), sterol 27-hydroxylase (Cyp27a1), and sterol 12α-hydroxylase (Cyp8b1)] in lactating rats relative to female virgin controls. The bile acid pool increased 1.9 to 2.5-fold [postpartum (PP) days 10, 14, and 19–23], compared with controls. A 1.5-fold increase in cholic acids and a 14 to 20% decrease in muricholic acids in lactation significantly increased the hydrophobicity index. In contrast, the hepatic concentration of bile acids and small heterodimer partner mRNA were unchanged in lactation. A 2.8-fold increase in Cyp7a1 mRNA expression at 16 h (10 h of light) demonstrated a shift in the diurnal rhythm at day 10 PP; Cyp7a1 protein expression and cholesterol 7α-hydroxylase activity were significantly increased at this time and remained elevated at day 14 PP but decreased to control levels by day 21 PP. There was an overall decrease in Cyp27a1 mRNA expression and a 20% decrease in Cyp27a1 protein expression, but there was no change in Cyp8b1 mRNA or protein expression at day 10 PP. The increase in Cyp7a1 expression PP provides a mechanism for the increase in the bile acid pool. PMID:18292185

  5. Metabolism of phytanic acid and 3-methyl-adipic acid excretion in patients with adult Refsum disease.

    Science.gov (United States)

    Wierzbicki, Anthony S; Mayne, Phillip D; Lloyd, Matthew D; Burston, David; Mei, Guam; Sidey, Margaret C; Feher, Michael D; Gibberd, F Brian

    2003-08-01

    Adult Refsum disease (ARD) is associated with defective alpha-oxidation of phytanic acid (PA). omega-Oxidation of PA to 3-methyl-adipic acid (3-MAA) occurs although its clinical significance is unclear. In a 40 day study of a new ARD patient, where the plasma half-life of PA was 22.4 days, omega-oxidation accounted for 30% initially and later all PA excretion. Plasma and adipose tissue PA and 3-MAA excretion were measured in a cross-sectional study of 11 patients. The capacity of the omega-oxidation pathway was 6.9 (2.8-19.4) mg [20.4 (8.3-57.4) micromol] PA/day. 3-MAA excretion correlated with plasma PA levels (r = 0.61; P = 0.03) but not adipose tissue PA content. omega-Oxidation during a 56 h fast was studied in five patients. 3-MAA excretion increased by 208 +/- 58% in parallel with the 158 (125-603)% rise in plasma PA. Plasma PA doubled every 29 h, while 3-MAA excretion followed second-order kinetics. Acute sequelae of ARD were noted in three patients (60%) after fasting. The omega-oxidation pathway can metabolise PA ingested by patients with ARD, but this activity is dependent on plasma PA concentration. omega-Oxidation forms a functional reserve capacity that enables patients with ARD undergoing acute stress to cope with limited increases in plasma PA levels.

  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. Bile acid-induced arrhythmia is mediated by muscarinic M2 receptors in neonatal rat cardiomyocytes.

    Directory of Open Access Journals (Sweden)

    Siti H Sheikh Abdul Kadir

    Full Text Available BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP is a common disease affecting up to 5% of pregnancies and which can cause fetal arrhythmia and sudden intrauterine death. We previously demonstrated that bile acid taurocholate (TC, which is raised in the bloodstream of ICP, can acutely alter the rate and rhythm of contraction and induce abnormal calcium destabilization in cultured neonatal rat cardiomyocytes (NRCM. Apart from their hepatic functions bile acids are ubiquitous signalling molecules with diverse systemic effects mediated by either the nuclear receptor FXR or by a recently discovered G-protein coupled receptor TGR5. We aim to investigate the mechanism of bile-acid induced arrhythmogenic effects in an in-vitro model of the fetal heart. METHODS AND RESULTS: Levels of bile acid transporters and nuclear receptor FXR were studied by quantitative real time PCR, western blot and immunostaining, which showed low levels of expression. We did not observe functional involvement of the canonical receptors FXR and TGR5. Instead, we found that TC binds to the muscarinic M(2 receptor in NRCM and serves as a partial agonist of this receptor in terms of inhibitory effect on intracellular cAMP and negative chronotropic response. Pharmacological inhibition and siRNA-knockdown of the M(2 receptor completely abolished the negative effect of TC on contraction, calcium transient amplitude and synchronisation in NRCM clusters. CONCLUSION: We conclude that in NRCM the TC-induced arrhythmia is mediated by the partial agonism at the M(2 receptor. This mechanism might serve as a promising new therapeutic target for fetal arrhythmia.

  8. Evaluation of a semiquantitative SNAP test for measurement of bile acids in dogs

    Directory of Open Access Journals (Sweden)

    Rachel L. Seibert

    2014-08-01

    Full Text Available Background. Serum bile acids (SBA are used as a routine screening tool of liver function in dogs. Serum samples are usually shipped to a referral laboratory for quantitative analysis with an enzymatic chemistry analyzer. The canine SNAP Bile Acids Test (SNAP-BAT provides an immediate, semi-quantitative measurement of bile acid concentrations in-house. With the SNAP-BAT, bile acids concentrations of 5–30 µmol/L are quantified, and results outside of that range are classified as 30 µmol/L. Agreement of the SNAP-BAT with the enzymatic method has not been extensively investigated.Objectives. The purposes of this prospective clinical study were to assess the precision of the SNAP-BAT and determine agreement of SNAP-BAT with results from an in-house chemistry analyzer.Methods. After verifying intra-assay precision of the SNAP-BAT, a prospective analysis was performed using blood samples collected from 56 dogs suspected to have liver disease. Each sample was analyzed with an enzymatic, in-house chemistry analyzer and the SNAP-BAT. Agreement between the two methods was statistically assessed using the κ index of agreement.Results. Intra-assay variability was minimal. The κ index for agreement between the SNAP-BAT and routine chemistry analyzer was between 0.752 and 0.819, indicating substantial to near perfect agreement.Conclusions. The SNAP-BAT is a highly accurate, semi-quantitative test that yields immediate results, and has very little intra-assay variability, particularly for results >30 µmol/L.

  9. Evaluation of a semiquantitative SNAP test for measurement of bile acids in dogs.

    Science.gov (United States)

    Seibert, Rachel L; Tobias, Karen M; Reed, Ann; Snyder, Karl R

    2014-01-01

    Background. Serum bile acids (SBA) are used as a routine screening tool of liver function in dogs. Serum samples are usually shipped to a referral laboratory for quantitative analysis with an enzymatic chemistry analyzer. The canine SNAP Bile Acids Test (SNAP-BAT) provides an immediate, semi-quantitative measurement of bile acid concentrations in-house. With the SNAP-BAT, bile acids concentrations of 5-30 µmol/L are quantified, and results outside of that range are classified as 30 µmol/L. Agreement of the SNAP-BAT with the enzymatic method has not been extensively investigated. Objectives. The purposes of this prospective clinical study were to assess the precision of the SNAP-BAT and determine agreement of SNAP-BAT with results from an in-house chemistry analyzer. Methods. After verifying intra-assay precision of the SNAP-BAT, a prospective analysis was performed using blood samples collected from 56 dogs suspected to have liver disease. Each sample was analyzed with an enzymatic, in-house chemistry analyzer and the SNAP-BAT. Agreement between the two methods was statistically assessed using the κ index of agreement. Results. Intra-assay variability was minimal. The κ index for agreement between the SNAP-BAT and routine chemistry analyzer was between 0.752 and 0.819, indicating substantial to near perfect agreement. Conclusions. The SNAP-BAT is a highly accurate, semi-quantitative test that yields immediate results, and has very little intra-assay variability, particularly for results >30 µmol/L.

  10. 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...

  11. Separating Tumorigenicity from Bile Acid Regulatory Activity for Endocrine Hormone FGF19.

    Science.gov (United States)

    Zhou, Mei; Wang, Xueyan; Phung, Van; Lindhout, Darrin A; Mondal, Kalyani; Hsu, Jer-Yuan; Yang, Hong; Humphrey, Mark; Ding, Xunshan; Arora, Taruna; Learned, R Marc; DePaoli, Alex M; Tian, Hui; Ling, Lei

    2014-06-15

    Hepatocellular carcinoma (HCC), one of the leading causes of cancer-related death, develops from premalignant lesions in chronically damaged livers. Although it is well established that FGF19 acts through the receptor complex FGFR4-β-Klotho (KLB) to regulate bile acid metabolism, FGF19 is also implicated in the development of HCC. In humans, FGF19 is amplified in HCC and its expression is induced in the liver under cholestatic and cirrhotic conditions. In mice, ectopic overexpression of FGF19 drives HCC development in a process that requires FGFR4. In this study, we describe an engineered FGF19 (M70) that fully retains bile acid regulatory activity but does not promote HCC formation, demonstrating that regulating bile acid metabolism is distinct and separable from tumor-promoting activity. Mechanistically, we show that FGF19 stimulates tumor progression by activating the STAT3 pathway, an activity eliminated by M70. Furthermore, M70 inhibits FGF19-dependent tumor growth in a rodent model. Our results suggest that selectively targeting the FGF19-FGFR4 pathway may offer a tractable approach to improve the treatment of chronic liver disease and cancer.

  12. Relationship between entero-hepatic bile acid circulation and interdigestive migrating myoelectrical activity in rats

    Institute of Scientific and Technical Information of China (English)

    Ping Fang; Lei Dong; Wei-Jin Zhang; Jin-Yan Luo

    2005-01-01

    AIM: To investigate the effects of entero-hepatic bile acid circulation on the inter-digestive migrating myoelectrical complex (MMC) in rats.METHODS: Thirty-two rats were divided into four groups.Three pairs of bipolar silver electrodes were chronically implanted in the antrum, duodenum and jejunum. Three groups of them were ligated around the upper part of common bile duct (CBD). The experiments were performed in conscious and fasting state. The gastrointestinal myoelectrical activity was recorded. Ursodeoxycholic acid (UDCA) and saline were then perfused into stomachs of two groups with CBD obstruction and the effects of them on the MMC were observed.RESULTS: A typical pattern of MMC was observed in normal fasting rats. MMC of antral and duodenal origin disappeared temporarily in earlier stage of CBD obstruction. While MMC of jejunum origin appeared.increased MMC cycle duration was seen after 4 d in rats with CBD obstruction. The MMC after CBD obstruction was characterized by an increased duration of phase Ⅱ-like activity and decreased duration of phase Ⅰ & Ⅲ activity.Perfusion into stomachs with UDCA resulted in a shorter MMC cycle duration and a longer duration of phase Ⅲ of duodenal origin compared to the normal group.CONCLUSION: Entero-hepatic bile acid circulation initiates inter-digestive MMC of duodenal origin.

  13. FGF15/FGFR4 integrates growth factor signaling with hepatic bile acid metabolism and insulin action.

    Science.gov (United States)

    Shin, Dong-Ju; Osborne, Timothy F

    2009-04-24

    The current studies show FGF15 signaling decreases hepatic forkhead transcription factor 1 (FoxO1) activity through phosphatidylinositol (PI) 3-kinase-dependent phosphorylation. The bile acid receptor FXR (farnesoid X receptor) activates expression of fibroblast growth factor (FGF) 15 in the intestine, which acts through hepatic FGFR4 to suppress cholesterol-7alpha hydroxylase (CYP7A1) and limit bile acid production. Because FoxO1 activity and CYP7A1 gene expression are both increased by fasting, we hypothesized CYP7A1 might be a FoxO1 target gene. Consistent with recently reported results, we show CYP7A1 is a direct target of FoxO1. Additionally, we show that the PI 3-kinase pathway is key for both the induction of CYP7A1 by fasting and the suppression by FGF15. FGFR4 is the major hepatic FGF receptor isoform and is responsible for the hepatic effects of FGF15. We also show that expression of FGFR4 in liver was decreased by fasting, increased by insulin, and reduced by streptozotocin-induced diabetes, implicating FGFR4 as a primary target of insulin regulation. Because insulin and FGF both target the PI 3-kinase pathway, these observations suggest FoxO1 is a key node in the convergence of FGF and insulin signaling pathways and functions as a key integrator for the regulation of glucose and bile acid metabolism.

  14. Effect of Roux-en-Y gastric bypass surgery on bile acid metabolism in normal and obese diabetic rats.

    Directory of Open Access Journals (Sweden)

    Hina Y Bhutta

    Full Text Available In addition to classic functions of facilitating hepatobiliary secretion and intestinal absorption of lipophilic nutrients, bile acids (BA are also endocrine factors and regulate glucose and lipid metabolism. Recent data indicate that antiobesity bariatric procedures e.g. Roux-en-Y gastric bypass surgery (RYGB, which also remit diabetes, increase plasma BAs in humans, leading to the hypothesis that BAs may play a role in diabetes resolution following surgery. To investigate the effect of RYGB on BA physiology and its relationship with glucose homeostasis, we undertook RYGB and SHAM surgery in Zucker diabetic fatty (ZDF and normoglycemic Sprague Dawley (SD rats and measured plasma and fecal BA levels, as well as plasma glucose, insulin, Glucagon like peptide 1 (GLP-1 and Peptide YY (PYY, 2 days before and 3, 7, 14 and 28 days after surgery. RYGB decreased body weight and increased plasma GLP-1 in both SD and ZDF rats while decreasing plasma insulin and glucose in ZDF rats starting from the first week. Compared to SHAM groups, both SD-RYGB and ZDF-RYGB groups started to have increases in plasma total BAs in the second week, which might not contribute to early post-surgery metabolic changes. While there was no significant difference in fecal BA excretion between SD-RYGB and SD-SHAM groups, the ZDF-RYGB group had a transient 4.2-fold increase (P<0.001 in 24-hour fecal BA excretion on post-operative day 3 compared to ZDF-SHAM, which paralleled a significant increase in plasma PYY. Ratios of plasma and fecal cholic acid/chenodeoxycholic acid derived BAs were decreased in RYGB groups. In addition, tissue mRNA expression analysis suggested early intestinal BA reabsorption and potentially reduced hepatic cholic acid production in RYGB groups. In summary, we present novel data on RYGB-mediated changes in BA metabolism to further understand the role of BAs in RYGB-induced metabolic effects in humans.

  15. [Ecogenetic aspects of the study of phenotypes and levels of beta-aminoisobutyric acid excretion].

    Science.gov (United States)

    Spitsyn, V A; Afanas'eva, I S; Alekseeva, N V

    1993-11-01

    The levels of excretion of beta-aminoisobutyric acid (BAIB) in urea were examined in five groups. The distribution of BAIB concentration revealed the existence of high and low excretors in each group. Asbestosis patients had the lowest frequency of high excretors. The BAIB concentration among high excretors was similar for all the groups. The BAIB levels of low excretors varied. The most alike were two children groups, asbestosis patients and the workers from the town Asbest.

  16. Hypercholesterolemia and changes in lipid and bile acid metabolism in male and female cyp7A1-deficient mice.

    Science.gov (United States)

    Erickson, Sandra K; Lear, Steven R; Deane, Sean; Dubrac, Sandrine; Huling, Sandra L; Nguyen, Lien; Bollineni, Jaya S; Shefer, Sarah; Hyogo, Hideyuki; Cohen, David E; Shneider, Benjamin; Sehayek, Ephraim; Ananthanarayanan, Meena; Balasubramaniyan, Natarajan; Suchy, Fredrick J; Batta, Ashok K; Salen, Gerald

    2003-05-01

    Cholesterol 7alpha-hydroxylase, a rate-limiting enzyme for bile acid synthesis, has been implicated in genetic susceptibility to atherosclerosis. The gene, CYP7A1, encoding a protein with this activity, is expressed normally only in hepatocytes and is highly regulated. Our cyp7A1 gene knockout mouse colony, as young adults on a chow diet, is hypercholesterolemic. These mice were characterized extensively to understand how cyp7A1 affects lipid and bile acid homeostasis in different tissue compartments and whether gender plays a modifying role. Both male and female cyp7A1-deficient mice had decreased hepatic LDL receptors, unchanged hepatic cholesterol synthesis, increased intestinal cholesterol synthesis and bile acid transporters, and decreased fecal bile acids but increased fecal sterols. In females, cyp7A1 deficiency also caused changes in hepatic fatty acid metabolism, decreased hepatic canalicular bile acid transporter, Bsep, and gallbladder bile composition altered to a lithogenic profile. Taken together, the data suggest that cyp7A1 deficiency results in a proatherogenic phenotype in both genders and leads to a prolithogenic phenotype in females.

  17. Pepsin and bile acid concentrations in sputum of mustard gas exposed patients

    Directory of Open Access Journals (Sweden)

    Ashraf Karbasi

    2013-01-01

    Full Text Available Background/Aim: Gastro-esophageal reflux has been suggested to be associated with several pulmonary complications such as asthma, and post-transplant bronchiolitis obliterans (BO. Pepsin or bile salts in the sputum is shown to be an optimal molecular marker of gastric contents macro/micro aspiration. In this study, we investigated sputum pepsin as a marker of micro-aspiration in sulfur mustard (SM exposed cases compared to healthy controls. Materials and Methods: In a case controlled study, 26 cases with BO and 12 matched healthy controls were recruited and all cases were symptomatic and their exposure to SM was previously documented during Iran-Iraq conflict. Pepsin levels in sputum and total bile acids were measured using enzymatic assay. The severity of respiratory disorder was categorized based upon the spirometric values. Result: The average concentration of pepsin in sputum was higher in the case group (0.29 ± 0.23 compared with healthy subjects (0.13 ± 0.07; P ± 0.003. Moreover, the average concentration of bile acids in the sputum cases was not significantly different in comparison to the controls ( P = 0.5. Conclusion: Higher pepsin concentrations in sputum of SM exposed patients compared with healthy control subjects indicate the occurrence of significantly more gastric micro-aspiration in SM exposed patients.

  18. Bile acid synthesis in man. In vivo activity of the 25-hydroxylation pathway.

    OpenAIRE

    Duane, W C; Pooler, P A; Hamilton, J N

    1988-01-01

    During biosynthesis of bile acid, carbons 25-26-27 are removed from the cholesterol side-chain. Side-chain oxidation begins either with hydroxylation at the 26-position, in which case the three-carbon fragment is released as propionic acid, or with hydroxylation at the 25-position, in which case the three-carbon fragment is released as acetone. We have previously shown in the rat that the contribution of the 25-hydroxylation pathway can be quantitated in vivo by measuring production of [14C]a...

  19. Effect of penicillin on fatty acid synthesis and excretion in Streptococcus mutans BHT

    Energy Technology Data Exchange (ETDEWEB)

    Brissette, J.L.; Pieringer, R.A.

    1985-03-01

    Treatment of exponentially growing cultures of Streptococcus mutans BHT with growth-inhibitory concentrations (0.2 microgram/ml) of benzylpenicillin stimulates the incorporation of (2-/sup 14/C) acetate into lipids excreted by the cells by as much as 69-fold, but does not change the amount of /sup 14/C incorporated into intracellular lipids. At this concentration of penicillin cellular lysis does not occur. The radioactive label is incorporated exclusively into the fatty acid moieties of the glycerolipids. During a 4-hr incubation in the presence of penicillin, the extracellular fatty acid ester concentration increases 1.5 fold, even though there is no growth or cellular lysis. An indication of the relative rate of fatty acid synthesis was most readily obtained by placing S. mutans BHT in a buffer containing /sup 14/C-acetate. Under these nongrowing conditions free fatty acids are the only lipids labeled, a factor which simplifies the assay. The addition of glycerol to the buffer causes all of the nonesterified fatty acids to be incorporated into glycerolipid. The cells excrete much of the lipid whether glycerol is present or not. Addition of penicillin to the nongrowth supporting buffer system does not stimulate the incorporation of (/sup 14/C)-acetate into fatty acids.

  20. Biotransformation of acrolein in rat: excretion of mercapturic acids after inhalation and intraperitoneal injection.

    Science.gov (United States)

    Linhart, I; Frantík, E; Vodicková, L; Vosmanská, M; Smejkal, J; Mitera, J

    1996-01-01

    Biotransformation of acrolein (ACR) was studied in vivo in the rat following inhalation and ip administration. The major and minor urinary metabolites were 3-hydroxypropylmercapturic acid (HPMA) and 2-carboxyethylmercapturic acid (CEMA), respectively. Male Wistar rats were exposed to ACR, 23, 42, 77 and 126 mg/m3, for 1 hr. The sum of mercapturic acids HPMA and CEMA excreted within 24 hr after the exposure amounted to 0.87 +/- 0.12, 1.34 +/- 0.5, 2.81 +/- 1.15, and 7.13 +/- 1.56 mumol/kg, i.e., 10.9 +/- 1.5, 13.3 +/- 5.0, 16.7 +/- 6.9, and 21.5 +/- 4.8% of the estimated absorbed dose, respectively. The dose estimate was based on reported values of minute respiratory volume and respiratory tract retention and was corrected for the ACR-induced changes in minute respiratory volume. In the relevant dose range (8.9 to 35.7 mumol/kg) the portion of mercapturic acids excreted was nearly constant for ip exposed rats. The sum of HPMA and CEMA amounted to 29.1 +/- 6.5% of the dose. These results indicate that the deficiency in rat lung metabolism of ACR to acrylic acid previously observed is not compensated by the other detoxication pathway in vivo, mercapturic acid formation. The health hazard arising from inhalation of ACR is likely to be higher than that from other routes of exposure.

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

    Science.gov (United States)

    Liu, Jie; Lu, Yuan-Fu; Zhang, Youcai; Wu, Kai Connie; Fan, Fang; Klaassen, Curtis D

    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.

  2. Bile acids stimulate chloride secretion through CFTR and calcium-activated Cl- channels in Calu-3 airway epithelial cells.

    Science.gov (United States)

    Hendrick, Siobhán M; Mroz, Magdalena S; Greene, Catherine M; Keely, Stephen J; Harvey, Brian J

    2014-09-01

    Bile acids resulting from the aspiration of gastroesophageal refluxate are often present in the lower airways of people with cystic fibrosis and other respiratory distress diseases. Surprisingly, there is little or no information on the modulation of airway epithelial ion transport by bile acids. The secretory effect of a variety of conjugated and unconjugated secondary bile acids was investigated in Calu-3 airway epithelial cells grown under an air-liquid interface and mounted in Ussing chambers. Electrogenic transepithelial ion transport was measured as short-circuit current (Isc). The taurine-conjugated secondary bile acid, taurodeoxycholic acid (TDCA), was found to be the most potent modulator of basal ion transport. Acute treatment (5 min) of Calu-3 cells with TDCA (25 μM) on the basolateral side caused a stimulation of Isc, and removal of extracellular Cl(-) abolished this response. TDCA produced an increase in the cystic fibrosis transmembrane conductance regulator (CFTR)-dependent current that was abolished by pretreatment with the CFTR inhibitor CFTRinh172. TDCA treatment also increased Cl(-) secretion through calcium-activated chloride (CaCC) channels and increased the Na(+)/K(+) pump current. Acute treatment with TDCA resulted in a rapid cellular influx of Ca(2+) and increased cAMP levels in Calu-3 cells. Bile acid receptor-selective activation with INT-777 revealed TGR5 localized at the basolateral membrane as the receptor involved in TDCA-induced Cl(-) secretion. In summary, we demonstrate for the first time that low concentrations of bile acids can modulate Cl(-) secretion in airway epithelial cells, and this effect is dependent on both the duration and sidedness of exposure to the bile acid.

  3. Intestinal absorption and postabsorptive metabolism of linoleic acid in rats with short-term bile duct ligation

    NARCIS (Netherlands)

    Minich, DM; Havinga, R; Stellaard, F; Vonk, RJ; Kuipers, F; Verkade, HJ

    2000-01-01

    We investigated in bile duct-ligated (BDL) and sham-operated control rats whether the frequent presence of essential fatty acid deficiency in cholestatic liver disease could be related to linoleic acid malabsorption, altered linoleic acid metabolism, or both. In plasma of BDL rats, the triene-to-tet

  4. 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.

  5. Distribution and excretion of arsenic in cynomolgus monkey following repeated administration of diphenylarsinic acid

    Energy Technology Data Exchange (ETDEWEB)

    Kobayashi, Yayoi [National Institute for Environmental Studies, Environmental Health Sciences Division, Tsukuba, Ibaraki (Japan); Negishi, Takayuki [Aoyama Gakuin University, Department of Chemistry and Biological Science, Tokyo (Japan); Mizumura, Ayano; Watanabe, Takayuki [Chiba University, Graduate School of Pharmaceutical Sciences, Chiba (Japan); Hirano, Seishiro [Chiba University, Graduate School of Pharmaceutical Sciences, Chiba (Japan); National Institute for Environmental Studies, Research Center for Environmental Risk, Tsukuba, Ibaraki (Japan)

    2008-08-15

    Diphenylarsinic acid (DPAA), a possible product of degradation of arsenic-containing chemical weapons, was detected in well water in Kamisu City, Ibaraki Prefecture, Japan, in 2003. Although some individuals in this area have been affected by drinking DPAA-containing water, toxicological findings on DPAA are limited. To elucidate the mechanism of its toxicity, it is necessary to determine the metabolic behavior of DPAA in the body. In this study, pregnant cynomolgus monkeys at the 50th day of pregnancy were used. The monkeys were treated daily with 1.0 mg DPAA/kg body weight using a nasogastric tube, and the distribution and excretion of arsenic were examined after the repeated administration and 198-237 days after the last administration of DPAA. Fecal excretion was higher than urinary excretion (ca. 3:2 ratio), and arsenic accumulated in the hair and erythrocytes. Distribution of DAPP to plasma and hemolyzed erythrocytes was also examined by high-performance liquid chromatography-inductively coupled argon plasma mass spectrometry (HPLC-ICP MS). Two peaks were found in the elution profile of arsenic, due to free and probably protein-bound DPAA. The protein-bound arsenic compounds were presumably trivalent diphenylarsenic compounds, since free DPAA was recovered after treatment of heat-denatured samples with hydrogen peroxide. (orig.)

  6. Role of bile acids in the regulation of the metabolic pathways

    Institute of Scientific and Technical Information of China (English)

    Hiroki; Taoka; Yoko; Yokoyama; Kohkichi; Morimoto; Naho; Kitamura; Tatsuya; Tanigaki; Yoko; Takashina; Kazuo; Tsubota; Mitsuhiro; Watanabe

    2016-01-01

    Recent studies have revealed that bile acids(BAs)are not only facilitators of dietary lipid absorption but also important signaling molecules exerting multiple physiological functions.Some major signaling pathways involving the nuclear BAs receptor farnesoid X receptor and the G protein-coupled BAs receptor TGR5/M-BAR have been identified to be the targets of BAs.BAs regulate their own homeostasis via signaling pathways.BAs also affect diverse metabolic pathways including glucose metabolism,lipid metabolism and energy expenditure.This paper suggests the mechanism of controlling metabolism via BA signaling and demonstrates that BA signaling is an attractive therapeutic target of the metabolic syndrome.

  7. 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

    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......-tocopherol acetate) in higher levels in the intestine of GF mice compared to MC mice, suggesting that NCFM either metabolizes the compound orindirectly affects the absorption by changing the metabolome in the intestine. The use of NCFM to increase the uptake of vitamin E supplements in humans and animals is a highly...

  8. 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

  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. 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...... intestinal adaptation in weanling pigs. During the first 6 d after weaning, piglets were intragastrically infused once daily with either deionized water (control), chenodeoxycholic acid (CDC; 60 mg/kg body weight), or β-sitoesterol (BSE; 100 mg/kg body weight). Infusing CDC increased plasma GLP-2 (P ....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...

  11. Megalin and cubilin expression in gallbladder epithelium and regulation by bile acids.

    Science.gov (United States)

    Erranz, Benjamín; Miquel, Juan Francisco; Argraves, W Scott; Barth, Jeremy L; Pimentel, Fernando; Marzolo, María-Paz

    2004-12-01

    Cholesterol crystal formation in the gallbladder is a key step in gallstone pathogenesis. Gallbladder epithelial cells might prevent luminal gallstone formation through a poorly understood cholesterol absorption process. Genetic studies in mice have highlighted potential gallstone susceptibility alleles, Lith genes, which include the gene for megalin. Megalin, in conjunction with the large peripheral membrane protein cubilin, mediates the endocytosis of numerous ligands, including HDL/apolipoprotein A-I (apoA-I). Although the bile contains apoA-I and several cholesterol-binding megalin ligands, the expression of megalin and cubilin in the gallbladder has not been investigated. Here, we show that both proteins are expressed by human and mouse gallbladder epithelia. In vitro studies using a megalin-expressing cell line showed that lithocholic acid strongly inhibits and cholic and chenodeoxycholic acids increase megalin expression. The effects of bile acids (BAs) were also demonstrated in vivo, analyzing gallbladder levels of megalin and cubilin from mice fed with different BAs. The BA effects could be mediated by the farnesoid X receptor, expressed in the gallbladder. Megalin protein was also strongly increased after feeding a lithogenic diet. These results indicate a physiological role for megalin and cubilin in the gallbladder and provide support for a role for megalin in gallstone pathogenesis.

  12. A liquid chromatography-tandem mass spectrometry-based method for the simultaneous determination of hydroxy sterols and bile acids.

    Science.gov (United States)

    John, Clara; Werner, Philipp; Worthmann, Anna; Wegner, Katrin; Tödter, Klaus; Scheja, Ludger; Rohn, Sascha; Heeren, Joerg; Fischer, Markus

    2014-12-01

    Recently, hydroxy sterols and bile acids have gained growing interest as they are important regulators of energy homoeostasis and inflammation. The high number of different hydroxy sterols and bile acid species requires powerful analytical tools to quantify these structurally and chemically similar analytes. Here, we introduce a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based method for rapid quantification of 34 sterols (hydroxy sterols, primary, secondary bile acids as well as their taurine and glycine conjugates). Chromatographic baseline separation of isomeric hydroxy sterols and bile acids is obtained using a rugged amide embedded C18 (polar embedded) stationary phase. The current method features a simple extraction protocol validated for blood plasma, urine, gall bladder, liver, feces, and adipose tissue avoiding solid phase extraction as well as derivatization procedures. The total extraction recovery for representative analytes ranged between 58-86% in plasma, 85% in urine, 79-92% in liver, 76-98% in adipose tissue, 93-104% in feces and 62-79% in gall bladder. The validation procedure demonstrated that the calibration curves were linear over the selected concentration ranges for 97% of the analytes, with calculated coefficients of determination (R2) of greater than 0.99. A feeding study in wild type mice with a standard chow and a cholesterol-enriched Western type diet illustrated that the protocol described here provides a powerful tool to simultaneously quantify cholesterol derivatives and bile acids in metabolically active tissues and to follow the enterohepatic circulation.

  13. Shortcut Access to Peptidosteroid Conjugates: Building Blocks for Solid-Phase Bile Acid Scaffold Decoration by Convergent Ligation

    Directory of Open Access Journals (Sweden)

    Sara Figaroli

    2011-12-01

    Full Text Available We present three versatile solid-supported scaffold building blocks based on the (deoxycholic acid framework and decorated with handles for further derivatization by modern ligation techniques such as click chemistry, Staudinger ligation or native chemical ligation. Straightforward procedures are presented for the synthesis and analysis of the steroid constructs. These building blocks offer a new, facile and shorter access route to bile acid-peptide conjugates on solid-phase with emphasis on heterodipodal conjugates with defined spatial arrangements. As such, we provide versatile new synthons to the toolbox for bile acid decoration.

  14. Developments in bile acid kinetic measurements using C-13 and H-2 : 10(5) times improved sensitivity during the last 40 years

    NARCIS (Netherlands)

    Stellaard, Frans; Brufau, Gemma; Boverhof, Renze; Jonkers, Elles Zwanet; Boer, Theo; Kuipers, Folkert

    2009-01-01

    Bile acid kinetics involve the measurement of pool sizes and turnover rates of individual bile acids. The technique is based on isotope dilution and was first described in the 1950s using radioactive C-14-labelled cholic acid (CA). It took until the 1970s before stable isotopes were introduced for t

  15. Arsenic species excretion after dimercaptopropanesulfonic acid (DMPS) treatment of an acute arsenic trioxide poisoning

    Energy Technology Data Exchange (ETDEWEB)

    Heinrich-Ramm, R. [Ordinariat fuer Arbeitsmedizin der Universitaet Hamburg und Zentralinstitut fuer Arbeitsmedizin, Hamburg (Germany); Schaller, K.H.; Angerer, J. [Institut und Poliklinik fuer Arbeits-, Sozial- und Umweltmedizin der Universitaet Erlangen-Nuernberg, Schillerstr. 25, 91054 Erlangen (Germany); Horn, J. [Medizinische Klinik II, Toxikologische-internistische Intensivstation, Klinikum Nuernberg, Nuernberg (Germany)

    2003-02-01

    We studied the urinary excretion of the different arsenic species in urine samples from a young man who tried to commit suicide by ingesting about 0.6 g arsenic trioxide. He received immediate therapy with dimercaptopropanesulfonic acid (DMPS) after his delivery into the hospital. We assessed urinary arsenite (inorganic trivalent arsenic), arsenate (inorganic pentavalent arsenic), pentavalent dimethylarsinic acid (DMA) and pentavalent monomethylarsonic acid (MMA) in urine with ion-exchange chromatography and on-line hydride-technique atomic absorption spectrometry. The predominant amount of the excreted arsenic was unchanged trivalent inorganic arsenic (37.4%), followed by pentavalent inorganic arsenic (2.6%), MMA (2.1%), DMA (0.2%) and one unidentified arsenic species (0.7%, if calculated as DMA). In the first urine voiding in the clinic, the total arsenic concentration was 215 mg/l, which fell 1000-fold after 8 days of DMPS therapy. A most striking finding was the almost complete inhibition of the second methylation step in arsenic metabolism. As mechanisms for the reduced methylation efficiency, the saturation of the enzymatic process of arsenic methylation, the high dosage of antidote DMPS, which might inhibit the activity of the methyl transferases, and analytical reasons are discussed. The high dosage of DMPS is the most likely explanation. The patient left the hospital after a 12-day treatment with antidote. (orig.)

  16. Urinary Excretion of Phenolic Acids by Infants and Children: A Randomised Double-Blind Clinical Assay

    Science.gov (United States)

    Uberos, J.; Fernández-Puentes, V.; Molina-Oya, M.; Rodríguez-Belmonte, R.; Ruíz-López, A.; Tortosa-Pinto, P.; Molina-Carballo, A.; Muñoz-Hoyos, A.

    2012-01-01

    Objectives: The present study, which is part of the ISRCTN16968287 clinical assay, is aimed at determining the effects of cranberry syrup or trimethoprim treatment for UTI. Methods: This Phase III randomised clinical trial was conducted at the San Cecilio Clinical Hospital (Granada, Spain) with a study population of 192 patients, aged between 1 month and 13 years. Criteria for inclusion were a background of recurrent UTI, associated or otherwise with vesico-ureteral reflux of any degree, or renal pelvic dilatation associated with urinary infection. Each child was randomly given 0.2 mL/Kg/day of either cranberry syrup or trimethoprim (8 mg/mL). The primary and secondary objectives, respectively, were to determine the risk of UTI and the levels of phenolic acids in urine associated with each intervention. Results: With respect to UTI, the cranberry treatment was non-inferior to trimethoprim. Increased urinary excretion of ferulic acid was associated with a greater risk of UTI developing in infants aged under 1 year (RR 1.06; CI 95% 1.024–1.1; P = 0.001). Conclusions: The results obtained show the excretion of ferulic acid is higher in infants aged under 1 year, giving rise to an increased risk of UTI, for both treatment options. PMID:23641168

  17. Inhibition of ileal bile acid uptake protects against nonalcoholic fatty liver disease in high-fat diet-fed mice.

    Science.gov (United States)

    Rao, Anuradha; Kosters, Astrid; Mells, Jamie E; Zhang, Wujuan; Setchell, Kenneth D R; Amanso, Angelica M; Wynn, Grace M; Xu, Tianlei; Keller, Brad T; Yin, Hong; Banton, Sophia; Jones, Dean P; Wu, Hao; Dawson, Paul A; Karpen, Saul J

    2016-09-21

    Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world, and safe and effective therapies are needed. Bile acids (BAs) and their receptors [including the nuclear receptor for BAs, farnesoid X receptor (FXR)] play integral roles in regulating whole-body metabolism and hepatic lipid homeostasis. We hypothesized that interruption of the enterohepatic BA circulation using a luminally restricted apical sodium-dependent BA transporter (ASBT) inhibitor (ASBTi; SC-435) would modify signaling in the gut-liver axis and reduce steatohepatitis in high-fat diet (HFD)-fed mice. Administration of this ASBTi increased fecal BA excretion and messenger RNA (mRNA) expression of BA synthesis genes in liver and reduced mRNA expression of ileal BA-responsive genes, including the negative feedback regulator of BA synthesis, fibroblast growth factor 15. ASBT inhibition resulted in a marked shift in hepatic BA composition, with a reduction in hydrophilic, FXR antagonistic species and an increase in FXR agonistic BAs. ASBT inhibition restored glucose tolerance, reduced hepatic triglyceride and total cholesterol concentrations, and improved NAFLD activity score in HFD-fed mice. These changes were associated with reduced hepatic expression of lipid synthesis genes (including liver X receptor target genes) and normalized expression of the central lipogenic transcription factor, Srebp1c Accumulation of hepatic lipids and SREBP1 protein were markedly reduced in HFD-fed Asbt(-/-) mice, providing genetic evidence for a protective role mediated by interruption of the enterohepatic BA circulation. Together, these studies suggest that blocking ASBT function with a luminally restricted inhibitor can improve both hepatic and whole body aspects of NAFLD.

  18. Acidic bile salts modulate the squamous epithelial barrier function by modulating tight junction proteins.

    Science.gov (United States)

    Chen, Xin; Oshima, Tadayuki; Tomita, Toshihiko; Fukui, Hirokazu; Watari, Jiro; Matsumoto, Takayuki; Miwa, Hiroto

    2011-08-01

    Experimental models for esophageal epithelium in vitro either suffer from poor differentiation or complicated culture systems. An air-liquid interface system with normal human bronchial epithelial cells can serve as a model of esophageal-like squamous epithelial cell layers. Here, we explore the influence of bile acids on barrier function and tight junction (TJ) proteins. The cells were treated with taurocholic acid (TCA), glycocholic acid (GCA), or deoxycholic acid (DCA) at different pH values, or with pepsin. Barrier function was measured by transepithelial electrical resistance (TEER) and the diffusion of paracellular tracers (permeability). The expression of TJ proteins, including claudin-1 and claudin-4, was examined by Western blotting of 1% Nonidet P-40-soluble and -insoluble fractions. TCA and GCA dose-dependently decreased TEER and increased paracellular permeability at pH 3 after 1 h. TCA (4 mM) or GCA (4 mM) did not change TEER and permeability at pH 7.4 or pH 4. The combination of TCA and GCA at pH 3 significantly decreased TEER and increased permeability at lower concentrations (2 mM). Pepsin (4 mg/ml, pH 3) did not have any effect on barrier function. DCA significantly decreased the TEER and increased permeability at pH 6, a weakly acidic condition. TCA (4 mM) and GCA (4 mM) significantly decreased the insoluble fractions of claudin-1 and claudin-4 at pH 3. In conclusion, acidic bile salts disrupted the squamous epithelial barrier function partly by modulating the amounts of claudin-1 and claudin-4. These results provide new insights for understanding the role of TJ proteins in esophagitis.

  19. Opposing effects of bile acids deoxycholic acid and ursodeoxycholic acid on signal transduction pathways in oesophageal cancer cells.

    Science.gov (United States)

    Abdel-Latif, Mohamed M; Inoue, Hiroyasu; Reynolds, John V

    2016-09-01

    Ursodeoxycholic acid (UDCA) was reported to reduce bile acid toxicity, but the mechanisms underlying its cytoprotective effects are not fully understood. The aim of the present study was to examine the effects of UDCA on the modulation of deoxycholic acid (DCA)-induced signal transduction in oesophageal cancer cells. Nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) activity was assessed using a gel shift assay. NF-κB activation and translocation was performed using an ELISA-based assay and immunofluorescence analysis. COX-2 expression was analysed by western blotting and COX-2 promoter activity was assessed by luciferase assay. DCA induced NF-κB and AP-1 DNA-binding activities in SKGT-4 and OE33 cells. UDCA pretreatment inhibited DCA-induced NF-κB and AP-1 activation and NF-κB translocation. This inhibitory effect was coupled with a blockade of IκB-α degradation and inhibition of phosphorylation of IKK-α/β and ERK1/2. Moreover, UDCA pretreatment inhibited COX-2 upregulation. Using transient transfection of the COX-2 promoter, UDCA pretreatment abrogated DCA-induced COX-2 promoter activation. In addition, UDCA protected oesophageal cells from the apoptotic effects of deoxycholate. Our findings indicate that UDCA inhibits DCA-induced signalling pathways in oesophageal cancer cells. These data indicate a possible mechanistic role for the chemopreventive actions of UDCA in oesophageal carcinogenesis.

  20. In vitro bile acid-binding capacity of dietary fibre sources and their effects with bile acid on broiler chicken performance and lipid digestibility.

    Science.gov (United States)

    Hemati Matin, H R; Shariatmadari, F; Karimi Torshizi, M A; Chiba, L I

    2016-06-01

    A 4 × 2 factorial experiment was conducted to study the effect of feeding diets-containing dietary fibre (DF) sources and a source of bile acid (BA) on growth performance and lipid metabolism. In addition, in vitro BA-binding capacity of fibre sources was investigated. A total of 256 one-d-old male broiler chickens (Ross 308) were assigned to DF sources [maize-soybean meal (control, C), or 30 g/kg of wheat bran (WB), barley bran (BB) or soybean hulls (SH)] and BA (with or without 1.5 g Na-deoxycholate/kg). Each treatment was replicated 4 times with 8 broiler chickens per cage. The highest in vitro BA-binding capacity was observed with BB (8.76 mg/g BB). From 0 to 21 d, with the addition of BA, the average daily feed intake (ADFI) decreased in broiler chickens fed on the C, WB or BB diets, while there was no difference with the SH diet. With added BA, the average daily gain decreased in broiler chickens fed on the C or SH diets, but it did not change in those fed on the other diets. The addition of BA decreased feed conversion ratio (FCR) in broiler chickens fed on the BB or WB diets, but it increased in those fed on the C or SH diets. Interaction results indicated that the apparent ileal digestibility of lipid increased in broiler chickens fed the C and other DF diets with BA compared to those fed the diets without BA. The addition of BA decreased the pancreas lipase activity (PLA) in broiler chickens fed on the C diet compared to those fed the C diet without BA, while no changes observed in those fed the DF diets with or without BA. No interaction was observed in total liver bile acid (TLBA). The WB, BB and SH with little Na-deoxycholate-binding capacity (chickens. The magnitude of improvement in digestibility of lipid with the addition of BA depends on the source of fibre used and the addition of BA in DF diets had little effect on growth performance in young broiler chicken diets.

  1. Organic acid metabolism and root excretion of malate in wheat cultivars under aluminium stress.

    Science.gov (United States)

    de Andrade, Leide Rovênia Miranda; Ikeda, Motoki; do Amaral, Lourdes Isabel Velho; Ishizuka, Junji

    2011-01-01

    The effects of aluminium (Al) on the metabolism of organic acids synthesised via nonphotosynthetic carbon fixation in the roots and on malate exudation were investigated in Al-tolerant Shirosanjyaku (SH) and Al-sensitive Chikushikomugi (CK) wheat cultivars labelled with bicarbonate-(14)C. Aluminum triggered the excretion of (14)C into the solution, especially in the SH that excreted 2.5 times more (14)C than the CK. The loss of radioactivity (about 10%) into the solution represented a small drain in the (14)C reserve found in the roots. In the organic acid fraction within the roots, malate contained the greatest amount of (14)C, and this amount decreased rapidly with time in both cultivars. The disappearance of radioactivity in the malate resulted from metabolism and translocation rather than to root efflux. Aluminium decreased the malate concentrations in roots of both cultivars. The Al-sensitive cultivar had higher concentrations of malate regardless of the presence of Al. It was therefore assumed that the decrease of malate concentration in roots under Al stress did not result from the decline in malate synthesis but due to an increase in malate decomposition. This response was interpreted as the result of the Al-induced stress and not as the cause of a differential Al-tolerance between the wheat cultivars. An important component of the differential Al tolerance between SH and CK is the greater ability of the Al-tolerant cultivar to excrete malate from the roots, which is independent of its internal concentration in the roots.

  2. Essential fatty acid supplemented diet increases renal excretion of prostaglandin E and water in essential fatty acid deficient rats

    DEFF Research Database (Denmark)

    Hansen, Harald S.

    1981-01-01

    Weanling male rats were fed an essential fatty acid (EFA)-deficient diet for 25 weeks and then switched to an EFA-supplemented diet for 3 weeks. Control rats received the EFA-supplemented diet for 25 weeks and then the EFA-deficient diet for 3 weeks. Throughout the last 19 weeks, the rats were...... housed in metabolic cages once a week for a 24-hr period. Urinary excretion of prostaglandin E (PGE) was estimated by radioimmunoassay. Throughout a period of 12 weeks (weeks 13-24) water consumption increased ca. 60%, and urine output and PGE excretion decreased ca. 45% and 70%, respectively, in the EFA......-deficient rats. Feeding EFA-supplemented diet to the EFA-deficient rats for 3 weeks decreased the water consumption and raised the urine output to that observed in the controls. However, the urine output was corrected within 1 day whereas the water consumption was not corrected until the second measurement 8...

  3. Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile

    Science.gov (United States)

    Buffie, Charlie G.; Bucci, Vanni; Stein, Richard R.; McKenney, Peter T.; Ling, Lilan; Gobourne, Asia; No, Daniel; Liu, Hui; Kinnebrew, Melissa; Viale, Agnes; Littmann, Eric; van den Brink, Marcel R. M.; Jenq, Robert R.; Taur, Ying; Sander, Chris; Cross, Justin R.; Toussaint, Nora C.; Xavier, Joao B.; Pamer, Eric G.

    2015-01-01

    The gastrointestinal tracts of mammals are colonized by hundreds of microbial species that contribute to health, including colonization resistance against intestinal pathogens. Many antibiotics destroy intestinal microbial communities and increase susceptibility to intestinal pathogens. Among these, Clostridium difficile, a major cause of antibiotic-induced diarrhoea, greatly increases morbidity and mortality in hospitalized patients. Which intestinal bacteria provide resistance to C. difficile infection and their in vivo inhibitory mechanisms remain unclear. Here we correlate loss of specific bacterial taxa with development of infection, by treating mice with different antibiotics that result in distinct microbiota changes and lead to varied susceptibility to C. difficile. Mathematical modelling augmented by analyses of the microbiota of hospitalized patients identifies resistance-associated bacteria common to mice and humans. Using these platforms, we determine that Clostridium scindens, a bile acid 7α-dehydroxylating intestinal bacterium, is associated with resistance to C. difficile infection and, upon administration, enhances resistance to infection in a secondary bile acid dependent fashion. Using a workflow involving mouse models, clinical studies, metagenomic analyses, and mathematical modelling, we identify a probiotic candidate that corrects a clinically relevant microbiome deficiency. These findings have implications for the rational design of targeted antimicrobials as well as microbiome-based diagnostics and therapeutics for individuals at risk of C. difficile infection.

  4. Lactobacillus acidophilus NCFM affects vitamin E acetate metabolism and intestinal bile acid signature in monocolonized mice.

    Science.gov (United States)

    Roager, Henrik M; Sulek, Karolina; Skov, Kasper; Frandsen, Henrik L; Smedsgaard, Jørn; Wilcks, Andrea; Skov, Thomas H; Villas-Boas, Silas G; Licht, Tine R

    2014-01-01

    Monocolonization of germ-free (GF) mice enables the study of specific bacterial species in vivo. Lactobacillus acidophilus NCFM(TM) (NCFM) is a probiotic strain; however, many of the mechanisms behind its health-promoting effect remain unknown. Here, we studied the effects of NCFM on the metabolome of jejunum, cecum, and colon of NCFM monocolonized (MC) and 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, in particular by deconjugation. Furthermore, we confirmed that carbohydrate metabolism is affected by NCFM in the mouse intestine as especially the digestion of oligosaccharides (penta- and tetrasaccharides) was increased in MC mice. Additionally, levels of α-tocopherol acetate (vitamin E acetate) were higher in the intestine of GF mice than in MC mice, suggesting that NCFM affects the vitamin E acetate metabolism. NCFM did not digest vitamin E acetate in vitro, suggesting that direct bacterial metabolism was not the cause of the altered metabolome in vivo. Taken together, our results suggest that NCFM affects intestinal carbohydrate metabolism, bile acid metabolism and vitamin E metabolism, although it remains to be investigated whether this effect is unique to NCFM.

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

    Science.gov (United States)

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

    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.

  6. The G protein-coupled bile acid receptor, TGR5, stimulates gallbladder filling.

    Science.gov (United States)

    Li, Tingting; Holmstrom, Sam R; Kir, Serkan; Umetani, Michihisa; Schmidt, Daniel R; Kliewer, Steven A; Mangelsdorf, David J

    2011-06-01

    TGR5 is a G protein-coupled bile acid receptor present in brown adipose tissue and intestine, where its agonism increases energy expenditure and lowers blood glucose. Thus, it is an attractive drug target for treating human metabolic disease. However, TGR5 is also highly expressed in gallbladder, where its functions are less well characterized. Here, we demonstrate that TGR5 stimulates the filling of the gallbladder with bile. Gallbladder volume was increased in wild-type but not Tgr5(-/-) mice by administration of either the naturally occurring TGR5 agonist, lithocholic acid, or the synthetic TGR5 agonist, INT-777. These effects were independent of fibroblast growth factor 15, an enteric hormone previously shown to stimulate gallbladder filling. Ex vivo analyses using gallbladder tissue showed that TGR5 activation increased cAMP concentrations and caused smooth muscle relaxation in a TGR5-dependent manner. These data reveal a novel, gallbladder-intrinsic mechanism for regulating gallbladder contractility. They further suggest that TGR5 agonists should be assessed for effects on human gallbladder as they are developed for treating metabolic disease.

  7. 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.

  8. Bile Acids and Dysbiosis in Non-Alcoholic Fatty Liver Disease.

    Directory of Open Access Journals (Sweden)

    Marialena Mouzaki

    Full Text Available Non-alcoholic fatty liver disease (NAFLD is characterized by dysbiosis. The bidirectional effects between intestinal microbiota (IM and bile acids (BA suggest that dysbiosis may be accompanied by an altered bile acid (BA homeostasis, which in turn can contribute to the metabolic dysregulation seen in NAFLD. This study sought to examine BA homeostasis in patients with NAFLD and to relate that with IM data.This was a prospective, cross-sectional study of adults with biopsy-confirmed NAFLD (non-alcoholic fatty liver: NAFL or non-alcoholic steatohepatitis: NASH and healthy controls (HC. Clinical and laboratory data, stool samples and 7-day food records were collected. Fecal BA profiles, serum markers of BA synthesis 7-alpha-hydroxy-4-cholesten-3-one (C4 and intestinal BA signalling, as well as IM composition were assessed.53 subjects were included: 25 HC, 12 NAFL and 16 NASH. Levels of total fecal BA, cholic acid (CA, chenodeoxycholic acid (CDCA and BA synthesis were higher in patients with NASH compared to HC (p<0.05 for all comparisons. The primary to secondary BA ratio was higher in NASH compared to HC (p = 0.004, but ratio of conjugated to unconjugated BAs was not different between the groups. Bacteroidetes and Clostridium leptum counts were decreased in in a subset of 16 patients with NASH compared to 25 HC, after adjusting for body mass index and weight-adjusted calorie intake (p = 0.028 and p = 0.030, respectively. C. leptum was positively correlated with fecal unconjugated lithocholic acid (LCA (r = 0.526, p = 0.003 and inversely with unconjugated CA (r = -0.669, p<0.0001 and unconjugated CDCA (r = - 0.630, p<0.0001. FGF19 levels were not different between the groups (p = 0.114.In adults with NAFLD, dysbiosis is associated with altered BA homeostasis, which renders them at increased risk of hepatic injury.

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

    Science.gov (United States)

    Prinz, Philip; Hofmann, Tobias; Ahnis, Anne; Elbelt, Ulf; Goebel-Stengel, Miriam; Klapp, Burghard F.; Rose, Matthias; Stengel, Andreas

    2015-01-01

    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 toward 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. PMID:26089773

  10. 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.

  11. Ablating L-FABP in SCP-2/SCP-x null mice impairs bile acid metabolism and biliary HDL-cholesterol secretion.

    Science.gov (United States)

    Martin, Gregory G; Atshaves, Barbara P; Landrock, Kerstin K; Landrock, Danilo; Storey, Stephen M; Howles, Philip N; Kier, Ann B; Schroeder, Friedhelm

    2014-12-01

    On the basis of their abilities to bind bile acids and/or cholesterol, the physiological role(s) of liver fatty acid-binding protein (L-FABP) and sterol carrier protein (SCP) 2/SCP-x (SCP-2/SCP-x) gene products in biliary bile acid and cholesterol formation was examined in gene-ablated male mice. L-FABP (LKO) or L-FABP/SCP-2/SCP-x [triple-knockout (TKO)] ablation markedly decreased hepatic bile acid concentration, while SCP-2/SCP-x [double-knockout (DKO)] ablation alone had no effect. In contrast, LKO increased biliary bile acid, while DKO and TKO had no effect on biliary bile acid levels. LKO and DKO also altered biliary bile acid composition to increase bile acid hydrophobicity. Furthermore, LKO and TKO decreased hepatic uptake and biliary secretion of high-density lipoprotein (HDL)-derived 22-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-23,24-bisnor-5-cholen-3β-ol (NBD-cholesterol), while DKO alone had no effect. Finally, LKO and, to a lesser extent, DKO decreased most indexes contributing to cholesterol solubility in biliary bile. These results suggest different, but complementary, roles for L-FABP and SCP-2/SCP-x in biliary bile acid and cholesterol formation. L-FABP appears to function more in hepatic retention of bile acids as well as hepatic uptake and biliary secretion of HDL-cholesterol. Conversely, SCP-2/SCP-x may function more in formation and biliary secretion of bile acid, with less impact on hepatic uptake or biliary secretion of HDL-cholesterol.

  12. Association between consumption of cruciferous vegetables and condiments and excretion in urine of isothiocyanate mercapturic acids.

    Science.gov (United States)

    Vermeulen, Martijn; van den Berg, Robin; Freidig, Andreas P; van Bladeren, Peter J; Vaes, Wouter H J

    2006-07-26

    A high intake of cruciferous vegetables is associated with a reduced risk of cancer and cardiovascular diseases. This protective effect has been linked to isothiocyanates, enzymatic hydrolysis products of glucosinolates. In this study, the metabolic fate of glucosinolates and isothiocyanates after ingestion of 19 different cruciferous vegetables was studied in three male subjects. After the consumption of 13 cruciferous vegetables (glucosinolate content, 0.01-0.94 mmol/kg) and six condiments (isothiocyanate content, 0.06-49.3 mmol/kg), eight different isothiocyanate mercapturic acids were determined in urine samples. Excretion levels after the consumption of raw vegetables and condiments were higher (bioavailability, 8.2-113%) as compared to cooked vegetables (bioavailability, 1.8-43%), but the excretion rate was similar (t1/2=2.1-3.9 h). Isothiocyanates in urine remain longer at a nonzero level after the consumption of glucosinolates from cooked vegetables, as compared to raw vegetables and condiments, and maximal levels in urine were reached about 4 h later. Isothiocyanate mercapturic acids can be used as a biomarker to reflect the active dose of isothiocyanates absorbed.

  13. Promotion of classic neutral bile acids synthesis pathway is responsible for cholesterol-lowing effect of Si-miao-yong-an decoction: Application of LC-MS/MS method to determine 6 major bile acids in rat liver and plasma.

    Science.gov (United States)

    Liu, Ziying; Zhang, Yu; Zhang, Ruowen; Gu, Liqiang; Chen, Xiaohui

    2017-02-20

    Si-miao-yong-an decoction (SMYAD), a traditional Chinese medicine formula, significantly reduced plasma TC, LDL-c levels and increased HDL-c level in hyperlipidemia rats. Liver function test and tissue section examination indicated that SMYAD improved liver function and reduced fat accumulation in hyperlipidemia rat liver. A LC-MS/MS method was established and well validated to evaluate major bile acids derived from cholesterol metabolism through the classic neutral pathway and the alternative acidic pathway (cholic acid, chenodeoxycholic acid and their taurine and glycine conjugates) in liver and plasma. Increased total 6 bile acids concentrations in both liver and plasma were observed after oral administration of 12g/kg/d, 24g/kg/d and 36g/kg/d of SMYAD in a dose dependent manner which contributed to eliminate of cholesterol. Cholic acid, taurocholic acid and glycocholic acid act as the main products of bile acid classic neutral synthesis pathway and show sharp increase (p<0.01) after treatment of SMYAD at dosage of 24-36g/kg/d. For liver samples, taurocholic acid level act as the largest growth section, while in plasma samples, cholic acid act as the largest growth section after SMYAD treatment, compared with Model group. By contrast, the main products of alternative acidic pathway (chenodeoxycholic acid and its glycine and taurine conjugates) show no significant increase after treatment of SMYAD. In conclusion, the cholesterol lowing effect of SMYAD may be related with the accelerated transformation of cholesterol into bile acids through the classic neutral pathway.

  14. Decreased bile-acid synthesis in livers of hepatocyte-conditional NADPH-cytochrome P450 reductase-null mice results in increased bile acids in serum.

    Science.gov (United States)

    Cheng, Xingguo; Zhang, Youcai; Klaassen, Curtis D

    2014-10-01

    NADPH-cytochrome P450 reductase (Cpr) is essential for the function of microsomal cytochrome P450 monooxygenases (P450), including those P450s involved in bile acid (BA) synthesis. Mice with hepatocyte-specific deletion of NADPH-cytochrome P450 reductase (H-Cpr-null) have been engineered to understand the in vivo function of hepatic P450s in the metabolism of xenobiotics and endogenous compounds. However, the impact of hepatic Cpr on BA homeostasis is not clear. The present study revealed that H-Cpr-null mice had a 60% decrease in total BA concentration in liver, whereas the total BA concentration in serum was almost doubled. The decreased level of cholic acid (CA) in both serum and livers of H-Cpr-null mice is likely due to diminished enzyme activity of Cyp8b1 that is essential for CA biosynthesis. Feedback mechanisms responsible for the reduced liver BA concentrations and/or increased serum BA concentrations in H-Cpr-null mice included the following: 1) enhanced alternative BA synthesis pathway, as evidenced by the fact that classic BA synthesis is diminished but chenodeoxycholic acid still increases in both serum and livers of H-Cpr-null mice; 2) inhibition of farnesoid X receptor activation, which increased the mRNA of Cyp7a1 and 8b1; 3) induction of intestinal BA transporters to facilitate BA absorption from the intestine to the circulation; 4) induction of hepatic multidrug resistance-associated protein transporters to increase BA efflux from the liver to blood; and 5) increased generation of secondary BAs. In summary, the present study reveals an important contribution of the alternative BA synthesis pathway and BA transporters in regulating BA concentrations in H-Cpr-null mice.

  15. Mutational characterization of the bile acid receptor TGR5 in primary sclerosing cholangitis.

    Directory of Open Access Journals (Sweden)

    Johannes R Hov

    Full Text Available BACKGROUND: TGR5, the G protein-coupled bile acid receptor 1 (GPBAR1, has been linked to inflammatory pathways as well as bile homeostasis, and could therefore be involved in primary sclerosing cholangitis (PSC a chronic inflammatory bile duct disease. We aimed to extensively investigate TGR5 sequence variation in PSC, as well as functionally characterize detected variants. METHODOLOGY/PRINCIPAL FINDINGS: Complete resequencing of TGR5 was performed in 267 PSC patients and 274 healthy controls. Six nonsynonymous mutations were identified in addition to 16 other novel single-nucleotide polymorphisms. To investigate the impact from the nonsynonymous variants on TGR5, we created a receptor model, and introduced mutated TGR5 constructs into human epithelial cell lines. By using confocal microscopy, flow cytometry and a cAMP-sensitive luciferase assay, five of the nonsynonymous mutations (W83R, V178M, A217P, S272G and Q296X were found to reduce or abolish TGR5 function. Fine-mapping of the previously reported PSC and UC associated locus at chromosome 2q35 in large patient panels revealed an overall association between the TGR5 single-nucleotide polymorphism rs11554825 and PSC (odds ratio = 1.14, 95% confidence interval: 1.03-1.26, p = 0.010 and UC (odds ratio = 1.19, 95% confidence interval 1.11-1.27, p = 8.5 x 10(-7, but strong linkage disequilibrium precluded demarcation of TGR5 from neighboring genes. CONCLUSIONS/SIGNIFICANCE: Resequencing of TGR5 along with functional investigations of novel variants provided unique insight into an important candidate gene for several inflammatory and metabolic conditions. While significant TGR5 associations were detected in both UC and PSC, further studies are needed to conclusively define the role of TGR5 variation in these diseases.

  16. Species-specific mechanisms for cholesterol 7alpha-hydroxylase (CYP7A1) regulation by drugs and bile acids

    OpenAIRE

    C. Handschin.; Gnerre, C; Fraser, D. J.; Martinez-Jimenez, C.; Jover, R; Meyer, U A

    2005-01-01

    The gene encoding cholesterol 7alpha-hydroxylase (CYP7A1) is tightly regulated in order to control intrahepatic cholesterol and bile acid levels. Ligands of the xenobiotic-sensing pregnane X receptor inhibit CYP7A1 expression. To retrace the evolution of the molecular mechanisms underlying CYP7A1 inhibition, we used a chicken hepatoma cell system that retains the ability to be induced by phenobarbital and other drugs. Whereas bile acids regulate CYP7A1 via small heterodimer partner and liver ...

  17. Plasma bile acids are not associated with energy metabolism in humans

    Directory of Open Access Journals (Sweden)

    Brufau Gemma

    2010-09-01

    Full Text Available Abstract Bile acids (BA have recently been shown to increase energy expenditure in mice, but this concept has not been tested in humans. Therefore, we investigated the relationship between plasma BA levels and energy expenditure in humans. Type 2 diabetic (T2DM patients (n = 12 and gender, age and BMI-matched healthy controls (n = 12 were studied before and after 8 weeks of treatment with a BA sequestrant. In addition, patients with liver cirrhosis (n = 46 were investigated, since these display elevated plasma BA together with increased energy expenditure. This group was compared to gender-, age- and BMI-matched healthy controls (n = 20. Fasting plasma levels of total BA and individual BA species as well as resting energy expenditure were determined. In response to treatment with the BA sequestrant, plasma deoxycholic acid (DCA levels decreased in controls (-60%, p

  18. Improved annotation of conjugated bile acid hydrolase superfamily members in Gram-positive bacteria.

    NARCIS (Netherlands)

    Lambert, J.M.; Siezen, R.J.; Vos, W.M. de; Kleerebezem, M.

    2008-01-01

    Most Gram-positive bacteria inhabiting the gastrointestinal tract are capable of hydrolysing bile salts. Bile salt hydrolysis is thought to play an important role in various biological processes in the host. Therefore, correct annotation of bacterial bile salt hydrolases (Bsh) in public databases (E

  19. Improved annotation of conjugated bile acid hydrolase superfamily members in Gram-positive bacteria

    NARCIS (Netherlands)

    Lambert, J.M.; Siezen, R.J.; Vos, de W.M.; Kleerebezem, M.

    2008-01-01

    Most Gram-positive bacteria inhabiting the gastrointestinal tract are capable of hydrolysing bile salts. Bile salt hydrolysis is thought to play an important role in various biological processes in the host. Therefore, correct annotation of bacterial bile salt hydrolases (Bsh) in public databases (E

  20. 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.

  1. Combined laboratory and epidemiological study of the effect of load on the excretion of Beta aminoisobutyric acid

    Energy Technology Data Exchange (ETDEWEB)

    Farkas, W.R.; Fischbein, A.; Sharma, O.K.S.

    1987-01-01

    Beta Aminoisobutyric Acid (BAIB) is the end product of the catabolism of thymine. BAIB is actively secreted and is a common component of human urine. Since lead has not been reported to degrade DNA we were surprised to find elevated amounts of BAIB in the urine of workers who had lead poisoning. To further study this phenomenon a group of 26 males engaged in demolition work which exposed them to lead was compared to a control group of 40 male hospital workers with regard to BAIB excretion. The exposed workers excreted an average of 19.26 nmoles of BAIB per ..mu..mole creatinine. The value for the control group was 6.02. In order to determine the effect of lead on BAIB excretion under controlled conditions, the authors exposed marmosets to different doses of lead and monitored the lead poisoning via the blood level of zinc protoporphyrin. They found a strong correlation between exposure to lead and excretion of BAIB.

  2. Improvements in glucose metabolism early after gastric bypass surgery are not explained by increases in total bile acids and fibroblast growth factor 19 concentrations

    DEFF Research Database (Denmark)

    Jørgensen, Nils B; Dirksen, Carsten; Bojsen-Møller, Kirstine N;

    2015-01-01

    Context: Bile acids and fibroblast growth factor 19 (FGF19) have been suggested as key mediators of the improvements in glucose metabolism after Roux-en-Y gastric bypass (RYGB). Objective: To describe fasting and postprandial state total bile acid (TBA) and FGF19 concentrations before and after...

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

    Science.gov (United States)

    Fu, Zidong Donna; Klaassen, Curtis D

    2013-12-15

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

  4. Excretion and detection of SARS coronavirus and its nucleic acid from digestive system

    Institute of Scientific and Technical Information of China (English)

    Xin-Wei Wang; Xiao-Ming Wu; Wen-Jun Xiao; Xiu-Mei Zhu; Chang-Qing Gu; Jing Yin; Wei Wei; Wei Yao; Chao Liu; Jian-Feng Li; Guo-Rong Ou; Jin-Song Li; Min-Nian Wang; Tong-Yu Fang; Gui-Jie Wang; Yao-Hui Qiu; Huai-Huan Wu; Fu-Huan Chao; Jun-Wen Li; Ting-Kai Guo; Bei Zhen; Qing-Xin Kong; Bin Yi; Zhong Li; Nong Song; Min Jin

    2005-01-01

    AIM: To study whether severe acute respiratory syndrome coronavirus (SARS-CoV) could be excreted from digestive system.METHODS: Cell culture and semi-nested RT-PCR were used to detect SARS-CoV and its RNA from 21 stool and urine samples, and a kind of electropositive filter media particles was used to concentrate the virus in 10 sewage samples from two hospitals receiving SAPS patients in Beijing in China.RESULTS: It was demonstrated that there was no live SARS-CoV in all samples collected, but the RNA of SARS-CoV could be detected in seven stool samples from SARS patients with any one of the symptoms of fever, malaise,cough, or dyspnea, in 10 sewage samples before disinfection and 3 samples after disinfection from the two hospitals.The RNA could not be detected in urine and stool samples from patients recovered from SARS.CONCLUSION: Nucleic acid of SARS-CoV can be excreted through the stool of patients into sewage system, and the possibility of SARS-CoV transmitting through digestive system cannot be excluded.

  5. 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.

  6. Effect of diethyl ether on the biliary excretion of acetaminophen.

    Science.gov (United States)

    Watkins, J B; Siegers, C P; Klaassen, C D

    1984-10-01

    The biliary and renal excretion of acetaminophen and its metabolites over 8 hr was determined in rats exposed to diethyl ether by inhalation for 1 hr. Additional rats were anesthetized with urethane (1 g/kg ip) while control animals were conscious throughout the experiment (surgery was performed under hexobarbital narcosis: 150 mg/kg ip; 30-min duration). The concentration of UDP-glucuronic acid was decreased 80% in livers from ether-anesthetized rats but was not reduced in urethane-treated animals when compared to that in control rats. The concentration of reduced glutathione was not affected by either urethane or diethyl ether. Basal bile flow was not altered by the anesthetic agents. Bile flow rate after acetaminophen injection (100 mg/kg iv) was increased slightly over basal levels for 2 hr in hexobarbital-treated control rats, was unaltered in urethane-anesthetized animals, and was decreased throughout the 8-hr experiment in rats exposed to diethyl ether for 1 hr. In control and urethane-anesthetized animals, approximately 30-35% of the total acetaminophen dose (100 mg/kg iv) was excreted into bile in 8 hr, while only 16% was excreted in rats anesthetized with diethyl ether. Urinary elimination (60-70% of the dose) was not altered by exposure to ether. Separation of metabolites by reverse-phase high-pressure liquid chromatography showed that ether decreased the biliary elimination of unchanged acetaminophen and its glucuronide, sulfate, and glutathione conjugates by 47, 40, 49, and 73%, respectively, as compared to control rats. Excretion of unchanged acetaminophen and the glutathione conjugate into bile was depressed in urethane-anesthetized animals by 45 and 66%, respectively, whereas elimination of the glucuronide and sulfate conjugates was increased by 27 and 50%, respectively. These results indicate that biliary excretion is influenced by the anesthetic agent and that diethyl ether depresses conjugation with sulfate and glutathione as well as glucuronic

  7. Transcription of the Human Microsomal Epoxide Hydrolase Gene (EPHX1) Is Regulated by PARP-1 and Histone H1.2. Association with Sodium-Dependent Bile Acid Transport.

    Science.gov (United States)

    Peng, Hui; Zhu, Qin-shi; Zhong, Shuping; Levy, Daniel

    2015-01-01

    Microsomal epoxide hydrolase (mEH) is a bifunctional protein that plays a central role in the metabolism of numerous xenobiotics as well as mediating the sodium-dependent transport of bile acids into hepatocytes. These compounds are involved in cholesterol homeostasis, lipid digestion, excretion of xenobiotics and the regulation of several nuclear receptors and signaling transduction pathways. Previous studies have demonstrated the critical role of GATA-4, a C/EBPα-NF/Y complex and an HNF-4α/CAR/RXR/PSF complex in the transcriptional regulation of the mEH gene (EPHX1). Studies also identified heterozygous mutations in human EPHX1 that resulted in a 95% decrease in mEH expression levels which was associated with a decrease in bile acid transport and severe hypercholanemia. In the present investigation we demonstrate that EPHX1 transcription is significantly inhibited by two heterozygous mutations observed in the Old Order Amish population that present numerous hypercholanemic subjects in the absence of liver damage suggesting a defect in bile acid transport into the hepatocyte. The identity of the regulatory proteins binding to these sites, established using biotinylated oligonucleotides in conjunction with mass spectrometry was shown to be poly(ADP-ribose)polymerase-1 (PARP-1) bound to the EPHX1 proximal promoter and a linker histone complex, H1.2/Aly, bound to a regulatory intron 1 site. These sites exhibited 71% homology and may represent potential nucleosome positioning domains. The high frequency of the H1.2 site polymorphism in the Amish population results in a potential genetic predisposition to hypercholanemia and in conjunction with our previous studies, further supports the critical role of mEH in mediating bile acid transport into hepatocytes.

  8. Risk modification of colorectal adenoma by CYP7A1 polymorphisms and the role of bile acid metabolism in carcinogenesis.

    Science.gov (United States)

    Wertheim, Betsy C; Smith, Jeffrey W; Fang, Changming; Alberts, David S; Lance, Peter; Thompson, Patricia A

    2012-02-01

    Cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting enzyme in the conversion of cholesterol to bile acids, is a postulated gene modifier of colorectal cancer risk and target for the therapeutic bile acid, ursodeoxycholic acid (UDCA). We investigated associations between CYP7A1 polymorphisms and fecal bile acids, colorectal adenoma (CRA), and UDCA efficacy for CRA prevention. Seven tagging, single-nucleotide polymorphisms (SNP) in CYP7A1 were measured in 703 (355 UDCA, 348 placebo) participants of a phase III chemoprevention trial, of which 495 had known baseline fecal bile acid concentrations. In the placebo arm, participants with two minor G(rs8192871) alleles (tag for a low activity promoter polymorphism at -204) had lower odds of high secondary bile acids (OR = 0.26, 95% CI: 0.10-0.69), and CRA at 3 years' follow-up (OR = 0.41, 95% CI: 0.19-0.89), than AA carriers. Haplotype construction from the six polymorphic SNPs showed participants with the third most common haplotype (C(rs10957057)C(rs8192879)G(rs8192877)T(rs11786580)A(rs8192871)G(rs13251096)) had higher odds of high primary bile acids (OR = 2.34, 95% CI: 1.12-4.89) and CRA (OR = 1.89, 95% CI: 1.00-3.57) than those with the most common CTACAG haplotype. Furthermore, three SNPs (rs8192877, rs8192871, and rs13251096) each modified UDCA efficacy for CRA prevention, and CCGTAG-haplotype carriers experienced 71% lower odds of CRA recurrence with UDCA treatment, an effect not present for other haplotypes (test for UDCA-haplotype interaction, P = 0.020). Our findings support CYP7A1 polymorphisms as determinants of fecal bile acids and risk factors for CRA. Furthermore, UDCA efficacy for CRA prevention may be modified by genetic variation in CYP7A1, limiting treatment benefit to a subgroup of the population.

  9. Biliary excretion of iron and ferritin in idiopathic hemochromatosis

    Energy Technology Data Exchange (ETDEWEB)

    Hultcrantz, R.; Angelin, B.; Bjoern-Rasmussen, E.E.; Ewerth, S.; Einarsson, K.

    1989-06-01

    The role of biliary excretion of iron and ferritin in iron overload was studied and evaluated. Ten patients with idiopathic hemochromatosis and two groups of controls (14 gallstone patients and 16 healthy subjects) were included. Liver tissue (obtained by percutaneous or operative biopsy) was investigated with light microscopy and transmission electron microscopy in combination with x-ray microanalysis. Fasting bile samples were obtained through duodenal aspiration or at cholecystectomy. Iron was determined in liver tissue and bile using atomic absorption spectroscopy, and ferritin was determined in serum and bile with a radioimmunoassay technique. All patients with hemochromatosis had iron-positive staining as seen in light microscopy. Electron microscopy showed iron-containing proteins in the lysosomes and cytosol of liver parenchymal cells, and this observation was supported by x-ray microanalysis. Hepatic iron concentration was increased about eightfold in the patients with hemochromatosis (p less than 0.001). Biliary iron concentration, expressed per millimole of bile acid, was increased about twofold (p less than 0.05) and biliary ferritin concentration about fivefold (p less than 0.001) in hemochromatosis. Four of the patients with hemochromatosis were reexamined after completed treatment with venesection; this resulted in normalized biliary concentrations of iron and ferritin. We conclude that biliary secretion of ferritin occurs in humans and that both iron and ferritin excretion are enhanced in hepatic iron overload. The apparently limited capacity of biliary iron excretion may be of importance for the hepatic iron accumulation in hemochromatosis.

  10. General (medium-chain) acyl-CoA dehydrogenase deficiency (non-ketotic dicarboxylic aciduria): quantitative urinary excretion pattern of 23 biologically significant organic acids in three cases.

    Science.gov (United States)

    Gregersen, N; Kølvraa, S; Rasmussen, K; Mortensen, P B; Divry, P; David, M; Hobolth, N

    1983-08-15

    Urinary analysis of the pattern of 23 organic acid metabolites derived from fatty acids in three patients with general (medium-chain) acyl-CoA dehydrogenase deficiency was performed. Although there exist quantitative differences in the excreted amounts of the different metabolites in the three patients the qualitative picture was the same. The excretion of adipic, suberic and sebacic acids was substantial, whereas that of dodecanedioic acid was within or just above control limit. The monounsaturated C6-C10-dicarboxylic acid excretion was only marginally or not increased. 5-OH-hexanoic acid and hexanoylglycine were excreted in excessive amounts, whereas 7-OH-octanoic acid, 9-OH-decanoic acid, octanoylglycine and decanoylglycine were excreted in limited amounts. The excreted amounts of 6-OH-hexanoic, 8-OH-octanoic and 10-OH-decanoic acids were not or only marginally elevated compared to controls. In one of the patients the excretion of ethylmalonic and methylsuccinic acids was enhanced, whereas the excretion of these two acids in the two other patients was comparable to that in controls. The urinary excretion of hexanoic, octanoic, decanoic and dodecanoic acids was just a little above the control limit, whereas the esterified hexanoic and octanoic acids were excreted in appreciable amounts. It is argued that the microsomal omega- and omega-1-oxidation systems are involved in the dicarboxylic and omega-1-OH-monocarboxylic acids formation at C10 and C12 level and that the C8-C6-dicarboxylic and omega-1-OH-monocarboxylic acids are formed from higher chained acids by beta-oxidation in both mitochondria and peroxisomes.

  11. A STUDY ON DETECTION OF SERUMFASTING TOTAL BILE ACID AND CHOLOYGLYCIN IN NEONATE FOR CHOLESTASIS

    Institute of Scientific and Technical Information of China (English)

    郭文; 吴明昌; 裴学义; 关德华; 徐洛

    1996-01-01

    Enzyme-linked colorimetric analysis and radioimmunossay were employed to detect serum fasting total bile acids(FBA) and choloyglyein (CG) respectively in eases of 32 neonatal hepatitis, 33 cases of neona-tal uneonjugated hyperbilirubinemia and 34 cases of breast milk jaundice(BMJ). FBA and CG in acute period of neonatal hepatitis were obviously elevated and decreased gradually in convalescent and recovered period. The difference was significant for each stage as compared with controls. Acute FBA correlated strongly with the course. Both neonatal unconjugated hyperbilirubinemia and BMJ differed significantlyfrom controls in FBA and CG. The results suggested that serum FBA and CGr were helpful in judging the course and state of neonatal hepatitis, and eholestasls might existed in neonatal unconjngated hyperbilirubinemia.

  12. Bile acids in regulation of inflammation and immunity: friend or foe?

    Science.gov (United States)

    Zhu, Ci; Fuchs, Claudia D; Halilbasic, Emina; Trauner, Michael

    2016-01-01

    Apart from their pivotal role in dietary lipid absorption and cholesterol homeostasis, bile acids (BAs) are increasingly recognised as important signalling molecules in the regulation of systemic endocrine functions. As such BAs are natural ligands for several nuclear hormone receptors and G-protein-coupled receptors. Through activating various signalling pathways, BAs not only regulate their own synthesis, enterohepatic recirculation and metabolism, but also immune homeostasis. This makes BAs attractive therapeutic agents for managing metabolic and inflammatory liver disorders. Recent experimental and clinical evidence indicates that BAs exert beneficial effects in cholestatic and metabolically driven inflammatory diseases. This review elucidates how different BAs function as pathogenetic factors and potential therapeutic agents for inflammation-driven liver diseases, focusing on their role in regulation of inflammation and immunity.

  13. Bile acid malabsorption in patients with chronic diarrhoea: clinical value of SeHCAT test

    DEFF Research Database (Denmark)

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

    2003-01-01

    BACKGROUND: 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. Clinical outcome after treatment with cholestyramine was also evaluated. METHODS: During a 5-year period (1997-2001) the SeHCAT test was performed in 135 patients in whom a primary programme for diagnostic evaluation of chronic diarrhoea had not revealed a cause. File data from 133 patients could...... as a second-line investigation with a high diagnostic yield. The only a priori parameter to predict BAM was the existence of ileocaecal resections. The result of the SeHCAT test seems to predict the benefit of treatment with cholestyramine....

  14. 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...

  15. Direct behavioral evidence that unique bile acids released by larval sea lamprey (Petromyzon marinus) function as a migratory pheromone

    Science.gov (United States)

    Bjerselius, R.; Li, W.; Teeter, J.H.; Seelye, J.G.; Johnsen, P.B.; Maniak, P.J.; Grant, G.C.; Polkinghorne, C.N.; Sorensen, P.W.

    2000-01-01

    Four behavioral experiments conducted in both the laboratory and the field provide evidence that adult sea lamprey (Petromyzon marinus) select spawning rivers based on the odor of larvae that they contain and that bile acids released by the larvae are part of this pheromonal odor. First, when tested in a recirculating maze, migratory adult lamprey spent more time in water scented with larvae. However, when fully mature, adults lost their responsiveness to larvae and preferred instead the odor of mature individuals. Second, when tested in a flowing stream, migratory adults swam upstream more actively when the water was scented with larvae. Third, when migratory adults were tested in a laboratory maze containing still water, they exhibited enhanced swimming activity in the presence of a 0.1 nM concentration of the two unique bile acids released by larvae and detected by adult lamprey. Fourth, when adults were exposed to this bile acid mixture within flowing waters, they actively swam into it. Taken together, these data suggest that adult lamprey use a bile acid based larval pheromone to help them locate spawning rivers and that responsiveness to this cue is influenced by current flow, maturity, and time of day. Although the precise identity and function of the larval pheromone remain to be fully elucidated, we believe that this cue will ultimately prove useful as an attractant in sea lamprey control.

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

    Science.gov (United States)

    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 des...

  17. Synthesis, Characterization, and Saccharide Binding Studies of Bile Acid − Porphyrin Conjugates

    Directory of Open Access Journals (Sweden)

    Vladimír Král

    2007-01-01

    Full Text Available Synthesis and characterization of bile acid-porphyrin conjugates (BAPs are reported. Binding of saccharides with BAPs in aqueous methanol was studied by monitoring changes in the visible absorption spectral of the porphyrin-moieties. Although these studies clearly showed absorbance changes, suggesting quite high if non-selective binding, the mass spectral studies do not unambiguously support these results.

  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...

  19. Bile acid-activated nuclear receptor FXR suppresses apolipoprotein A-I transcription via a negative FXR response element

    Science.gov (United States)

    Claudel, Thierry; Sturm, Ekkehard; Duez, Hélène; Torra, Inés Pineda; Sirvent, Audrey; Kosykh, Vladimir; Fruchart, Jean-Charles; Dallongeville, Jean; Hum, Dean W.; Kuipers, Folkert; Staels, Bart

    2002-01-01

    Serum levels of HDL are inversely correlated with the risk of coronary heart disease. The anti-atherogenic effect of HDL is partially mediated by its major protein constituent apoA-I. In this study, we identify bile acids that are activators of the nuclear receptor farnesoid X receptor (FXR) as negative regulators of human apoA-I expression. Intrahepatocellular accumulation of bile acids, as seen in patients with progressive familial intrahepatic cholestasis and biliary atresia, was associated with diminished apoA-I serum levels. In human apoA-I transgenic mice, treatment with the FXR agonist taurocholic acid strongly decreased serum concentrations and liver mRNA levels of human apoA-I, which was associated with reduced serum HDL levels. Incubation of human primary hepatocytes and hepatoblastoma HepG2 cells with bile acids resulted in a dose-dependent downregulation of apoA-I expression. Promoter mutation analysis and gel-shift experiments in HepG2 cells demonstrated that bile acid–activated FXR decreases human apoA-I promoter activity by a negative FXR response element mapped to the C site. FXR bound this site and repressed transcription in a manner independent of retinoid X receptor. The nonsteroidal synthetic FXR agonist GW4064 likewise decreased apoA-I mRNA levels and promoter activity in HepG2 cells. PMID:11927623

  20. 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

    2016-01-01

    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...

  1. An Attempt to Determine the Prevalence of Two Inborn Errors of Primary Bile Acid Synthesis : Results of a European survey

    NARCIS (Netherlands)

    Zöhrer, Evelyn; Fischler, Björn; D'Antiga, Lorenzo; Debray, Dominique; Dezsofi, Antal; Haas, Dorothea; Hadzic, Nedim; Jacquemin, Emmanuel; Lamireau, Thierry; Maggiore, Giuseppe; McKiernan, Pat J; Calvo, Pier Luigi; Verkade, Henkjan J; Hierro, Loreto; McLin, Valerie; Baumann, Ulrich; Gonzales, Emmanuel

    2017-01-01

    OBJECTIVE: Inborn errors of primary bile acid (BA) synthesis are genetic cholestatic disorders leading to accumulation of atypical BA with deficiency of normal BA. Unless treated with primary BA, chronic liver disease usually progresses to cirrhosis and liver failure before adulthood. We sought to d

  2. Hepatic alterations are accompanied by changes to bile acid transporter-expressing neurons in the hypothalamus after traumatic brain injury

    Science.gov (United States)

    Nizamutdinov, Damir; DeMorrow, Sharon; McMillin, Matthew; Kain, Jessica; Mukherjee, Sanjib; Zeitouni, Suzanne; Frampton, Gabriel; Bricker, Paul Clint S.; Hurst, Jacob; Shapiro, Lee A.

    2017-01-01

    Annually, there are over 2 million incidents of traumatic brain injury (TBI) and treatment options are non-existent. While many TBI studies have focused on the brain, peripheral contributions involving the digestive and immune systems are emerging as factors involved in the various symptomology associated with TBI. We hypothesized that TBI would alter hepatic function, including bile acid system machinery in the liver and brain. The results show activation of the hepatic acute phase response by 2 hours after TBI, hepatic inflammation by 6 hours after TBI and a decrease in hepatic transcription factors, Gli 1, Gli 2, Gli 3 at 2 and 24 hrs after TBI. Bile acid receptors and transporters were decreased as early as 2 hrs after TBI until at least 24 hrs after TBI. Quantification of bile acid transporter, ASBT-expressing neurons in the hypothalamus, revealed a significant decrease following TBI. These results are the first to show such changes following a TBI, and are compatible with previous studies of the bile acid system in stroke models. The data support the emerging idea of a systemic influence to neurological disorders and point to the need for future studies to better define specific mechanisms of action. PMID:28106051

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

    Directory of Open Access Journals (Sweden)

    Sahbaie Peyman

    2007-06-01

    Full Text Available Abstract Background Esophageal reflux and Barrett's esophagus represent two major risk factors for the development of esophageal adenocarcinoma. Previous studies have shown that brief exposure of the Barrett's-associated adenocarcinoma cell line, SEG-1, or primary cultures of Barrett's esophageal tissues to acid or bile results in changes consistent with cell proliferation. In this study, we determined whether similar exposure to acid or bile salts results in gene expression changes that provide insights into malignant transformation. Methods Using previously published methods, Barrett's-associated esophageal adenocarcinoma cell lines and primary cultures of Barrett's esophageal tissue were exposed to short pulses of acid or bile salts followed by incubation in culture media at pH 7.4. A genome-wide assessment of gene expression was then determined for the samples using cDNA microarrays. Subsequent analysis evaluated for statistical differences in gene expression with and without treatment. Results The SEG-1 cell line showed changes in gene expression that was dependent on the length of exposure to pH 3.5. Further analysis using the Gene Ontology, however, showed that representation by genes associated with cell proliferation is not enhanced by acid exposure. The changes in gene expression also did not involve genes known to be differentially expressed in esophageal adenocarcinoma. Similar experiments using short-term primary cultures of Barrett's esophagus also did not result in detectable changes in gene expression with either acid or bile salt exposure. Conclusion Short-term exposure of esophageal adenocarcinoma SEG-1 cells or primary cultures of Barrett's esophagus does not result in gene expression changes that are consistent with enhanced cell proliferation. Thus other model systems are needed that may reflect the impact of acid and bile salt exposure on the esophagus in vivo.

  4. Choleretic effect of valproic acid in the rat.

    Science.gov (United States)

    Watkins, J B; Klaassen, C D

    1981-01-01

    Valproic acid (VPA) is an anticonvulsant agent which produced marked choleresis in the rat. Bile flow rate increased from 50 to 60 microliter per min per kg to 120 to 145 microliter per min per kg immediately after i.v. injection of VPA (37.5 to 150 mg per kg; 2 ml per kg) in male Sprague-Dawley rats. The duration of maximal bile flow was dose-dependent and increased from 30 min (37.5 mg VPA per kg) to approximately 2 hr (150 mg VPA per kg). Choleresis diluted the biliary concentrations of bile acids, Cl-, cholesterol, and phospholipids. VPA did not change the bile/plasma ratio for erythritol suggesting that the increased bile flow is of canalicular origin. VPA did not influence the excretion of bile acids or their osmotic activity, whereas bile salt-independent flow doubled in rats treated with 150 mg VPA per kg. The bile/plasma, bile/liver, and liver/plasma concentration ratios for VPA were 11.7, 1.6, and 7.3, respectively. Approximately 90% of VPA appearing in bile was biotransformed, primarily as a glucuronide. Bile flow correlated with VPA excretion; 16 microliter of bile was produced per micromole VPA which suggests that choleresis is primarily due to the osmotic activity of VPA metabolites in bile. VPA enhanced the excretion of inorganic ions which may also contribute to choleresis. Biliary excretion of phenol-3,6-dibromophthalein disulfonate and ouabain was unaffected. Thus, VPA is an effective choleretic which stimulates bile salt-independent flow of canalicular origin largely as a consequence of the osmotic properties of VPA conjugates in bile.

  5. REV-ERBalpha participates in circadian SREBP signaling and bile acid homeostasis.

    Directory of Open Access Journals (Sweden)

    Gwendal Le Martelot

    2009-09-01

    Full Text Available In mammals, many aspects of behavior and physiology, and in particular cellular metabolism, are coordinated by the circadian timing system. Molecular clocks are thought to rely on negative feedback loops in clock gene expression that engender oscillations in the accumulation of transcriptional regulatory proteins, such as the orphan receptor REV-ERBalpha. Circadian transcription factors then drive daily rhythms in the expression of clock-controlled output genes, for example genes encoding enzymes and regulators of cellular metabolism. To gain insight into clock output functions of REV-ERBalpha, we carried out genome-wide transcriptome profiling experiments with liver RNA from wild-type mice, Rev-erbalpha knock-out mice, or REV-ERBalpha overexpressing mice. On the basis of these genetic loss- and gain-of-function experiments, we concluded that REV-ERBalpha participates in the circadian modulation of sterol regulatory element-binding protein (SREBP activity, and thereby in the daily expression of SREBP target genes involved in cholesterol and lipid metabolism. This control is exerted via the cyclic transcription of Insig2, encoding a trans-membrane protein that sequesters SREBP proteins to the endoplasmic reticulum membranes and thereby interferes with the proteolytic activation of SREBPs in Golgi membranes. REV-ERBalpha also participates in the cyclic expression of cholesterol-7alpha-hydroxylase (CYP7A1, the rate-limiting enzyme in converting cholesterol to bile acids. Our findings suggest that this control acts via the stimulation of LXR nuclear receptors by cyclically produced oxysterols. In conclusion, our study suggests that rhythmic cholesterol and bile acid metabolism is not just driven by alternating feeding-fasting cycles, but also by REV-ERBalpha, a component of the circadian clockwork circuitry.

  6. Effects of CYP7A1 overexpression on cholesterol and bile acid homeostasis.

    Science.gov (United States)

    Pandak, W M; Schwarz, C; Hylemon, P B; Mallonee, D; Valerie, K; Heuman, D M; Fisher, R A; Redford, K; Vlahcevic, Z R

    2001-10-01

    The initial and rate-limiting step in the classic pathway of bile acid biosynthesis is 7alpha-hydroxylation of cholesterol, a reaction catalyzed by cholesterol 7alpha-hydroxylase (CYP7A1). The effect of CYP7A1 overexpression on cholesterol homeostasis in human liver cells has not been examined. The specific aim of this study was to determine the effects of overexpression of CYP7A1 on key regulatory steps involved in hepatocellular cholesterol homeostasis, using primary human hepatocytes (PHH) and HepG2 cells. Overexpression of CYP7A1 in HepG2 cells and PHH was accomplished by using a recombinant adenovirus encoding a CYP7A1 cDNA (AdCMV-CYP7A1). CYP7A1 overexpression resulted in a marked activation of the classic pathway of bile acid biosynthesis in both PHH and HepG2 cells. In response, there was decreased HMG-CoA-reductase (HMGR) activity, decreased acyl CoA:cholesterol acyltransferase (ACAT) activity, increased cholesteryl ester hydrolase (CEH) activity, and increased low-density lipoprotein receptor (LDLR) mRNA expression. Changes observed in HMGR, ACAT, and CEH mRNA levels paralleled changes in enzyme specific activities. More specifically, LDLR expression, ACAT activity, and CEH activity appeared responsive to an increase in cholesterol degradation after increased CYP7A1 expression. Conversely, accumulation of the oxysterol 7alpha-hydroxycholesterol in the microsomes after CYP7A1 overexpression was correlated with a decrease in HMGR activity.

  7. Dipeptidyl peptidase IV inhibition potentiates amino acid- and bile acid-induced bicarbonate secretion in rat duodenum.

    Science.gov (United States)

    Inoue, Takuya; Wang, Joon-Ho; Higashiyama, Masaaki; Rudenkyy, Sergiy; Higuchi, Kazuhide; Guth, Paul H; Engel, Eli; Kaunitz, Jonathan D; Akiba, Yasutada

    2012-10-01

    Intestinal endocrine cells release gut hormones, including glucagon-like peptides (GLPs), in response to luminal nutrients. Luminal L-glutamate (L-Glu) and 5'-inosine monophosphate (IMP) synergistically increases duodenal HCO3- secretion via GLP-2 release. Since L cells express the bile acid receptor TGR5 and dipeptidyl peptidase (DPP) IV rapidly degrades GLPs, we hypothesized that luminal amino acids or bile acids stimulate duodenal HCO3- secretion via GLP-2 release, which is enhanced by DPPIV inhibition. We measured HCO3- secretion with pH and CO2 electrodes using a perfused rat duodenal loop under isoflurane anesthesia. L-Glu (10 mM) and IMP (0.1 mM) were luminally coperfused with or without luminal perfusion (0.1 mM) or intravenous (iv) injection (3 μmol/kg) of the DPPIV inhibitor NVP728. The loop was also perfused with a selective TGR5 agonist betulinic acid (BTA, 10 μM) or the non-bile acid type TGR5 agonist 3-(2-chlorophenyl)-N-(4-chlorophenyl)-N,5-dimethylisoxazole-4-carboxamide (CCDC; 10 μM). DPPIV activity visualized by use of the fluorogenic substrate was present on the duodenal brush border and submucosal layer, both abolished by the incubation with NVP728 (0.1 mM). An iv injection of NVP728 enhanced L-Glu/IMP-induced HCO3- secretion, whereas luminal perfusion of NVP728 had no effect. BTA or CCDC had little effect on HCO3- secretion, whereas NVP728 iv markedly enhanced BTA- or CCDC-induced HCO3- secretion, the effects inhibited by a GLP-2 receptor antagonist. Coperfusion of the TGR5 agonist enhanced L-Glu/IMP-induced HCO3- secretion with the enhanced GLP-2 release, suggesting that TGR5 activation amplifies nutrient sensing signals. DPPIV inhibition potentiated luminal L-Glu/IMP-induced and TGR5 agonist-induced HCO3- secretion via a GLP-2 pathway, suggesting that the modulation of the local concentration of the endogenous secretagogue GLP-2 by luminal compounds and DPPIV inhibition helps regulate protective duodenal HCO3- secretion.

  8. The role of resistance to bile salts and acid tolerance of exopolysaccharides (EPSS produced by yogurt starter bacteria

    Directory of Open Access Journals (Sweden)

    Boke Hatice

    2010-01-01

    Full Text Available The aim of this study was to investigate a possible relation between EPS production and resistance to bile salts and tolerance to low pH. Eight strains which produced the highest and lowest amount of EPS (16- 211mg/l were selected among 54 bacteria isolated from yogurt. Additionally, they were tested for resistance to bile salts (0.15, 0.3 % and tolerance to low pH (2.0-3.0. After treatment with bile salts and acid, viable bacteria (log cfu ml-1 were determined by surface plating. The high EPS producing strains (B3, G12, W22 showed a significant (P<0.05 protective effect against low pH (pH 2.0. All Streptococcus thermophilus strains showed a higher tolerance to bile salts than the Lactobacillus delbrueckii subsp. bulgaricus strains. The high EPS-producing S. thermophilus (W22, T12 and L. bulgaricus (B3, G2 strains showed a significant (P<0.01 protective effect against bile salts (0.3 %.

  9. Reduction in Bile Acid Pool Causes Delayed Liver Regeneration Accompanied by Down-regulated Expression of FXR and C-Jun mRNA in Rats

    Institute of Scientific and Technical Information of China (English)

    董秀山; 赵浩亮; 马晓明; 王世明

    2010-01-01

    The present study attempted to examine the effects of bile acid pool size on liver regeneration after hepatectomy.The rats were fed on 0.2% cholic acid(CA)or 2% cholestyramine for 7 days to induce a change in the bile acid size,and then a partial hepatectomy(PH)was performed.Rats fed on the normal diet served as the controls.Measurements were made on the rate of liver regeneration,the labeling indices of PCNA,the plasma total bile acids(TBA),and the mRNA expression of cholesterol 7alpha-hydroxylase(CYP7A1),...

  10. Bile acids regulate intestinal cell proliferation by modulating EGFR and FXR signaling.

    Science.gov (United States)

    Dossa, Avafia Y; Escobar, Oswaldo; Golden, Jamie; Frey, Mark R; Ford, Henri R; Gayer, Christopher P

    2016-01-15

    Bile acids (BAs) are synthesized in the liver and secreted into the intestine. In the lumen, enteric bacteria metabolize BAs from conjugated, primary forms into more toxic unconjugated, secondary metabolites. Secondary BAs can be injurious to the intestine and may contribute to disease. The epidermal growth factor receptor (EGFR) and the nuclear farnesoid X receptor (FXR) are known to interact with BAs. In this study we examined the effects of BAs on intestinal epithelial cell proliferation and investigated the possible roles for EGFR and FXR in these effects. We report that taurine-conjugated cholic acid (TCA) induced proliferation, while its unconjugated secondary counterpart deoxycholic acid (DCA) inhibited proliferation. TCA stimulated phosphorylation of Src, EGFR, and ERK 1/2. Pharmacological blockade of any of these pathways or genetic ablation of EGFR abrogated TCA-stimulated proliferation. Interestingly, Src or EGFR inhibitors eliminated TCA-induced phosphorylation of both molecules, suggesting that their activation is interdependent. In contrast to TCA, DCA exposure diminished EGFR phosphorylation, and pharmacological or siRNA blockade of FXR abolished DCA-induced inhibition of proliferation. Taken together, these results suggest that TCA induces intestinal cell proliferation via Src, EGFR, and ERK activation. In contrast, DCA inhibits proliferation via an FXR-dependent mechanism that may include downstream inactivation of the EGFR/Src/ERK pathway. Since elevated secondary BA levels are the result of specific bacterial modification, this may provide a mechanism through which an altered microbiota contributes to normal or abnormal intestinal epithelial cell proliferation.

  11. Interaction of Cytotoxic and Cytoprotective Bile Acids with Model Membranes: Influence of the Membrane Composition.

    Science.gov (United States)

    Esteves, M; Ferreira, M J; Kozica, A; Fernandes, A C; Gonçalves da Silva, A; Saramago, B

    2015-08-18

    To understand the role of bile acids (BAs) in cell function, many authors have investigated their effect on biomembrane models which are less complex systems, but there are still many open questions. The present study aims to contribute for the deepening of the knowledge of the interaction between BAs and model membranes, in particular, focusing on the effect of BA mixtures. The cytotoxic deoxycholic acid (DCA), the cytoprotective ursodeoxycholic acid (UDCA), and the equimolar mixture (DCA + UDCA) were investigated. Monolayers and liposomes were taken as model membranes with two lipid compositions: an equimolar mixture of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), sphingomyelin (SM), and cholesterol (Chol)) traditionally associated with the formation of lipid rafts and an equimolar POPC/SM binary mixture. The obtained results showed that DCA causes the fluidization of monolayers and bilayers, leading to the eventual rupture of POPC/SM liposomes at high concentration. UDCA may provide a stabilization of POPC/SM membranes but has a negligible effect on the Chol-containing liposomes. In the case of equimolar mixture DCA/UDCA, the interactions depend not only on the lipid composition but also on the design of the experiment. The BA mixture has a greater impact on the monolayers than do pure BAs, suggesting a cooperative DCA-UDCA interaction that enhances the penetration of UDCA in both POPC/SM and POPC/SM/Chol monolayers. For the bilayers, the presence of UDCA in the mixture decreases the disturbing effect of DCA.

  12. Tranexamic acid, an inhibitor of plasminogen activation, reduces urinary collagen cross-link excretion in both experimental and rheumatoid arthritis

    NARCIS (Netherlands)

    Ronday, H.K.; TeKoppele, J.M.; Greenwald, R.A.; Moak, S.A.; Roos, J.A.D.M. de; Dijkmans, B.A.C.; Breedveld, F.C.; Verheijen, J.H.

    1998-01-01

    The plasminogen activation system is one of the enzyme systems held responsible for bone and cartilage degradation in rheumatoid arthritis (RA). In this study, we evaluated the effect of tranexamic acid (TEA), an inhibitor of plasminogen activation, on urinary collagen cross-link excretion and radio

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-12-15

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

  14. Ménage-à-trois of bariatric surgery, bile acids and the gutmicrobiome

    Institute of Scientific and Technical Information of China (English)

    Rajendra Raghow

    2015-01-01

    Bariatric surgeries have emerged as highly effectivetreatments for obesity associated type-2 diabetesmellitus. Evidently, the desired therapeutic endpointssuch as rates of weight loss, lower levels of glycatedhemoglobin and remission of diabetes are achievedmore rapidly and last longer following bariatric surgery,as opposed to drug therapies alone. In light of thesefindings, it has been suspected that in addition tocausing weight loss dependent glucose intolerance,bariatric surgery induces other physiological changesthat contribute to the alleviation of diabetes. However,the putative post-surgical neuro-hormonal pathwaysthat underpin the therapeutic benefits of bariatricsurgery remain undefined. In a recent report, Ryan andcolleagues shed new light on the potential mechanismsthat determine the salutary effects of bariatric surgeryin mice. The authors demonstrated that the improvedglucose tolerance and weight loss in mice after verticalsleeve gastrectomy (VSG) surgery were likely to becaused by post-surgical changes in circulating bileacids and farnesoid-X receptor (FXR) signaling, both ofwhich were also mechanistically linked to changes inthe microbial ecology of the gut. The authors arrivedat this conclusion from a comparison of genome-wide,metabolic consequences of VSG surgery in obese wildtype (WT) and FXR knockout mice. Gene expressionin the distal small intestines of WT and FXR knockoutmice revealed that the pathways regulating bile acidcomposition, nutrient metabolism and anti-oxidantdefense were differentially altered by VSG surgeryin WT and FXR-/- mice. Based on these data Ryanet al , hypothesized that bile acid homeostasis andFXR signaling were mechanistically linked to the gutmicrobiota that played a role in modulating post-surgicalchanges in total body mass and glucose tolerance.The authors' data provide a plausible explanation forputative weight loss-independent benefits of bariatricsurgery and its relationship with metabolism of bileacids.

  15. Resveratrol Attenuates Trimethylamine-N-Oxide (TMAO-Induced Atherosclerosis by Regulating TMAO Synthesis and Bile Acid Metabolism via Remodeling of the Gut Microbiota

    Directory of Open Access Journals (Sweden)

    Ming-liang Chen

    2016-04-01

    Full Text Available The gut microbiota is found to be strongly associated with atherosclerosis (AS. Resveratrol (RSV is a natural phytoalexin with anti-AS effects; however, its mechanisms of action remain unclear. Therefore, we sought to determine whether the anti-AS effects of RSV were related to changes in the gut microbiota. We found that RSV attenuated trimethylamine-N-oxide (TMAO-induced AS in ApoE−/− mice. Meanwhile, RSV decreased TMAO levels by inhibiting commensal microbial trimethylamine (TMA production via gut microbiota remodeling in mice. Moreover, RSV increased levels of the genera Lactobacillus and Bifidobacterium, which increased the bile salt hydrolase activity, thereby enhancing bile acid (BA deconjugation and fecal excretion in C57BL/6J and ApoE−/− mice. This was associated with a decrease in ileal BA content, repression of the enterohepatic farnesoid X receptor (FXR-fibroblast growth factor 15 (FGF15 axis, and increased cholesterol 7a-hydroxylase (CYP7A1 expression and hepatic BA neosynthesis. An FXR antagonist had the same effect on FGF15 and CYP7A1 expression as RSV, while an FXR agonist abolished RSV-induced alterations in FGF15 and CYP7A1 expression. In mice treated with antibiotics, RSV neither decreased TMAO levels nor increased hepatic BA synthesis. Additionally, RSV-induced inhibition of TMAO-caused AS was also markedly abolished by antibiotics. In conclusion, RSV attenuated TMAO-induced AS by decreasing TMAO levels and increasing hepatic BA neosynthesis via gut microbiota remodeling, and the BA neosynthesis was partially mediated through the enterohepatic FXR-FGF15 axis.

  16. Effect of casein-based semi-synthetic food on renal acid excretion and acid-base state of blood in dogs.

    Science.gov (United States)

    Zijlstra, W G; Langbroek, A J; Kraan, J; Rispens, P; Nijmeijer, A

    1995-01-01

    Urinary acid excretion and blood acid-base state were determined in dogs fed a casein-based semi-synthetic food (SSF), to which different amounts of salts had been added, in comparison with feeding normal dog food. Net acid excretion (NAE) and inorganic acid excretion (IAE) increased during SSF feeding. IAE was higher than the acid load calculated from the sulphur and phosphorus content of the casein. This higher IAE appeared to be due to the presence of calcium and magnesium phosphate in the diet, because calcium and magnesium may be in part precipitated as carbonate, leaving phosphate to be absorbed as phosphoric acid. Acid excretion decreased by addition of CaO. When no neutral Na+ and K+ salts were added, the increase in NAE was accompanied by a metabolic acidosis. K+ was more effective in attenuating the acidosis than Na+. On the basis of these findings a diet can be made which imposes a known acid load, and provides stable baseline values. Hence, any additions that influence the acid-base balance can be properly studied. The data obtained in these and future studies utilising this diet may be of help in optimising the composition of nutrient solutions to be used in the care of critically ill patients.

  17. Bile Acid Malabsorption After Pelvic and Prostate Intensity Modulated Radiation Therapy: An Uncommon but Treatable Condition

    Energy Technology Data Exchange (ETDEWEB)

    Harris, Victoria [Academic Urology Unit, Institute of Cancer Research and The Royal Marsden Hospital, London and Sutton (United Kingdom); Benton, Barbara [Gastroenterology Unit, Institute of Cancer Research and The Royal Marsden Hospital, London and Sutton (United Kingdom); Sohaib, Aslam [Department of Radiology, Institute of Cancer Research and The Royal Marsden Hospital, London and Sutton (United Kingdom); Dearnaley, David [Academic Urology Unit, Institute of Cancer Research and The Royal Marsden Hospital, London and Sutton (United Kingdom); Andreyev, H. Jervoise N., E-mail: j@andreyev.demon.co.uk [Gastroenterology Unit, Institute of Cancer Research and The Royal Marsden Hospital, London and Sutton (United Kingdom)

    2012-12-01

    Purpose: Intensity modulated radiation therapy (IMRT) is a significant therapeutic advance in prostate cancer, allowing increased tumor dose delivery and increased sparing of normal tissues. IMRT planning uses strict dose constraints to nearby organs to limit toxicity. Bile acid malabsorption (BAM) is a treatable disorder of the terminal ileum (TI) that presents with symptoms similar to radiation therapy toxicity. It has not been described in patients receiving RT for prostate cancer in the contemporary era. We describe new-onset BAM in men after IMRT for prostate cancer. Methods and Materials: Diagnosis of new-onset BAM was established after typical symptoms developed, selenium-75 homocholic acid taurine (SeHCAT) scanning showed 7-day retention of <15%, and patients' symptoms unequivocally responded to a bile acid sequestrant. The TI was identified on the original radiation therapy plan, and the radiation dose delivered was calculated and compared with accepted dose-volume constraints. Results: Five of 423 men treated in a prospective series of high-dose prostate and pelvic IMRT were identified with new onset BAM (median age, 65 years old). All reported having normal bowel habits before RT. The volume of TI ranged from 26-141 cc. The radiation dose received by the TI varied between 11.4 Gy and 62.1 Gy (uncorrected). Three of 5 patients had TI treated in excess of 45 Gy (equivalent dose calculated in 2-Gy fractions, using an {alpha}/{beta} ratio of 3) with volumes ranging from 1.6 cc-49.0 cc. One patient had mild BAM (SeHCAT retention, 10%-15%), 2 had moderate BAM (SeHCAT retention, 5%-10%), and 2 had severe BAM (SeHCAT retention, <5%). The 3 patients whose TI received {>=}45 Gy developed moderate to severe BAM, whereas those whose TI received <45 Gy had only mild to moderate BAM. Conclusions: Radiation delivered to the TI during IMRT may cause BAM. Identification of the TI from unenhanced RT planning computed tomography scans is difficult and may impede

  18. Urinary Acid Excretion Can Predict Changes in Bone Metabolism During Space Flight

    Science.gov (United States)

    Zwart, Sara R.; Smith, Scott M.

    2011-01-01

    Mitigating space flight-induced bone loss is critical for space exploration, and a dietary countermeasure would be ideal. We present here preliminary data from a study where we examined the role of dietary intake patterns as one factor that can influence bone mineral loss in astronauts during space flight. Crewmembers (n=5) were asked to consume a prescribed diet with either a low (0.3-0.6) or high (1.0-1.3) ratio of animal protein to potassium (APro:K) before and during space flight for 4-d periods. Diets were controlled for energy, total protein, calcium, and sodium. 24-h urine samples were collected on the last day of each of the 4-d controlled diet sessions. 24-h urinary acid excretion, which was predicted by dietary potential renal acid load, was correlated with urinary n-telopeptide (NTX, Pearson R = 0.99 and 0.80 for the high and low APro:K sessions, respectively, p<0.001). The amount of protein when expressed as the percentage of total energy (but not as total grams) was also correlated with urinary NTX (R = 0.66, p<0.01). These results, from healthy individuals in a unique environment, will be important to better understand diet and bone interrelationships during space flight as well as on Earth. The study was funded by the NASA Human Research Program.

  19. Crystal structure of axolotl (Ambystoma mexicanum) liver bile acid-binding protein bound to cholic and oleic acid.

    Science.gov (United States)

    Capaldi, Stefano; Guariento, Mara; Perduca, Massimiliano; Di Pietro, Santiago M; Santomé, José A; Monaco, Hugo L

    2006-07-01

    The family of the liver bile acid-binding proteins (L-BABPs), formerly called liver basic fatty acid-binding proteins (Lb-FABPs) shares fold and sequence similarity with the paralogous liver fatty acid-binding proteins (L-FABPs) but has a different stoichiometry and specificity of ligand binding. This article describes the first X-ray structure of a member of the L-BABP family, axolotl (Ambystoma mexicanum) L-BABP, bound to two different ligands: cholic and oleic acid. The protein binds one molecule of oleic acid in a position that is significantly different from that of either of the two molecules that bind to rat liver FABP. The stoichiometry of binding of cholate is of two ligands per protein molecule, as observed in chicken L-BABP. The cholate molecule that binds buried most deeply into the internal cavity overlaps well with the analogous bound to chicken L-BABP, whereas the second molecule, which interacts with the first only through hydrophobic contacts, is more external and exposed to the solvent.

  20. Caveolin-1 is necessary for hepatic oxidative lipid metabolism: evidence for crosstalk between caveolin-1 and bile acid signaling.

    Science.gov (United States)

    Fernández-Rojo, Manuel A; Gongora, Milena; Fitzsimmons, Rebecca L; Martel, Nick; Martin, Sheree D; Nixon, Susan J; Brooks, Andrew J; Ikonomopoulou, Maria P; Martin, Sally; Lo, Harriet P; Myers, Stephen A; Restall, Christina; Ferguson, Charles; Pilch, Paul F; McGee, Sean L; Anderson, Robin L; Waters, Michael J; Hancock, John F; Grimmond, Sean M; Muscat, George E O; Parton, Robert G

    2013-07-25

    Caveolae and caveolin-1 (CAV1) have been linked to several cellular functions. However, a model explaining their roles in mammalian tissues in vivo is lacking. Unbiased expression profiling in several tissues and cell types identified lipid metabolism as the main target affected by CAV1 deficiency. CAV1-/- mice exhibited impaired hepatic peroxisome proliferator-activated receptor α (PPARα)-dependent oxidative fatty acid metabolism and ketogenesis. Similar results were recapitulated in CAV1-deficient AML12 hepatocytes, suggesting at least a partial cell-autonomous role of hepatocyte CAV1 in metabolic adaptation to fasting. Finally, our experiments suggest that the hepatic phenotypes observed in CAV1-/- mice involve impaired PPARα ligand signaling and attenuated bile acid and FXRα signaling. These results demonstrate the significance of CAV1 in (1) hepatic lipid homeostasis and (2) nuclear hormone receptor (PPARα, FXRα, and SHP) and bile acid signaling.

  1. The bile acid-sensitive ion channel (BASIC), the ignored cousin of ASICs and ENaC.

    Science.gov (United States)

    Wiemuth, Dominik; Assmann, Marc; Gründer, Stefan

    2014-01-01

    The DEG/ENaC gene family of ion channels is characterized by a high degree of structural similarity and an equally high degree of diversity concerning the physiological function. In humans and rodents, the DEG/ENaC family comprises 2 main subgroups: the subunits of the epithelial Na(+) channel (ENaC) and the subunits of the acid sensing ion channels (ASICs). The bile acid-sensitive channel (BASIC), previously known as BLINaC or INaC, represents a third subgroup within the DEG/ENaC family. Although BASIC was identified more than a decade ago, very little is known about its physiological function. Recent progress in the characterization of this neglected member of the DEG/ENaC family, which is summarized in this focused review, includes the discovery of surprising species differences, its pharmacological characterization, and the identification of bile acids as putative natural activators.

  2. Structure-based drug design targeting the cell membrane receptor GPBAR1: exploiting the bile acid scaffold towards selective agonism

    Science.gov (United States)

    di Leva, Francesco Saverio; Festa, Carmen; Renga, Barbara; Sepe, Valentina; Novellino, Ettore; Fiorucci, Stefano; Zampella, Angela; Limongelli, Vittorio

    2015-11-01

    Bile acids can regulate nutrient metabolism through the activation of the cell membrane receptor GPBAR1 and the nuclear receptor FXR. Developing an exogenous control over these receptors represents an attractive strategy for the treatment of enterohepatic and metabolic disorders. A number of dual GPBAR1/FXR agonists are known, however their therapeutic use is limited by multiple unwanted effects due to activation of the diverse downstream signals controlled by the two receptors. On the other hand, designing selective GPBAR1 and FXR agonists is challenging since the two proteins share similar structural requisites for ligand binding. Here, taking advantage of our knowledge of the two targets, we have identified through a rational drug design study a series of amine lithocholic acid derivatives as selective GPBAR1 agonists. The presence of the 3α-NH2 group on the steroidal scaffold is responsible for the selectivity over FXR unveiling unprecedented structural insights into bile acid receptors activity modulation.

  3. Caveolin-1 Is Necessary for Hepatic Oxidative Lipid Metabolism: Evidence for Crosstalk between Caveolin-1 and Bile Acid Signaling

    Directory of Open Access Journals (Sweden)

    Manuel A. Fernández-Rojo

    2013-07-01

    Full Text Available Caveolae and caveolin-1 (CAV1 have been linked to several cellular functions. However, a model explaining their roles in mammalian tissues in vivo is lacking. Unbiased expression profiling in several tissues and cell types identified lipid metabolism as the main target affected by CAV1 deficiency. CAV1−/− mice exhibited impaired hepatic peroxisome proliferator-activated receptor α (PPARα-dependent oxidative fatty acid metabolism and ketogenesis. Similar results were recapitulated in CAV1-deficient AML12 hepatocytes, suggesting at least a partial cell-autonomous role of hepatocyte CAV1 in metabolic adaptation to fasting. Finally, our experiments suggest that the hepatic phenotypes observed in CAV1−/− mice involve impaired PPARα ligand signaling and attenuated bile acid and FXRα signaling. These results demonstrate the significance of CAV1 in (1 hepatic lipid homeostasis and (2 nuclear hormone receptor (PPARα, FXRα, and SHP and bile acid signaling.

  4. GPBAR1/TGR5 mediates bile acid-induced cytokine expression in murine Kupffer cells.

    Directory of Open Access Journals (Sweden)

    Guiyu Lou

    Full Text Available GPBAR1/TGR5 is a novel plasma membrane-bound G protein-coupled bile acid (BA receptor. BAs are known to induce the expression of inflammatory cytokines in the liver with unknown mechanism. Here we show that without other external stimuli, TGR5 activation alone induced the expression of interleukin 1β (IL-1β and tumor necrosis factor-α (TNF-α in murine macrophage cell line RAW264.7 or murine Kupffer cells. The TGR5-mediated increase of pro-inflammatory cytokine expression was suppressed by JNK inhibition. Moreover, the induced pro-inflammatory cytokine expression in mouse liver by 1% cholic acid (CA diet was blunted in JNK-/- mice. TGR5 activation by its ligands enhanced the phosphorylation levels, DNA-binding and trans-activities of c-Jun and ATF2 transcription factors. Finally, the induced pro-inflammatory cytokine expression in Kupffer cells by TGR5 activation correlated with the suppression of Cholesterol 7α-hydroxylase (Cyp7a1 expression in murine hepatocytes. These results suggest that TGR5 mediates the BA-induced pro-inflammatory cytokine production in murine Kupffer cells through JNK-dependent pathway. This novel role of TGR5 may correlate to the suppression of Cyp7a1 expression in hepatocytes and contribute to the delicate BA feedback regulation.

  5. StAR-related lipid transfer domain protein 5 binds primary bile acids[S

    Science.gov (United States)

    Létourneau, Danny; Lorin, Aurélien; Lefebvre, Andrée; Frappier, Vincent; Gaudreault, Francis; Najmanovich, Rafael; Lavigne, Pierre; LeHoux, Jean-Guy

    2012-01-01

    Steroidogenic acute regulatory-related lipid transfer (START) domain proteins are involved in the nonvesicular intracellular transport of lipids and sterols. The STARD1 (STARD1 and STARD3) and STARD4 subfamilies (STARD4–6) have an internal cavity large enough to accommodate sterols. To provide a deeper understanding on the structural biology of this domain, the binding of sterols to STARD5, a member of the STARD4 subfamily, was monitored. The SAR by NMR [1H-15N heteronuclear single-quantum coherence (HSQC)] approach, complemented by circular dichroism (CD) and isothermal titration calorimetry (ITC), was used. Titration of STARD5 with cholic (CA) and chenodeoxycholic acid (CDCA), ligands of the farnesoid X receptor (FXR), leads to drastic perturbation of the 1H-15N HSQC spectra and the identification of the residues in contact with those ligands. The most perturbed residues in presence of ligands are lining the internal cavity of the protein. Ka values of 1.8·10−4 M−1 and 6.3·104 M−1 were measured for CA and CDCA, respectively. This is the first report of a START domain protein in complex with a sterol ligand. Our original findings indicate that STARD5 may be involved in the transport of bile acids rather than cholesterol. PMID:23018617

  6. Do sensory neurons mediate adaptive cytoprotection of gastric mucosa against bile acid injury?

    Science.gov (United States)

    Mercer, D W; Ritchie, W P; Dempsey, D T

    1992-01-01

    Pretreatment with the mild irritant 1 mmol acidified taurocholate protects the gastric mucosa from the injury induced by the subsequent application of 5 mmol acidified taurocholate, a phenomenon referred to as "adaptive cytoprotection." How this occurs remains an enigma. The purpose of this study was to investigate the role of sensory neurons and mucus secretion in this phenomenon. Prior to injury with 5 mmol acidified taurocholate (pH 1.2), the stomachs of six groups of rats were subjected to the following protocol. Two groups were topically pretreated with either saline or the mild irritant 1 mmol acidified taurocholate. Two other groups received the topical anesthetic 1% lidocaine prior to pretreatment with either saline or 1 mmol acidified taurocholate. The last two groups got the mucolytic agent 10% N-acetylcysteine (NAC) after pretreatment with either saline or 1 mmol acidified taurocholate. Injury was assessed by measuring net transmucosal ion fluxes, luminal appearance of deoxyribonucleic acid (DNA), and gross and histologic injury. Pretreatment with the mild irritant 1 mmol acidified taurocholate significantly decreased bile acid-induced luminal ion fluxes and DNA accumulation, suggesting mucosal protection (corroborated by gross and histologic injury analysis). This effect was negated by lidocaine but not by NAC. Thus, it appears that sensory neurons, and not increased mucus secretion, play a critical role in adaptive cytoprotection.

  7. Diagnosis of bile acid diarrhoea by fasting and postprandial measurements of fibroblast growth factor 19

    DEFF Research Database (Denmark)

    Borup, Christian; Syversen, Charlotte; Bouchelouche, Pierre

    2015-01-01

    BACKGROUND: A deficiency in the ileal hormone fibroblast growth factor 19 (FGF19) has been described in patients with bile acid diarrhoea (BAD), but fasting FGF19 levels have insufficient diagnostic power. We assess whether single postprandial sampling of FGF19 has greater discriminative value than...... fasting FGF19 for detection of BAD and we evaluate the reproducibility of fasting FGF19. MATERIALS AND METHODS: Twenty-six patients consecutively referred to Se homocholic acid retention test (SeHCAT) were included. Serum FGF19 was measured after an overnight fast and again 1 h postprandially and again...... in the fasting state 1 week later. RESULTS: Nine of 26 patients had SeHCAT less than 10% and fasting FGF19 was lower [median 62 pg/ml, interquartile range (IQR): 47-67] than in the 17 diarrhoea controls with SeHCAT at least 10% (median 103 pg/ml, IQR: 77-135, P=0.006). Postprandial FGF19 in BAD patients (61 pg...

  8. Bile acid-surfactant interactions at the liquid crystal/aqueous interface.

    Science.gov (United States)

    He, Sihui; Liang, Wenlang; Cheng, Kung-Lung; Fang, Jiyu; Wu, Shin-Tson

    2014-07-14

    The interaction between bile acids and surfactants at interfaces plays an important role in fat digestion. In this paper, we study the competitive adsorption of cholic acid (CA) at the sodium dodecyl sulfate (SDS)-laden liquid crystal (LC)/aqueous interface formed with cyanobiphenyl (nCB, n = 5-8) and the mixture of 5CB with 4-(4-pentylcyclohexyl)benzonitrile (5PCH). We find that the critical concentration of CA required to displace SDS from the interface linearly decreases from 160 μM to 16 μM by reducing the alkyl chain length of nCB from n = 8 to n = 5 and from 16 μM to 1.5 μM by increasing the 5PCH concentration from 0 wt% to 19 wt% in the 5PCH-5CB binary mixture. Our results clearly demonstrate that the sensitivity of 5PCH-5CB mixtures for monitoring the interaction between CA and SDS at the LC/aqueous interface can be increased by one order of magnitude, compared to 5CB.

  9. Techno-functional properties and in vitro bile acid-binding capacities of tamarillo (Solanum betaceum Cav.) hydrocolloids.

    Science.gov (United States)

    Gannasin, Sri Puvanesvari; Adzahan, Noranizan Mohd; Mustafa, Shuhaimi; Muhammad, Kharidah

    2016-04-01

    Hydrocolloids were extracted from seed mucilage and the pulp fractions from red tamarillo (Solanum betaceum Cav.) mesocarp, and characterisation of their techno-functional properties and in vitro bile acid-binding capacities was performed. The seed mucilage hydrocolloids that were extracted, using either 1% citric acid (THC) or water (THW), had a good foaming capacity (32-36%), whereas the pulp hydrocolloids that were extracted, using 72% ethanol (THE) or 20mM HEPES buffer (THH), had no foaming capacity. The pulp hydrocolloid, however, possessed high oil-holding and water-holding capacities in the range of 3.3-3.6 g oil/g dry sample and 25-27 g water/g dry sample, respectively. This enabled the pulp hydrocolloid to entrap more bile acids (35-38% at a hydrocolloid concentration of 2%) in its gelatinous network in comparison to commercial oat fibre and other hydrocolloids studied. The exceptional emulsifying properties (80-96%) of both hydrocolloids suggest their potential applications as food emulsifiers and bile acid binders.

  10. Gender-divergent profile of bile acid homeostasis during aging of mice.

    Directory of Open Access Journals (Sweden)

    Zidong Donna Fu

    Full Text Available Aging is a physiological process with a progressive decline of adaptation and functional capacity of the body. Bile acids (BAs have been recognized as signaling molecules regulating the homeostasis of glucose, lipid, and energy. The current study characterizes the age-related changes of individual BA concentrations by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS in serum and liver of male and female C57BL/6 mice from 3 to 27 months of age. Total BA concentrations in serum increased 340% from 3 to 27 months in female mice, whereas they remained relatively constant with age in male mice. During aging, male and female mice shared the following changes: (1 BA concentrations in liver remained relatively constant; (2 the proportions of beta-muricholic acid (βMCA increased and deoxycholic acid (DCA decreased between 3 and 27 months in serum and liver; and (3 total BAs in serum and liver became more hydrophilic between 3 and 27 months. In female mice, (1 the mRNAs of hepatic BA uptake transporters, the Na(+/taurocholate cotransporting polypeptide (Ntcp and the organic anion transporting polypeptide 1b2 (Oatp1b2, decreased after 12 months, and similar trends were observed for their proteins; (2 the mRNA of the rate-limiting enzyme for BA synthesis, cholesterol 7α-hydroxylase (Cyp7a1, increased from 3 to 9 months and remained high thereafter. However, in male mice, Ntcp, Oatp1b2, and Cyp7a1 mRNAs remained relatively constant with age. In summary, the current study shows gender-divergent profiles of BA concentrations and composition in serum and liver of mice during aging, which is likely due to the gender-divergent expression of BA transporters Ntcp and Oatp1b2 as well as the synthetic enzyme Cyp7a1.

  11. Elevated First-Trimester Total Bile Acid is Associated with the Risk of Subsequent Gestational Diabetes

    Science.gov (United States)

    Hou, Wolin; Meng, Xiyan; Zhao, Weijing; Pan, Jiemin; Tang, Junling; Huang, Yajuan; Tao, Minfang; Liu, Fang; Jia, Weiping

    2016-01-01

    The aim of the current study is to assess whether total bile acid (TBA) level in first trimester pregnancy is associated with gestational diabetes mellitus (GDM). Biochemical parameters including serum TBA of 742 pregnant women were collected within 12 weeks of gestation and compared. At 24–28th weeks of gestation, 75 g oral glucose tolerance test (OGTT) was performed. The perinatal data of 330 women were collected. The results demonstrated women with GDM (n = 268) had higher first-trimester serum levels of TBA compared with healthy subjects (n = 474) (2.3 ± 1.4 μmol/L vs. 1.9 ± 1.0 μmol/L, P < 0.001). TBA was independently associated with GDM [adjusted odds ratio (AOR), 1.38; 95% confidence interval (CI), 1.18–1.61, P < 0.001]. Compared to the first category of TBA, women in the highest category had a marked increase in risk for GDM (AOR, 7.72; 95% CI, 3.22–18.50, P < 0.001). In conclusion, higher first-trimester TBA levels, even within normal range, may help indicate increased risk of GDM. PMID:27667090

  12. Bile acid signaling through farnesoid X and TGR5 receptors in hepatobiliary and intestinal diseases

    Institute of Scientific and Technical Information of China (English)

    Bojan Stanimirov; Karmen Stankovand Momir Mikov

    2015-01-01

    BACKGROUND: The well-known functions of bile acids (BAs) are the emulsification and absorption of lipophilic xenobiotics. However, the emerging evidences in the past decade showed that BAs act as signaling molecules that not only autoregulate their own metabolism and enterohepatic recirculation, but also as important regulators of integrative metabolism by ac-tivating nuclear and membrane-bound G protein-coupled re-ceptors. The present review was to get insight into the role of maintenance of BA homeostasis and BA signaling pathways in development and management of hepatobiliary and intestinal diseases. DATA SOURCES: Detailed and comprehensive search of PubMed and Scopus databases was carried out for original and review articles. RESULTS: Disturbances in BA homeostasis contribute to the development of several hepatobiliary and intestinal disorders, such as non-alcoholic fatty liver disease, liver cirrhosis, choles-terol gallstone disease, intestinal diseases and both hepatocel-lular and colorectal carcinoma. CONCLUSION: Further efforts made in order to advance the understanding of sophisticated BA signaling network may be promising in developing novel therapeutic strategies related not only to hepatobiliary and gastrointestinal but also sys-temic diseases.

  13. Farnesoid X receptor, the bile acid sensing nuclear receptor, in liver regeneration

    Directory of Open Access Journals (Sweden)

    Guodong Li

    2015-03-01

    Full Text Available The liver is unique in regenerative potential, which could recover the lost mass and function after injury from ischemia and resection. The underlying molecular mechanisms of liver regeneration have been extensively studied in the past using the partial hepatectomy (PH model in rodents, where 2/3 PH is carried out by removing two lobes. The whole process of liver regeneration is complicated, orchestrated event involving a network of connected interactions, which still remain fully elusive. Bile acids (BAs are ligands of farnesoid X receptor (FXR, a nuclear receptor of ligand-activated transcription factor. FXR has been shown to be highly involved in liver regeneration. BAs and FXR not only interact with each other but also regulate various downstream targets independently during liver regeneration. Moreover, recent findings suggest that tissue-specific FXR also contributes to liver regeneration significantly. These novel findings suggest that FXR has much broader role than regulating BA, cholesterol, lipid and glucose metabolism. Therefore, these researches highlight FXR as an important pharmaceutical target for potential use of FXR ligands to regulate liver regeneration in clinic. This review focuses on the roles of BAs and FXR in liver regeneration and the current underlying molecular mechanisms which contribute to liver regeneration.

  14. Hypocholesterolemic effects of hydroxypropyl methylcellulose are mediated by altered gene expression in hepatic bile and cholesterol pathways of male hamsters

    Science.gov (United States)

    Hydroxypropyl methylcellulose (HPMC), a semi-synthetic non-fermentable soluble dietary fiber (SDF) modulates plasma lipoprotein profiles and hepatic lipid levels. HPMC is not absorbed by the body but its presence in the intestinal lumen increases fecal fat, sterol, and bile acid excretion and decrea...

  15. Effects of chronic lithium administration on renal acid excretion in humans and rats

    OpenAIRE

    Weiner, I. David; Leader, John P.; Bedford, Jennifer J.; Verlander, Jill W.; Ellis, Gaye; Kalita, Priyakshi; Vos, Frederiek; de Jong, Sylvia; Walker, Robert J.

    2014-01-01

    Abstract Lithium therapy's most common side effects affecting the kidney are nephrogenic diabetes insipidus (NDI) and chronic kidney disease. Lithium may also induce a distal renal tubular acidosis. This study investigated the effect of chronic lithium exposure on renal acid–base homeostasis, with emphasis on ammonia and citrate excretion. We compared 11 individuals on long‐term lithium therapy with six healthy individuals. Under basal conditions, lithium‐treated individuals excreted signific...

  16. Quercetin regulates hepatic cholesterol metabolism by promoting cholesterol-to-bile acid conversion and cholesterol efflux in rats.

    Science.gov (United States)

    Zhang, Min; Xie, Zongkai; Gao, Weina; Pu, Lingling; Wei, Jingyu; Guo, Changjiang

    2016-03-01

    Quercetin, a common member of the flavonoid family, is widely present in plant kingdom. Despite that quercetin is implicated in regulating cholesterol metabolism, the molecular mechanism is poorly understood. We hypothesized that quercetin regulates cholesterol homeostasis through regulating the key enzymes involved in hepatic cholesterol metabolism. To test this hypothesis, we compared the profile of key enzymes and transcription factors involved in the hepatic cholesterol metabolism in rats with or without quercetin supplementation. Twenty male Wistar rats were randomly divided into control and quercetin-supplemented groups. Serum total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and total bile acids in feces and bile were measured. Hepatic enzymatic activities were determined by activity assay kit and high-performance liquid chromatography-based analyses. The messenger RNA (mRNA) and protein expressions were determined by reverse transcriptase polymerase chain reaction and Western blot analyses, respectively. The results showed that the activity of hepatic cholesterol 7α-hydroxylase, a critical enzyme in the conversion of cholesterol to bile acids, was significantly elevated by quercetin. The expression of cholesterol 7α-hydroxylase, as well as liver X receptor α, an important transcription factor, was also increased at both mRNA and protein levels by quercetin. However, quercetin exposure had no impact on the activity of hepatic HMG-CoA reductase, a rate-limiting enzyme in the biosynthesis of cholesterol. We also found that quercetin treatment significantly increased ATP binding cassette transporter G1 mRNA and protein expression in the liver, suggesting that quercetin may increase hepatic cholesterol efflux. Collectively, the results presented here indicate that quercetin regulates hepatic cholesterol metabolism mainly through the pathways that promote cholesterol-to-bile acid conversion and

  17. A possible role for bile acid in the control of methanogenesis and the accumulation of hydrogen gas in the human colon.

    Science.gov (United States)

    Florin, T H; Jabbar, I A

    1994-01-01

    This study investigated a possible role for primary bile acid in the control of methanogenesis in the human colon. Production of hydrogen and methane was measured in anaerobic faecal cultures derived from faeces of six 'non-methanogenic' and three methanogenic healthy humans. Using a sensitive technique for gas measurement, methane was detected in all faecal cultures, including those from 'non-methanogenic' humans. Bile acid inhibited methanogenesis in a dose-response fashion in the in vitro 'non-methanogenic' and methanogenic faecal cultures. Inhibition was significant at bile acid concentrations > 0.05%. Methanogenesis correlated with methanogen (methanogenic bacteria) numbers. If this inhibition occurs in vivo, then it would explain much of the epidemiology of non-methanogenesis in humans. From an analysis of net hydrogen production by the faecal cultures, it is inferred that bile acid inhibits other hydrogen-consuming bacteria in addition to methanogens. These in vitro data suggest a major role for bile acid in the accumulation of hydrogen gas in the colon. Possible links between bile acid induced accumulation of gas and irritable bowel syndrome are discussed.

  18. Administration of ascorbic acid and an aldose reductase inhibitor (tolrestat) in diabetes: effect on urinary albumin excretion.

    Science.gov (United States)

    McAuliffe, A V; Brooks, B A; Fisher, E J; Molyneaux, L M; Yue, D K

    1998-11-01

    The important role of ascorbic acid (AA) as an anti-oxidant is particularly relevant in diabetes mellitus where plasma concentrations of AA are reduced. This study was conducted to evaluate the effects of treatment with AA or an aldose reductase inhibitor, tolrestat, on AA metabolism and urinary albumin excretion in diabetes. Blood and urine samples were collected at 0, 3, 6, 9, and 12 months from 20 diabetic subjects who were randomized into two groups to receive either oral AA 500 mg twice daily or placebo. Systolic and diastolic blood pressures, HbA1c, plasma lipids, urinary albumin, and total glycosaminoglycan excretion were measured at all time points, and heparan sulphate (glycosaminoglycan) was measured at 0 and 12 months. The same parameters, as well as urinary AA excretion, were determined at 0 and 3 months for 16 diabetes subjects receiving 200 mg tolrestat/day. AA treatment increased plasma AA (ANOVA, F ratio = 12.1, p = 0.004) and reduced albumin excretion rate (AER) after 9 months (ANOVA, F ratio = 3.2, p = 0.03), but did not change the other parameters measured. Tolrestat lowered plasma AA (Wilcoxon's signed-rank test, p benefits in attenuating the progression of diabetic complications.

  19. Novel artificial cell microencapsulation of a complex gliclazide-deoxycholic bile acid formulation: a characterization study

    Directory of Open Access Journals (Sweden)

    Mooranian A

    2014-07-01

    Full Text Available Armin Mooranian,1 Rebecca Negrulj,1 Nigel Chen-Tan,2 Hesham S Al-Sallami,3 Zhongxiang Fang,4 Trilochan Mukkur,5 Momir Mikov,6,7 Svetlana Golocorbin-Kon,6,7 Marc Fakhoury,8 Frank Arfuso,5 Hani Al-Salami1 1Biotechnology and Drug Development Research Laboratory, School of Pharmacy, Curtin Health Innovation Research Institute, Biosciences Research Precinct, Curtin University, Perth, WA, Australia; 2Faculty of Science and Engineering, Curtin University, Perth, WA, Australia; 3School of Pharmacy, University of Otago, Dunedin, New Zealand; 4School of Public Health, Curtin University, Perth, WA, Australia; 5Curtin Health Innovation Research Institute, Biosciences Research Precinct, School of Biomedical Science, Curtin University, Perth, WA, Australia; 6Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia; 7Department of Pharmacy, Faculty of Medicine, University of Montenegro, Podgorica, Montenegro; 8Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada Abstract: Gliclazide (G is an antidiabetic drug commonly used in type 2 diabetes. It has extrapancreatic hypoglycemic effects, which makes it a good candidate in type 1 diabetes (T1D. In previous studies, we have shown that a gliclazide-bile acid mixture exerted a hypoglycemic effect in a rat model of T1D. We have also shown that a gliclazide-deoxycholic acid (G-DCA mixture resulted in better G permeation in vivo, but did not produce a hypoglycemic effect. In this study, we aimed to develop a novel microencapsulated formulation of G-DCA with uniform structure, which has the potential to enhance G pharmacokinetic and pharmacodynamic effects in our rat model of T1D. We also aimed to examine the effect that DCA will have when formulated with our new G microcapsules, in terms of morphology, structure, and excipients' compatibility. Microencapsulation was carried out using the Büchi-based microencapsulating system

  20. Retinoic acid regulates several genes in bile acid and lipid metabolism via upregulation of small heterodimer partner in hepatocytes.

    Science.gov (United States)

    Mamoon, Abulkhair; Subauste, Angela; Subauste, Maria C; Subauste, Jose

    2014-10-25

    Retinoic acid (RA) affects multiple aspects of development, embryogenesis and cell differentiation processes. The liver is a major organ that stores RA suggesting that retinoids play an important role in the function of hepatocytes. In our previous studies, we have demonstrated the involvement of small heterodimer partner (SHP) in RA-induced signaling in a non-transformed hepatic cell line AML 12. In the present study, we have identified several critical genes in lipid homeostasis (Apoa1, Apoa2 and ApoF) that are repressed by RA-treatment in a SHP dependent manner, in vitro and also in vivo with the use of the SHP null mice. In a similar manner, RA also represses several critical genes involved in bile acid metabolism (Cyp7a1, Cyp8b1, Mdr2, Bsep, Baat and Ntcp) via upregulation of SHP. Collectively our data suggest that SHP plays a major role in RA-induced potential changes in pathophysiology of metabolic disorders in the liver.

  1. Bile-acid-mediated decrease in endoplasmic reticulum stress: a potential contributor to the metabolic benefits of ileal interposition surgery in UCD-T2DM rats

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    Bethany P. Cummings

    2013-03-01

    Post-operative increases in circulating bile acids have been suggested to contribute to the metabolic benefits of bariatric surgery; however, their mechanistic contributions remain undefined. We have previously reported that ileal interposition (IT surgery delays the onset of type 2 diabetes in UCD-T2DM rats and increases circulating bile acids, independently of effects on energy intake or body weight. Therefore, we investigated potential mechanisms by which post-operative increases in circulating bile acids improve glucose homeostasis after IT surgery. IT, sham or no surgery was performed on 2-month-old weight-matched male UCD-T2DM rats. Animals underwent an oral fat tolerance test (OFTT and serial oral glucose tolerance tests (OGTT. Tissues were collected at 1.5 and 4.5 months after surgery. Cell culture models were used to investigate interactions between bile acids and ER stress. IT-operated animals exhibited marked improvements in glucose and lipid metabolism, with concurrent increases in postprandial glucagon-like peptide-1 (GLP-1 secretion during the OFTT and OGTTs, independently of food intake and body weight. Measurement of circulating bile acid profiles revealed increases in circulating total bile acids in IT-operated animals, with a preferential increase in circulating cholic acid concentrations. Gut microbial populations were assessed as potential contributors to the increases in circulating bile acid concentrations, which revealed proportional increases in Gammaproteobacteria in IT-operated animals. Furthermore, IT surgery decreased all three sub-arms of ER stress signaling in liver, adipose and pancreas tissues. Amelioration of ER stress coincided with improved insulin signaling and preservation of β-cell mass in IT-operated animals. Incubation of hepatocyte, adipocyte and β-cell lines with cholic acid decreased ER stress. These results suggest that postoperative increases in circulating cholic acid concentration contribute to improvements in

  2. Synthesis of 24-phenyl-24-oxo steroids derived from bile acids by palladium-catalyzed cross coupling with phenylboronic acid. NMR characterization and X-ray structures.

    Science.gov (United States)

    Mayorquín-Torres, Martha C; Romero-Ávila, Margarita; Flores-Álamo, Marcos; Iglesias-Arteaga, Martin A

    2013-11-01

    Palladium-catalyzed cross coupling of phenyboronic acid with acetylated bile acids in which the carboxyl functions have been activated by formation of a mixed anhydride with pivalic anhydride afforded moderate to good yield of 24-phenyl-24-oxo-steroids. Unambiguous assignments of the NMR signals were made with the aid of combined 1D and 2D NMR techniques. X-ray diffraction studies confirmed the obtained structures.

  3. Excretion of biliary compounds during intrauterine life

    Science.gov (United States)

    Macias, Rocio IR; Marin, Jose JG; Serrano, Maria A

    2009-01-01

    In adults, the hepatobiliary system, together with the kidney, constitute the main routes for the elimination of several endogenous and xenobiotic compounds into bile and urine, respectively. However, during intrauterine life the biliary route of excretion for cholephilic compounds, such as bile acids and biliary pigments, is very poor. Although very early in pregnancy the fetal liver produces bile acids, bilirubin and biliverdin, these compounds cannot be efficiently eliminated by the fetal hepatobiliary system, owing to the immaturity of the excretory machinery in the fetal liver. Therefore, the potentially harmful accumulation of cholephilic compounds in the fetus is prevented by their elimination across the placenta. Owing to the presence of detoxifying enzymes and specific transport systems at different locations of the placental barrier, such as the endothelial cells of chorionic vessels and trophoblast cells, this organ plays an important role in the hepatobiliary-like function during intrauterine life. The relevance of this excretory function in normal fetal physiology is evident in situations where high concentrations of biliary compounds are accumulated in the mother. This may result in oxidative stress and apoptosis, mainly in the placenta and fetal liver, which might affect normal fetal development and challenge the fate of the pregnancy. The present article reviews current knowledge of the mechanisms underlying the hepatobiliary function of the fetal-placental unit and the repercussions of several pathological conditions on this tandem. PMID:19230042

  4. Gender, but not CYP7A1 or SLCO1B1 polymorphism, affects the fasting plasma concentrations of bile acids in human beings.

    Science.gov (United States)

    Xiang, Xiaoqiang; Backman, Janne T; Neuvonen, Pertti J; Niemi, Mikko

    2012-03-01

    Cholesterol 7α-hydroxylase (CYP7A1) is the rate-limiting enzyme of bile acid production in human beings, and organic anion-transporting polypeptide 1B1 (OATP1B1) may influence bile acid hepatic uptake and cholesterol and bile acid synthesis rate. Our purpose was to investigate the effects of gender and CYP7A1 and SLCO1B1 polymorphisms on the fasting plasma concentrations of bile acids, bile acid synthesis marker and total cholesterol in a Finnish population. Fasting plasma concentrations of 16 endogenous bile acids, their synthesis marker (7α-hydroxy-4-cholesten-3-one) and total cholesterol were measured in 243 samples from 143 healthy volunteers. The volunteers were genotyped for 6 haplotype-tagging single-nucleotide polymorphisms (SNPs) of CYP7A1 and two functionally relevant SNPs in SLCO1B1. The mean plasma concentrations of chenodeoxycholic acid, glycochenodeoxycholic acid, ursodeoxycholic acid and glycoursodeoxycholic acid were 61-111% higher in men than in women (P ≤ 0.001). Accordingly, the mean concentration of total bile acids was 51% higher in men than in women (P = 0.001). The CYP7A1 rs8192879 and rs1023652 SNPs were associated with deoxycholic acid and hyodeoxycholic acid concentrations, respectively, but the associations were not significant after correction for multiple testing. None of the six CYP7A1 SNPs was associated with the plasma concentrations of cholesterol or 7α-hydroxy-4-cholesten-3-one. SLCO1B1 genotype was associated with total plasma cholesterol concentration only, but the association was not significant after correction for multiple testing. In general, the gender contributes substantially more to variation in fasting plasma bile acid concentrations than CYP7A1 or SLCO1B1 polymorphism do. Common genetic variability in CYP7A1 is unlikely to play a significant role in cholesterol metabolism and bile acid homeostasis under normal physiological conditions.

  5. Role of bile acids, prostaglandins and COX inhibitors in chronic esophagitis in a mouse model

    Institute of Scientific and Technical Information of China (English)

    C Poplawski; D Sosnowski; A Szaflarska-Poplawska; J Sarosiek; R McCallum; Z Bartuzi

    2006-01-01

    AIM: To develop a new experimental model of esophagitis that serves a complementary tool to clinical investigation in an insight into the mechanism of the damage to the esophagus mucosa by aggressive factors, and role of COX inhibitors in this process.METHODS: The study was conducted in 56 male mice.Animals were divided into seven groups: (1) perfused with HCl, (2) perfused with HCl and physiologic concentration of pepsin (HCl/P), (3) perfused with similar HCl/P solution enriched with conjugated bile acids (glycho- and tauro-sodium salts) designated esophageal infusion catheter under the general anesthesia, (4) perfused as in group 2 treated with indometacin, (5) perfused as in group 2 treated with NS-398, (6) perfused as in group 3 treated with indometacin, and (7) perfused as in group 3 treated with NS-398.The esophagus was divided into 3 parts: upper, middle and lower. The PGE2 concentration was measured in all parts of esophagus using RIA method. Esophagus of sacrificed animals was macroscopically evaluated using a low power dissecting microscope (20x). Specimeris, representing the most frequently seen changes were fixed,stained with H&E and assessed microscopically using the damage score, and inflammatory score.RESULTS: The macroscopic changes were significantly severer in HCl/P than those in HCl animals (77%) and in HCl/P/BA group (43%). In HCl/P NS-398 group we noticed significantly less changes than those in not treated group (42%) and in analogical group treated with indometacine (45%). In HCl/P/BA INDO group we observed significantly severer changes than that in not treated group (52%). We noticed less changes in HCl/P NS-398 than that in group with indometacine (46%). In HCl/P/BA NS-398 group we had less changes than that in indometacin group (34%). The microscopic changes observed in HCl/P/BA INDO group were severer than that in not treated group (48%). Esophagitis index in HCl group was significantly lower than in HCl/P and also HCl/P/BA group (32% and

  6. Bile acids modulate signaling by functional perturbation of plasma membrane domains.

    Science.gov (United States)

    Zhou, Yong; Maxwell, Kelsey N; Sezgin, Erdinc; Lu, Maryia; Liang, Hong; Hancock, John F; Dial, Elizabeth J; Lichtenberger, Lenard M; Levental, Ilya

    2013-12-13

    Eukaryotic cell membranes are organized into functional lipid and protein domains, the most widely studied being membrane rafts. Although rafts have been associated with numerous plasma membrane functions, the mechanisms by which these domains themselves are regulated remain undefined. Bile acids (BAs), whose primary function is the solubilization of dietary lipids for digestion and absorption, can affect cells by interacting directly with membranes. To investigate whether these interactions affected domain organization in biological membranes, we assayed the effects of BAs on biomimetic synthetic liposomes, isolated plasma membranes, and live cells. At cytotoxic concentrations, BAs dissolved synthetic and cell-derived membranes and disrupted live cell plasma membranes, implicating plasma membrane damage as the mechanism for BA cellular toxicity. At subtoxic concentrations, BAs dramatically stabilized domain separation in Giant Plasma Membrane Vesicles without affecting protein partitioning between coexisting domains. Domain stabilization was the result of BA binding to and disordering the nonraft domain, thus promoting separation by enhancing domain immiscibility. Consistent with the physical changes observed in synthetic and isolated biological membranes, BAs reorganized intact cell membranes, as evaluated by the spatial distribution of membrane-anchored Ras isoforms. Nanoclustering of K-Ras, related to nonraft membrane domains, was enhanced in intact plasma membranes, whereas the organization of H-Ras was unaffected. BA-induced changes in Ras lateral segregation potentiated EGF-induced signaling through MAPK, confirming the ability of BAs to influence cell signal transduction by altering the physical properties of the plasma membrane. These observations suggest general, membrane-mediated mechanisms by which biological amphiphiles can produce their cellular effects.

  7. The Role of Sirt1 in Bile Acid Regulation during Calorie Restriction in Mice.

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    Zidong Donna Fu

    Full Text Available Sirtuin 1 (Sirt1 is an NAD+-dependent protein deacetylase that is proposed to mediate many health-promoting effects of calorie restriction (CR. We recently reported that short-term CR increased the bile acid (BA pool size in mice, likely due to increased BA synthesis in liver. Given the important role of Sirt1 in the regulation of glucose, lipid, as well as BA metabolism, we hypothesized that the CR-induced increase in BAs is Sirt1-dependent. To address this, the present study utilized genetically-modified mice that were Sirt1 loss of function (liver knockout, LKO or Sirt1 gain of function (whole body-transgenic, TG. Three genotypes of mice (Sirt1-LKO, wild-type, and Sirt1-TG were each randomly divided into ad libitum or 40% CR feeding for one month. BAs were extracted from various compartments of the enterohepatic circulation, followed by BA profiling by UPLC-MS/MS. CR increased the BA pool size and total BAs in serum, gallbladder, and small intestine. The CR-induced increase in BA pool size correlated with the tendency of increase in the expression of the rate-limiting BA-synthetic enzyme Cyp7a1. However, in contrast to the hypothesis, the CR-induced increase in BA pool size and Cyp7a1 expression was still observed with ablated expression of Sirt1 in liver, and completely suppressed with whole-body overexpression of Sirt1. Furthermore, in terms of BA composition, CR increased the ratio of 12α-hydroxylated BAs regardless of Sirt1 genotypes. In conclusion, the CR-induced alterations in BA pool size, BA profiles, and expression of BA-related genes do not appear to be dependent on Sirt1.

  8. The Role of Sirt1 in Bile Acid Regulation during Calorie Restriction in Mice.

    Science.gov (United States)

    Fu, Zidong Donna; Cui, Julia Yue; Klaassen, Curtis D

    2015-01-01

    Sirtuin 1 (Sirt1) is an NAD+-dependent protein deacetylase that is proposed to mediate many health-promoting effects of calorie restriction (CR). We recently reported that short-term CR increased the bile acid (BA) pool size in mice, likely due to increased BA synthesis in liver. Given the important role of Sirt1 in the regulation of glucose, lipid, as well as BA metabolism, we hypothesized that the CR-induced increase in BAs is Sirt1-dependent. To address this, the present study utilized genetically-modified mice that were Sirt1 loss of function (liver knockout, LKO) or Sirt1 gain of function (whole body-transgenic, TG). Three genotypes of mice (Sirt1-LKO, wild-type, and Sirt1-TG) were each randomly divided into ad libitum or 40% CR feeding for one month. BAs were extracted from various compartments of the enterohepatic circulation, followed by BA profiling by UPLC-MS/MS. CR increased the BA pool size and total BAs in serum, gallbladder, and small intestine. The CR-induced increase in BA pool size correlated with the tendency of increase in the expression of the rate-limiting BA-synthetic enzyme Cyp7a1. However, in contrast to the hypothesis, the CR-induced increase in BA pool size and Cyp7a1 expression was still observed with ablated expression of Sirt1 in liver, and completely suppressed with whole-body overexpression of Sirt1. Furthermore, in terms of BA composition, CR increased the ratio of 12α-hydroxylated BAs regardless of Sirt1 genotypes. In conclusion, the CR-induced alterations in BA pool size, BA profiles, and expression of BA-related genes do not appear to be dependent on Sirt1.

  9. Antibacterial and Antioxidant Activities of Acid and Bile Resistant Strains of Lactobacillus fermentum Isolated from Miang

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    Srikanjana Klayraung

    2009-12-01

    Full Text Available Miang is a kind of traditional fermented tea leaves, widely consumed in northern Thailand as a snack. It contains several kinds of Lactobacilli spp. The aim of this study was to isolate strains of Lactobacillus fermentum from miang and to investigate their antibacterial and antioxidant activities. The agar spot and well assays were used for determination of antibacterial power. The antibacterial mechanism was investigated by cell morphologic change under scanning electron microscope (SEM. Antioxidant activity was studied by means of free radical scavenging and ferric reducing power assays. The acid and bile screening tests indicated that L. fermentum FTL2311 and L. fermentum FTL10BR presented antibacterial activity against several pathogenic bacteria: Listeria monocytogenes DMST 17303, Salmonella Typhi DMST 5784, Shigella sonnei DMST 561 (ATCC 11060and Staphylococcus aureus subsp. aureus DMST 6512 (ATCC 6538Ptm. The results from SEM suggested that the antibacterial action was due to the destruction of cell membrane which consequently caused the pathogenic cell shrinking or cracking. The antioxidant study suggested that both L. fermentum FTL2311 and L. fermentum FTL10BR strains could liberate certain substances that possessed antioxidant activity expressed as trolox equivalent antioxidant capacity (TEAC and equivalent concentration (EC values for free radical scavenging and reducing mechanisms, respectively. The supernatant of L. fermentum FTL2311 broth revealed TEAC and EC values of 22.54±0.12 and 20.63±0.17 µM.mg-1 respectively, whereas that of L. fermentum FTL10BR yielded TEAC and EC values of 24.09±0.12 and 21.26±0.17 µM.mg-1 respectively. These two strains isolated from miang present high potential as promising health-promoting probiotics.

  10. Total serum bile acid as a potential marker for the diagnosis of cholangiocarcinoma without jaundice.

    Science.gov (United States)

    Sombattheera, Sutthikan; Proungvitaya, Tanakorn; Limpaiboon, Temduang; Wongkham, Sopit; Wongkham, Chaisiri; Luvira, Vor; Proungvitaya, Siriporn

    2015-01-01

    Diagnosis of cholangiocarcinoma (CCA) is difficult when patients do not show jaundice. The aim of this study was to examine the feasibility of using the total serum bile acid (TSBA) level as an aid for the diagnosis of CCA in patients without jaundice. For this purpose, TSBA of the following groups were measured using a Beckman Synchron CX4 clinical chemistry analyzer: 60 cases of CCA with total serum bilirubin ≤2 mg/dL (low total bilirubin group, LTB); 32 cases of CCA with total serum bilirubin >2 mg/dL (high total bilirubin group, HTB); and 115 healthy controls. Liver function parameters such as serum cholesterol, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) were also examined. The results showed that the TSBA of both LTB and HTB groups of the CCA patients were significantly higher than that of the healthy controls. Also, significant correlation was observed between TSBA and total bilirubin levels in the HTB group of CCA patients. However, no such correlation was seen in the LTB group. The cut-off value of TSBA was determined for the LTB group of CCA patients using the receiver operating characteristic curve analysis, and it was 6.05 μmol/L with the sensitivity and specificity of 46.7% and 84.4%, respectively. In addition, the ALP level was correlated well with the TSBA level and ALP in HTB group was significantly higher than that of LTB group. Moreover, the combination of high TSBA and high ALP levels gave higher specificity up to 97.4%. TSBA might be useful for the diagnosis of CCA patients without jaundice.

  11. 75Se HCAT test in the detection of bile acid malabsorption in functional diarrhoea and its correlation with small bowel transit.

    Science.gov (United States)

    Sciarretta, G; Fagioli, G; Furno, A; Vicini, G; Cecchetti, L; Grigolo, B; Verri, A; Malaguti, P

    1987-01-01

    The purpose of this study was to evaluate whether bile acid malabsorption assessed by the 75SeHCAT test, had a pathogenetic role in functional chronic diarrhoea and to ascertain whether the small bowel transit time (SBTT) could be correlated with the 75SeHCAT test results. The test was based on the counting of the abdominal retention of a 75-selenium labelled homotaurocholic acid. The 75SeHCAT test was carried out in a control group of 23 healthy adults and in 46 patients, 38 of whom were suffering from irritable bowel syndrome (IBS) of diarrhoeic form and eight patients who had undergone cholecystectomy and were suffering from chronic diarrhoea. Faecal bile acid loss was determined in nine patients, and in 14, serum bile acid increase after a standard meal was measured. In 17, SBTT was studied by hydrogen breath test after lactulose administration (21 g in 300 ml water). In 15 patients, choledochocaecal transit time was estimated by Tc99m-HIDA (111 MBq) cholescintigraphy. In 20 of 46 subjects, 75SeHCAT retention was below normal level, and in 19 cholestyramine administration relieved diarrhoea. 75SeHCAT results were related to faecal bile acid loss, while no correlation was found with serum bile acids and SBTT. The data suggest a possible wider use of the 75SeHCAT test in chronic diarrhoea to estimate bile acid malabsorption in irritable bowel syndrome, diarrhoeic form, and provide an effective treatment. In our patients small bowel transit velocity does not seem to be a pathogenetic factor of bile acid malabsorption. PMID:3666565

  12. Effect of pyridoxine treatment of a homocystinuric patient on the urinary excretion of some sulfur-containing amino acids

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    Kodama,H.

    1974-08-01

    Full Text Available The effect of pyridoxine treatment of a homocystinuric patient on the urinary excretion of some sulfur-containing amino acids was studied and the following results were obtained. As a result of pyridoxine treatment, urinary homocystine decreased to a fairly great extent, and its unusual metabolites S.(3-hydroxy-3-carboxyn- propylthio homocysteine (HCPTHC and S-C8-carboxyethylthio homocysteine (j3-CETHC increased to some extent. But its oxidation product (homocysteic acid showed a tendency to decrease slightly. Urinary methionine and cystine increased to some extent, but cysteinehomocysteine mixed disulfide showed no remarkable change.

  13. The influence of bile acids on the oral bioavailability of vitamin K encapsulated in polymeric micelles.

    Science.gov (United States)

    van Hasselt, P M; Janssens, G E P J; Slot, T K; van der Ham, M; Minderhoud, T C; Talelli, M; Akkermans, L M; Rijcken, C J F; van Nostrum, C F

    2009-01-19

    The purpose of this study was to assess the ability of polymeric micelles to enable gastrointestinal absorption of the extremely hydrophobic compound vitamin K, by comparison of its absorption in bile duct ligated and sham operated rats. Hereto, vitamin K was encapsulated in micelles composed of mPEG(5000)-b-p(HPMAm-lac(2)), a thermosensitive block copolymer. Vitamin K plasma levels rose significantly upon gastric administration of 1 mg vitamin K encapsulated in polymeric micelles in sham operated rats, but not after bile duct ligation (AUC 4543 and 1.64 ng/mL/h respectively, pvitamin K from polymeric micelles is mediated by free bile and that uptake of intact micelles through pinocytosis is insignificant.

  14. Increase of Urinary 5-Hydroxyindoleacetic Acid Excretion but Not Serum Chromogranin a Following Over-The-Counter 5-Hydroxytryptophan Intake

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    Tisha Joy

    2008-01-01

    Full Text Available BACKGROUND: 5-hydroxyindoleacetic acid (5-HIAA excretion is commonly measured for biochemical detection of carcinoid tumours. A 77-year-old woman was referred for elevated 24 h urine 5-HIAA excretion (510 μmol/day; normal is less than 45 μmol/day and serum chromogranin A (CgA (72.1 U/L; normal is less than 18 U/L, both subsequently normalized after discontinuation of 5-hydroxytryptophan (5-HTP. 5-HTP, a precursor of serotonin, is not commonly listed as a substance that increases 5-HIAA levels in urine. The effect of 5-HTP on CgA has not been previously described.

  15. 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-MM12). It is representative of the major murine intestinal bacterial phyla, but is deficient for 7α-dehydroxylation. We find that the Oligo-MM12 consortium carries out bile acid deconjugation, a prerequisite for 7α-dehydroxylation, and confers no resistance to C. difficile infection (CDI). Amendment of Oligo-MM12 with C. scindens normalized the large intestinal bile acid composition by reconstituting 7

  16. Urinary excretion of fatty acid-binding protein 4 is associated with albuminuria and renal dysfunction.

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    Yusuke Okazaki

    Full Text Available Fatty acid-binding protein 4 (FABP4/A-FABP/aP2 is expressed in not only adipocytes and macrophages but also peritubular capillaries in the normal kidney. We recently demonstrated that ectopic expression of FABP4, but not FABP1 known as liver FABP (L-FABP, in the glomerulus is associated with progression of proteinuria and renal dysfunction. However, urinary excretion of FABP4 has not been investigated.Subjects who participated in the Tanno-Sobetsu Study, a study with a population-based cohort design, in 2011 (n = 392, male/female: 166/226 were enrolled. Urinary FABP4 (U-FABP4 and urinary albumin-to-creatinine ratio (UACR were measured. Change in estimated glomerular filtration rate (eGFR was followed up one year later.In 93 (23.7% of the 392 subjects, U-FABP4 level was below the sensitivity of the assay. Subjects with undetectable U-FABP4 were younger and had lower UACR and higher eGFR levels than subjects with measurable U-FABP4. U-FABP4 level was positively correlated with age, systolic blood pressure and levels of serum FABP4 (S-FABP4, triglycerides, hemoglobin A1c (HbA1c, urinary FABP1 (U-FABP1 and UACR (r = 0.360, p<0.001. Age, S-FABP4, U-FABP1 and UACR were independent predictors of U-FABP4. On the other hand, systolic blood pressure, HbA1c and U-FABP4 were independently correlated with UACR. Reduction in eGFR after one year was significantly larger in a group with the highest tertile of baseline U-FABP4 than a group with the lowest tertile.Urinary FABP4 level is independently correlated with level of albuminuria and possibly predicts yearly decline of eGFR. U-FABP4 would be a novel biomarker of glomerular damage.

  17. Strawberry processing does not affect the production and urinary excretion of urolithins, ellagic acid metabolites, in humans.

    Science.gov (United States)

    Truchado, Pilar; Larrosa, Mar; García-Conesa, María Teresa; Cerdá, Begoña; Vidal-Guevara, María Luisa; Tomás-Barberán, Francisco A; Espín, Juan Carlos

    2012-06-13

    The study of fruit and vegetable processing and its effects on the levels of health-promoting constituents and their bioavailability and metabolism is very relevant to understanding the role of these constituents in human health. Strawberry polyphenols, and particularly ellagitannins and ellagic acid, have been associated with the health benefits of this berry for humans. These compounds are transformed into urolithins by the gut microbiota, and these metabolites exert several biological activities that could be responsible for the health effects of strawberries. Processing potentially increases the extraction of ellagitannins from the strawberry achenes and the release of ellagic acid from ellagitannins. It is of interest to evaluate the effect of processing on strawberry ellagitannin microbial metabolism compared with fresh strawberries. This study shows that no significant differences in the production and excretion of urolithins were found between the intake of fresh strawberries and that of a thermally processed strawberry puree containing the same amount of strawberries. Processing increases the amount of free ellagic acid 2.5-fold, but this had no effect on the transformation in urolithins by the gut microbiota or in the excretion of urolithin metabolites (urolithin glucuronides) in urine, showing that the release of ellagic acid from ellagitannins is not a relevant factor affecting the microbial metabolism. All of the volunteers produced urolithin A, but only 3 of 20 volunteers produced and excreted urolithin B. It is confirmed that some volunteers were efficient producers of urolithins, whereas other produced much lower amounts. These results show that processing does not modify the potential health effects of strawberry polyphenols.

  18. FGF19 Regulates Cell Proliferation, Glucose and Bile Acid Metabolism via FGFR4-Dependent and Independent Pathways

    OpenAIRE

    Ai-Luen Wu; Sally Coulter; Christopher Liddle; Anne Wong; Jeffrey Eastham-Anderson; French, Dorothy M.; Peterson, Andrew S.; Junichiro Sonoda

    2011-01-01

    Fibroblast growth factor 19 (FGF19) is a hormone-like protein that regulates carbohydrate, lipid and bile acid metabolism. At supra-physiological doses, FGF19 also increases hepatocyte proliferation and induces hepatocellular carcinogenesis in mice. Much of FGF19 activity is attributed to the activation of the liver enriched FGF Receptor 4 (FGFR4), although FGF19 can activate other FGFRs in vitro in the presence of the coreceptor βKlotho (KLB). In this report, we investigate the role of FGFR4...

  19. Functional analyses of three acyl-CoA synthetases involved in bile acid degradation in Pseudomonas putida DOC21.

    Science.gov (United States)

    Barrientos, Álvaro; Merino, Estefanía; Casabon, Israël; Rodríguez, Joaquín; Crowe, Adam M; Holert, Johannes; Philipp, Bodo; Eltis, Lindsay D; Olivera, Elías R; Luengo, José M

    2015-01-01

    Pseudomonas putida DOC21, a soil-dwelling proteobacterium, catabolizes a variety of steroids and bile acids. Transposon mutagenesis and bioinformatics analyses identified four clusters of steroid degradation (std) genes encoding a single catabolic pathway. The latter includes three predicted acyl-CoA synthetases encoded by stdA1, stdA2 and stdA3 respectively. The ΔstdA1 and ΔstdA2 deletion mutants were unable to assimilate cholate or other bile acids but grew well on testosterone or 4-androstene-3,17-dione (AD). In contrast, a ΔstdA3 mutant grew poorly in media containing either testosterone or AD. When cells were grown with succinate in the presence of cholate, ΔstdA1 accumulated Δ(1/4) -3-ketocholate and Δ(1,4) -3-ketocholate, whereas ΔstdA2 only accumulated 7α,12α-dihydroxy-3-oxopregna-1,4-diene-20-carboxylate (DHOPDC). When incubated with testosterone or bile acids, ΔstdA3 accumulated 3aα-H-4α(3'propanoate)-7aβ-methylhexahydro-1,5-indanedione (HIP) or the corresponding hydroxylated derivative. Biochemical analyses revealed that StdA1 converted cholate, 3-ketocholate, Δ(1/4) -3-ketocholate, and Δ(1,4) -3-ketocholate to their CoA thioesters, while StdA2 transformed DHOPDC to DHOPDC-CoA. In contrast, purified StdA3 catalysed the CoA thioesterification of HIP and its hydroxylated derivatives. Overall, StdA1, StdA2 and StdA3 are acyl-CoA synthetases required for the complete degradation of bile acids: StdA1 and StdA2 are involved in degrading the C-17 acyl chain, whereas StdA3 initiates degradation of the last two steroid rings. The study highlights differences in steroid catabolism between Proteobacteria and Actinobacteria.

  20. Effect of urine pH changed by dietary intervention on uric acid clearance mechanism of pH-dependent excretion of urinary uric acid

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    Kanbara Aya

    2012-06-01

    Full Text Available Abstract Background The finding reported in a previous paper - alkalization of urine facilitates uric acid excretion - is contradictory to what one might expect to occur: because food materials for the alkalization of urine contain fewer purine bodies than those for acidification, less uric acid in alkaline urine should have been excreted than in acid urine. To make clear what component of uric acid excretion mechanisms is responsible for this unexpected finding, we simultaneously collected data for the concentration of both creatinine and uric acid in serum as well as in urine, in order to calculate both uric acid and creatinine clearances. Methods Within the framework of the Japanese government’s health promotion program, we made recipes which consisted of protein-rich and less vegetable-fruit food materials for H + -load (acidic diet and others composed of less protein and more vegetable-fruit rich food materials (alkaline diet. This is a crossover study within some limitations. Healthy female students, who had no medical problems at the regular physical examination provided by the university, were enrolled in this consecutive 5-day study for each test. From whole-day collected urine, total volume, pH, organic acid, creatinine, uric acid, titratable acid and all cations (Na+,K+,Ca2+,Mg2+,NH4+ and anions (Cl−,SO42−,PO4− necessary for the estimation of acid–base balance were measured. In the early morning before breakfast of the 1st, 3rd and 5th experimental day, we sampled 5 mL of blood to estimate the creatinine and uric acid concentration in serum. Results and discussion Urine pH reached a steady state 3 days after switching from ordinary daily diets to specified regimens. The amount of acid generated ([SO42−] + organic acid − gut alkaliwas linearly related with the excretion of acid (titratable acid + [NH4+] − [HCO3−], indicating that H + in urine is generated by the metabolic degradation of

  1. In Vitro and in Vivo Evaluation of Novel Cross-Linked Saccharide Based Polymers as Bile Acid Sequestrants

    Directory of Open Access Journals (Sweden)

    Francisco Javier Lopez-Jaramillo

    2015-02-01

    Full Text Available Bile acid sequestrants (BAS represent a therapeutic approach for the management of hypercholesterolemia that relies on the cationic polymeric nature of BAS to selectively bind negatively charged bile acids. We hypothesized that the cross-linking of β-cyclodextrin (β-CD and saccharides such as starch or dextrin with divinyl sulfone (DVS yields homo- and hetero-polymeric materials with the ability to trap sterols. Our hypothesis was put to test by synthesizing a library of 22 polymers that were screened to evaluate their capability to sequester both cholesterol (CHOL and cholic and deoxycholic acids (CA and DCA. Three polymers synthesized in high yield were identified as promising. Two were neutral hetero-polymers of β-CD and starch or dextrin and the third was a weakly cationic homo-polymer of starch, highlighting the importance of the cavity effect. They were tested in hypercholesterolemic male Wistar rats and their ability to regulate hypercholesterolemia was similar to that for the reference BAS cholestyramine, but with two additional advantages: (i they normalized the TG level and (ii they did not increase the creatinine level. Neither hepatotoxicity nor kidney injury was detected, further supporting them as therapeutical candidates to manage hypercholesterolemia.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1991-05-01

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

  3. Molecular field analysis and 3D-quantitative structure-activity relationship study (MFA 3D-QSAR) unveil novel features of bile acid recognition at TGR5.

    Science.gov (United States)

    Macchiarulo, Antonio; Gioiello, Antimo; Thomas, Charles; Massarotti, Alberto; Nuti, Roberto; Rosatelli, Emiliano; Sabbatini, Paola; Schoonjans, Kristina; Auwerx, Johan; Pellicciari, Roberto

    2008-09-01

    Bile acids regulate nongenomic actions through the activation of TGR5, a membrane receptor that is G protein-coupled to the induction of adenylate cyclase. In this work, a training set of 43 bile acid derivatives is used to develop a molecular interaction field analysis (MFA) and a 3D-quantitative structure-activity relationship study (3D-QSAR) of TGR5 agonists. The predictive ability of the resulting model is evaluated using an external set of compounds with known TGR5 activity, and six bile acid derivatives whose unknown TGR5 activity is herein assessed with in vitro luciferase assay of cAMP formation. The results show a good predictive model and indicate a statistically relevant degree of correlation between the TGR5 activity and the molecular interaction fields produced by discrete positions of the bile acid scaffold. This information is instrumental to extend on a quantitative basis the current structure-activity relationships of bile acids as TGR5 modulators and will be fruitful to design new potent and selective agonists of the receptor.

  4. Influence of dietary sugar on cholesterol and bile acid metabolism in the rat: Marked reduction of hepatic Abcg5/8 expression following sucrose ingestion.

    Science.gov (United States)

    Apro, Johanna; Beckman, Lena; Angelin, Bo; Rudling, Mats

    2015-06-12

    Previous studies have indicated that dietary intake of sugar may lower bile acid production, and may promote cholesterol gallstone formation in humans. We studied the influence of dietary sucrose on cholesterol and bile acid metabolism in the rat. In two different experiments, rats received high-sucrose diets. In the first, 60% of the weight of standard rat chow was replaced with sucrose (high-sucrose diet). In the second, rats received a diet either containing 65% sucrose (controlled high-sucrose diet) or 65% complex carbohydrates, in order to keep other dietary components constant. Bile acid synthesis, evaluated by measurements of the serum marker 7-alpha-hydroxy-4-cholesten-3-one (C4) and of the hepatic mRNA expression of Cyp7a1, was markedly reduced by the high-sucrose diet, but not by the controlled high-sucrose diet. Both diets strongly reduced the hepatic - but not the intestinal - mRNA levels of Abcg5 and Abcg8. The differential patterns of regulation of bile acid synthesis induced by the two sucrose-enriched diets indicate that it is not sugar per se in the high-sucrose diet that reduces bile acid synthesis, but rather the reduced content of fiber or fat. In contrast, the marked reduction of hepatic Abcg5/8 observed is an effect of the high sugar content of the diets.

  5. 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.

  6. Importance of ornithine transcarbamylase (OTC) deficiency in small intestine for urinary orotic acid excretion: analysis of OTC-deficient spf-ash mice with OTC transgene.

    Science.gov (United States)

    Saheki, T; Mori, K; Kobayashi, K; Horiuchi, M; Shige, T; Obara, T; Suzuki, S; Mori, M; Yamamura, K

    1995-01-25

    We report the effect of the ornithine transcarbamylase (OTC) transgene composed of 1.3 kb of the 5' flanking region of the rat OTC gene fused to rat OTC cDNA on urinary orotic acid excretion in OTC-deficient spf-ash (sparse-fur with abnormal skin and hair) mice during overnight-starvation and nitrogen loading. During starvation, spf-ash mice with about 6% and 2% of control levels of OTC activity in the liver and small intestine excreted a large amount of orotic acid in the urine. Transgenic spf-ash mice with about 10% and 30% of the control OTC activities in the liver and small intestine did not excrete more than the normal level of orotic acid. Accidental parasitization of transgenic spf-ash mice with ticks (Myocoptes musculinus) resulted in decrease of the OTC activities in the liver and small intestine to the levels in spf-ash mice, and increased excretion of orotic acid. During extermination of the ticks, the mice showed varied levels of OTC activity and orotic acid excretion. On nitrogen loading, transgenic spf-ash mice as well as spf-ash mice excreted larger amounts of orotic acid, while control mice showed no increase in its excretion. The levels of urinary orotic acid were inversely correlated to the logarithms of the OTC activities in the liver and small intestine, the correlation being significantly higher with intestinal OTC than with hepatic OTC activity. These results suggest that the level of OTC activity in the small intestine is important for production of orotic acid.

  7. Effects of lunar soil, Zagami meteorite, and ocean ridge basalt on the excretion of itoic acid, a siderophore, and coproporphyrin by Bacillus subtilis

    Science.gov (United States)

    Ito, T.

    1986-01-01

    Samples of lunar soil (10084,151), Zagami meteorite, postulated to be ejected from Mars, and ocean ridge basalt, the most abundant volcanic rock on earth, all completely inhibited the excretion of itoic acid and of coproporphyrin by Bacillus subtilis, a common airborne bacterium. Since such inhibition has been known to occur only under iron rich growth conditions(the excretion of these compounds occurs under iron deficient growth conditions), the result indicated that the organism was capable of extracting iron quite readily from these materials. A sample of synthetic ilmenite completely failed to inhibit the excretion of coproporphyrin, and inhibited the excretion of itoic acid only slightly. The result suggested that much of the iron extracted by the organism must have come from iron sources other than ilmenite,such as pyroxenes and olivines,in these natural materials tested.

  8. Bile Acid Sequestrants: Glucose-lowering mechanisms, treatment effects and application prospects%BAS作为降糖药——降糖机制、临床疗效及应用前景

    Institute of Scientific and Technical Information of China (English)

    洪珊珊

    2012-01-01

    胆汁酸(Bile acids)用于治疗血脂异常已超过25年,其与不可吸收的树脂在肠腔内结合形成胆汁酸螯合物BAS(考来烯胺、考来维仑、colestimide、考来替泊)调节胆汁酸代谢,BAS经便排泄,并经由肠肝循环重吸收.胆汁酸可通过影响核受体FXR和TGR5调节肝糖代谢、外周胰岛素敏感性和能量代谢等.临床研究表明胆汁酸能够降低LDL,有利于预防冠心病.另外,2008年已证明BAS盐酸考来维仑(colesevelam HCl)联合饮食控制和运动疗法可改善T2DM血糖控制.最早Garg A等1994年一项为期6周的随机双盲交叉对照证明,盐酸考来烯胺降低血糖和HbA1c,随后2008年Goldberg RB等对胰岛素治疗DM控制不满意的患者、Fonseca等对二甲双胍或磺脲类药物(SUs)治疗DM控制不满意的患者研究发现,盐酸考来维仑均可改善这些患者的血糖控制情况.%Bile acids have been used for over 25 years for the therapy of dyslipidemia. Nonabsorbable resins could chelate bile acids in the intestinal lumen as Bile Acids Sequestrant(BAS, colestyramine, colesevelam, colestimide, colestipol) to regulate biles acids metabolism, decreasing their enterohepatic recirculation. BAS are excreted in the feces and only a part of BAS was reabsorbed into the enterohepatic circulation. Bile acids have been reported to regulate hepatic glucose metabolism, peripheral insulin sensitivity and energy metabolism by FXR- and TGR5-dependent pathways. Several clinical studies have indicated the benefit of their cholesterol-lowering effect for the prevention of coronary heart disease Additionally, colesevelam hydrochloride (HC1) was approved in 2008 as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. The first observation for such an effect of BAS came from a randomized, double-blind, crossover study in 1994 by Garg A, et al in which cholestyramine was administered to T2DM patients for 6 weeks and resulted in reduction of plasma glucose

  9. Species-specific mechanisms for cholesterol 7alpha-hydroxylase (CYP7A1) regulation by drugs and bile acids.

    Science.gov (United States)

    Handschin, Christoph; Gnerre, Carmela; Fraser, David J; Martinez-Jimenez, Celia; Jover, Ramiro; Meyer, Urs A

    2005-02-01

    The gene encoding cholesterol 7alpha-hydroxylase (CYP7A1) is tightly regulated in order to control intrahepatic cholesterol and bile acid levels. Ligands of the xenobiotic-sensing pregnane X receptor inhibit CYP7A1 expression. To retrace the evolution of the molecular mechanisms underlying CYP7A1 inhibition, we used a chicken hepatoma cell system that retains the ability to be induced by phenobarbital and other drugs. Whereas bile acids regulate CYP7A1 via small heterodimer partner and liver receptor homolog-1, mRNA expression of these nuclear receptors is unchanged by xenobiotics. Instead, drugs repress chicken hepatic nuclear factor 4alpha (HNF4alpha) transcript levels concomitant with a reduction in CYP7A1 expression. Importantly, no reduction of HNF4alpha levels is found in mouse liver in vivo and in human primary hepatocyte cultures, respectively. Thus, besides the importance of HNF4alpha in CYP7A1 regulation in all species, birds and mammals use different signaling pathways to adjust CYP7A1 levels after exposure to xenobiotics.

  10. FGF19 regulates cell proliferation, glucose and bile acid metabolism via FGFR4-dependent and independent pathways.

    Directory of Open Access Journals (Sweden)

    Ai-Luen Wu

    Full Text Available Fibroblast growth factor 19 (FGF19 is a hormone-like protein that regulates carbohydrate, lipid and bile acid metabolism. At supra-physiological doses, FGF19 also increases hepatocyte proliferation and induces hepatocellular carcinogenesis in mice. Much of FGF19 activity is attributed to the activation of the liver enriched FGF Receptor 4 (FGFR4, although FGF19 can activate other FGFRs in vitro in the presence of the coreceptor βKlotho (KLB. In this report, we investigate the role of FGFR4 in mediating FGF19 activity by using Fgfr4 deficient mice as well as a variant of FGF19 protein (FGF19v which is specifically impaired in activating FGFR4. Our results demonstrate that FGFR4 activation mediates the induction of hepatocyte proliferation and the suppression of bile acid biosynthesis by FGF19, but is not essential for FGF19 to improve glucose and lipid metabolism in high fat diet fed mice as well as in leptin-deficient ob/ob mice. Thus, FGF19 acts through multiple receptor pathways to elicit pleiotropic effects in regulating nutrient metabolism and cell proliferation.

  11. FGF19 regulates cell proliferation, glucose and bile acid metabolism via FGFR4-dependent and independent pathways.

    Science.gov (United States)

    Wu, Ai-Luen; Coulter, Sally; Liddle, Christopher; Wong, Anne; Eastham-Anderson, Jeffrey; French, Dorothy M; Peterson, Andrew S; Sonoda, Junichiro

    2011-03-18

    Fibroblast growth factor 19 (FGF19) is a hormone-like protein that regulates carbohydrate, lipid and bile acid metabolism. At supra-physiological doses, FGF19 also increases hepatocyte proliferation and induces hepatocellular carcinogenesis in mice. Much of FGF19 activity is attributed to the activation of the liver enriched FGF Receptor 4 (FGFR4), although FGF19 can activate other FGFRs in vitro in the presence of the coreceptor βKlotho (KLB). In this report, we investigate the role of FGFR4 in mediating FGF19 activity by using Fgfr4 deficient mice as well as a variant of FGF19 protein (FGF19v) which is specifically impaired in activating FGFR4. Our results demonstrate that FGFR4 activation mediates the induction of hepatocyte proliferation and the suppression of bile acid biosynthesis by FGF19, but is not essential for FGF19 to improve glucose and lipid metabolism in high fat diet fed mice as well as in leptin-deficient ob/ob mice. Thus, FGF19 acts through multiple receptor pathways to elicit pleiotropic effects in regulating nutrient metabolism and cell proliferation.

  12. Non-Alcoholic Fatty Liver Disease: The Bile Acid-Activated Farnesoid X Receptor as an Emerging Treatment Target

    Directory of Open Access Journals (Sweden)

    Michael Fuchs

    2012-01-01

    Full Text Available Non-alcoholic fatty liver disease (NAFLD is currently evolving as the most common liver disease worldwide. It may progress to liver cirrhosis and liver cancer and is poised to represent the most common indication for liver transplantation in the near future. The pathogenesis of NAFLD is multifactorial and not fully understood, but it represents an insulin resistance state characterized by a cluster of cardiovascular risk factors including obesity, dyslipidemia, hyperglycemia, and hypertension. Importantly, NAFLD also has evolved as independent risk factor for cardiovascular disease. Unfortunately thus far no established treatment does exist for NAFLD. The bile acid-activated nuclear farnesoid X receptor (FXR has been shown to play a role not only in bile acid but also in lipid and glucose homeostasis. Specific targeting of FXR may be an elegant and very effective way to readjust dysregulated nuclear receptor-mediated metabolic pathways. This review discusses the body's complex response to the activation of FXR with its beneficial actions but also potential undesirable side effects.

  13. Structural elucidation of the hormonal inhibition mechanism of the bile acid cholate on human carbonic anhydrase II

    Energy Technology Data Exchange (ETDEWEB)

    Boone, Christopher D. [University of Florida, PO Box 100267, Gainesville, FL 32610 (United States); Tu, Chingkuang [University of Florida, PO Box 100245, Gainesville, FL 32610 (United States); McKenna, Robert, E-mail: rmckenna@ufl.edu [University of Florida, PO Box 100267, Gainesville, FL 32610 (United States)

    2014-06-01

    The structure of human carbonic anhydrase II in complex with cholate has been determined to 1.54 Å resolution. Elucidation of the novel inhibition mechanism of cholate will aid in the development of a nonsulfur-containing, isoform-specific therapeutic agent. The carbonic anhydrases (CAs) are a family of mostly zinc metalloenzymes that catalyze the reversible hydration/dehydration of CO{sub 2} into bicarbonate and a proton. Human isoform CA II (HCA II) is abundant in the surface epithelial cells of the gastric mucosa, where it serves an important role in cytoprotection through bicarbonate secretion. Physiological inhibition of HCA II via the bile acids contributes to mucosal injury in ulcerogenic conditions. This study details the weak biophysical interactions associated with the binding of a primary bile acid, cholate, to HCA II. The X-ray crystallographic structure determined to 1.54 Å resolution revealed that cholate does not make any direct hydrogen-bond interactions with HCA II, but instead reconfigures the well ordered water network within the active site to promote indirect binding to the enzyme. Structural knowledge of the binding interactions of this nonsulfur-containing inhibitor with HCA II could provide the template design for high-affinity, isoform-specific therapeutic agents for a variety of diseases/pathological states, including cancer, glaucoma, epilepsy and osteoporosis.

  14. Conserved Aspartic Acid Residues Lining the Extracellular Loop I of Sodium-coupled Bile Acid Transporter ASBT Interact with Na+ and 7α-OH Moieties on the Ligand Cholestane Skeleton*

    Science.gov (United States)

    Hussainzada, Naissan; Da Silva, Tatiana Claro; Zhang, Eric Y.; Swaan, Peter W.

    2008-01-01

    Functional contributions of residues Val-99—Ser-126 lining extracellular loop (EL) 1 of the apical sodium-dependent bile acid transporter were determined via cysteine-scanning mutagenesis, thiol modification, and in silico interpretation. Despite membrane expression for all but three constructs (S112C, Y117C, S126C), most EL1 mutants (64%) were inactivated by cysteine mutation, suggesting a functional role during sodium/bile acid co-transport. A negative charge at conserved residues Asp-120 and Asp-122 is required for transport function, whereas neutralization of charge at Asp-124 yields a functionally active transporter. D124A exerts low affinity for common bile acids except deoxycholic acid, which uniquely lacks a 7α-hydroxyl (OH) group. Overall, we conclude that (i) Asp-122 functions as a Na+ sensor, binding one of two co-transported Na+ ions, (ii) Asp-124 interacts with 7α-OH groups of bile acids, and (iii) apolar EL1 residues map to hydrophobic ligand pharmacophore features. Based on these data, we propose a comprehensive mechanistic model involving dynamic salt bridge pairs and hydrogen bonding involving multiple residues to describe sodium-dependent bile acid transporter-mediated bile acid and cation translocation. PMID:18508772

  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.

  16. Different pathways for copper sulphate and copper nitrate antioxidation and organic acid excretion in Typha latifolia?

    OpenAIRE

    Lyubenova L.; Kuhn A.; Höltkemeier A.; Bipuah H.; Belford E.; Schröder P.

    2013-01-01

    The major topic of the present experiment was the investigation of the antioxidative enzymes and the root exudate excretion after plant exposure to copper. The copper was added for each treatment as copper sulphate and copper nitrate in the concentrations of 10 μM, 50 μM and 100 μM, respectively. The plant species chosen for the study was Typha latifolia. The experiment gives insight into the plant responses to different copper supplies during the same conditions of exposure. Remarkable resul...

  17. Urinary prostaglandin E and vasopressin excretion in essential fatty acid-deficient rats

    DEFF Research Database (Denmark)

    Hansen, Harald S.; Jensen, B.

    1983-01-01

    and the (n-3) rats, even though large differences were found in the percentage of arachidonic acid (20:4[n-6]), icosapentaenoic acid (20:5[n-3]), and icosatrienoic acid (20:3[n-9]) of total kidney fatty acids as well as of kidney phosphatidylinositol fatty acids. Fractionation of urine extracts on high...... an arachidonic acid pool, which is rather resistant to restriction in dietary linoleate. © 1983 American Oil Chemists' Society (AOCS)....

  18. Excretion of 3-Mercaptolactate-Cysteine Disulfide, Sulfate and Taurine in human Urine before and after Oral Administration of Sulfur-containing Amino Acids.

    Directory of Open Access Journals (Sweden)

    Yuasa,Shigeki

    1990-06-01

    Full Text Available The excretion of 3-mercaptolactate-cysteine mixed disulfide [S-(2-hydroxy-2-carboxyethylthio-L-cysteine, HCETC], sulfate and taurine in the urine of normal adults was investigated before and after oral administration of L-cysteine and related sulfur-containing amino acids. Before the loading of amino acids, the excretion (mean +/- SD per kg of body weight per day of HCETC, free sulfate and taurine was 0.096 +/- 0.042, 305.7 +/- 66.1 and 31.9 +/- 8.7 mumols, respectively. After the loading of L-cysteine (800 mumols/kg of body weight, the average excretion in the 24-h urine of HCETC increased 2-fold and that of taurine increased 1.6-fold. The average excretion of free sulfate after the L-cysteine loading was 989.4 +/- 145.1 and 388.8 +/- 51.6 mumols/kg per day in the first and second 24-h urine, respectively, indicating that the sulfur corresponding to 85% of the L-cysteine loaded was excreted as free sulfate in 24 h. Administration of L-cystine (400 mumols/kg resulted in similar results. The increase in HCETC after L-cysteine or L-cystine administration indicates that L-cysteine is metabolized in part through the transamination pathway (3-mercaptopyruvate pathway and that an equilibrium exists between the intake and excretion of sulfur in humans.

  19. Oral administration of Bifidobacterim bifidum for modulating microflora, acid and bile resistance, and physiological indices in mice.

    Science.gov (United States)

    Wang, Bao-Gui; Xu, Hai-Bo; Wei, Hua; Zeng, Zhe-Ling; Xu, Feng

    2015-02-01

    Bifidobacteria are generally acknowledged as major gut microflora used as probiotics, which promote human health. In this study, the effects of the administration of Bifidobacterim bifidum on modulating gastrointestinal (GI) tract microflora, acid and bile resistance, and physiological indices in BALB/c mice were investigated. Results showed that B. bifidum can significantly improve the ecosystem of the GI tract by increasing the amount of probiotics and reducing the populations of pathogenic bacteria, as measured by plate count and real-time PCR. After exposure to simulated GI tract conditions, the growth of gut microflora in the B. bifidum group was higher than that in the control group when incubated for 12 h in MRS or nutrient broth adjusted to pH 2.0 or 3.0 or in the presence of a concentration of bile salt (0.45% m/v). The blood biochemical index was examined, and the physiological effect of the cell-free extract of gut microflora was evaluated by measuring the activity of various enzymes, including α-glucosidases, esterase, and lactate dehydrogenase. This study suggested that a B. bifidum strain can stabilize blood sugar, lower cholesterol levels in serum, and improve metabolic activity. Moreover, B. bifidum was a promising enhancer of microbial diversity in mouse intestine and played a vital role in human physiological processes, which can benefit the health of a host.

  20. Effects of gomisin A on the promotor action and serum bile acid concentration in hepatocarcinogenesis induced by 3'-methyl-4-dimethylamino-azobenzene.

    Science.gov (United States)

    Miyamoto, K; Hiramatsu, K; Ohtaki, Y; Kanitani, M; Nomura, M; Aburada, M

    1995-10-01

    The effects of gomisin A, a lignan component of Schizandra fruits, on the promotion stage of hepatocarcinogenesis initiated by 3'-methyl-4-dimethylamino-azobenzene (3'-MeDAB) in male Donryu rats were investigated. When different types of tumor promotors, phenobarbital (PB) and deoxycholic acid (DCA), were administered for 5 weeks after initiation by 3'-MeDAB, preneoplastic alterations in the liver, determined by glutathione S-transferase placental form (GST-P), were markedly increased. Gomisin A significantly inhibited the increase in number and size of GST-P positive foci, regardless of the promotor. This lignan inhibited the increase in serum bile acid concentration by administration of DCA, but hardly influenced the serum bile acids in the PB-combined group. These results suggest that the inhibitory effect of gomisin A on the promotive action of DCA is based on improving bile acid metabolism, but regarding the action of PB, the effect could not be elucidated from the metabolism of bile acids.

  1. Properties of lignin, cellulose, and hemicelluloses isolated from olive cake and olive stones: binding of water, oil, bile acids, and glucose.

    Science.gov (United States)

    Rodríguez-Gutiérrez, Guillermo; Rubio-Senent, Fátima; Lama-Muñoz, Antonio; García, Aránzazu; Fernández-Bolaños, Juan

    2014-09-10

    A process based on a steam explosion pretreatment and alkali solution post-treatment was applied to fractionate olive stones (whole and fragmented, without seeds) and olive cake into their main constitutive polymers of cellulose (C), hemicelluloses (H), and lignin (L) under optimal conditions for each fraction according to earlier works. The chemical characterization (chromatographic method and UV and IR spectroscopy) and the functional properties (water- and oil-holding capacities, bile acid binding, and glucose retardation index) of each fraction were analyzed. The in vitro studies showed a substantial bile acid binding activity in the fraction containing lignin from olive stones (L) and the alkaline extractable fraction from olive cake (Lp). Lignin bound significantly more bile acid than any other fraction and an amount similar to that bound by cholestyramine (a cholesterol-lowering, bile acid-binding drug), especially when cholic acid (CA) was tested. These results highlight the health-promoting potential of lignin from olive stones and olive cake extracted from olive byproducts.

  2. Effect of dietary supplementation of gallic acid on nitrogen balance, nitrogen excretion pattern and urinary nitrogenous constituents in beef cattle.

    Science.gov (United States)

    Wei, Chen; Yang, Kai; Zhao, Guangyong; Lin, Shixin; Xu, Zhiwei

    2016-10-01

    The objective of the trial was to study the effects of dietary supplementation of gallic acid (GA) on nitrogen (N) balance, N excretion pattern and urinary N constituents in beef cattle. In a 4 × 4 Latin square design, four male 30-month-old Simmental cattle (443 ± 22 kg live weight) received four levels of GA (purity ≥ 98.5%), i.e. 0, 5.3, 10.5, 21.1 g/kg DM, added to a basal ration. Each experimental period lasted 17 d, consisting of 12 d adaptation and 5 d sampling. The results showed that supplementation of GA at 5.3, 10.5 or 21.1 g/kg DM did not affect the N balance but regulated the N excretion pattern by increasing the ratio of faecal N/urinary N and decreasing the ratio of urinary urea N/total urinary N in beef cattle fed at maintenance level.

  3. Excretion of biliary compounds during intrauterine life

    Institute of Scientific and Technical Information of China (English)

    Rocio IR Macias; Jose JG Marin; Maria A Serrano

    2009-01-01

    In adults, the hepatobiliary system, together with thekidney, constitute the main routes for the eliminationof several endogenous and xenobiotic compounds intobile and urine, respectively. However, during intrauterinelife the biliary route of excretion for cholephiliccompounds, such as bile acids and biliary pigments, isvery poor. Although very early in pregnancy the fetal liver produces bile acids, bilirubin and biliverdin, these compounds cannot be efficiently eliminated by the fetal hepatobiliary system, owing to the immaturity of the excretory machinery in the fetal liver. Therefore, the potentially harmful accumulation of cholephilic compounds in the fetus is prevented by their elimination across the placenta. Owing to the presence of detoxifying enzymes and specific transport systems at different locations of the placental barrier, such as the endothelial cells of chorionic vessels and trophoblast cells, this organ plays an important role in the hepatobiliary-like function during intrauterine life. The relevance of this excretory function in normal fetal physiology is evident in situations where high concentrations of biliary compounds are accumulated in the mother. This may result in oxidative stress and apoptosis, mainly in the placenta and fetal liver, which might affect normal fetal development and challenge the fate of the pregnancy. The present article reviews current knowledge of the mechanisms underlying the hepatobiliary function of the fetal-placental unit and the repercussions of several pathological conditions on this tandem.

  4. Effects of low-phytic acid corn, low-phytic acid soybean meal, and phytase on nutrient digestibility and excretion in growing pigs.

    Science.gov (United States)

    Hill, B E; Sutton, A L; Richert, B T

    2009-04-01

    Forty-eight grower pigs were used to evaluate the effects of feeding low phytic acid (LPA) corn, LPA soybean meal, normal corn (NC), normal soybean meal (NSBM), and phytase on nutrient digestibility and excretion. Barrows were blocked by BW (initial BW=45.3+/-1.6 kg) and randomly assigned to 1 of 8 dietary treatments in a 2 x 2 x 2 factorial arrangement (6 pigs/treatment). Pigs were fed twice daily (0700 and 1700 h) at 3 times the ME requirement for maintenance. Phytase was added to the diet at 510 phytase units/kg of feed (where 1 phytase unit is the quantity of enzyme that liberates 1 mumol of inorganic P/min from 0.005 mol/L of sodium phytate at pH 5.5 and 37 degrees C), at the expense of corn starch, and all diets were formulated to provide 0.39% total P, 0.50% Ca, and 1.0% lysine with no supplemental inorganic P. Pigs were adapted to metabolism crates and dietary treatments for 7 d, followed by a 3-d total collection of urine and feces. Total fecal DM excreted, percentage of DM of feces, and percentage of DM digested were not different (P>0.53) among treatments. Fecal P excretion was reduced for pigs fed LPA corn vs. NC (2.85 vs. 3.24+/-0.119 g/d; P=0.024), for pigs fed LPA soybean meal vs. NSBM (2.79 vs. 3.30+/-0.119 g/d; P=0.007), for pigs fed phytase vs. nonphytase diets (2.80 vs. 3.29+/-0.119 g/d; P=0.009), and for pigs fed LPA corn, LPA soybean meal, and phytase vs. NC and NSBM without phytase (2.16 vs. 3.70+/-0.237 g/d; Psoybean meal, and phytase diet vs. the NC and soybean meal diet (60.1 vs. 34.1+/-4.5%; Psoybean meal vs. NSBM (47.2 vs. 41.1+/-2.27%; P=0.075). Corn type and soybean meal type had no effect (P>0.11) on water-soluble P excretion. However, pigs fed diets containing phytase tended to excrete less total water-soluble P than those without phytase inclusion (1.99 vs. 2.27+/-0.099 g/d; Psoybean meal, and phytase was additive, significantly improving P digestibility and dramatically decreasing P excretion to reduce the potential impacts of P

  5. [Using thin-layer chromatography of fecal bile acid to study the Persian leopard (Panthera pardus ciscaucasica) population].

    Science.gov (United States)

    Khorozian, I G; Cazon, A; Malkhasian, A G; Abramov, A V

    2007-01-01

    Thin-layer chromatography (TLC) of fecal bile acids has been used to confirm visual identification of 30 scat samples found in Armenia from April 2004 to November 2005 and attributed to the Persian leopard (Panthera pardus ciscaucasica). The results of TLC do not differ significantly from those of visual identification, confirming the reliability of the latter method. All samples identified incorrectly (lynx and wolf scats) are from the Meghri Ridge, indicating that the ecological niches of the three predators apparently overlap in this area. Taking into account the frequency and distribution of scats, two priority areas for leopard conservation have been identified: the Central and Khachadzor districts of the Khosrov Nature Reserve and the Nuvadi-Shvanidzor area in eastern Meghri ridge.

  6. Adverse reactions of Achilles tendon xanthomas in three hypercholesterolemic patients after treatment intensification with niacin and bile acid sequestrants.

    Science.gov (United States)

    Lakey, Wanda C; Greyshock, Nicole; Guyton, John R

    2013-01-01

    Multiple cholesterol-reducing therapies have been shown to induce the regression of tendon xanthoma in patients with familial hypercholesterolemia. We present 3 cases of adverse reactions in Achilles tendon xanthomas after the addition of niacin and bile acid sequestrants to ongoing statin therapy. Reduction in tendon dimensions and marked softening of xanthomas were interpreted as cholesterol removal from heavily infiltrated tissue sites. In 2 cases, changes in the xanthomas occurred despite only minor lipoprotein improvements, raising the possibility of direct drug effects in cholesterol-infiltrated tissue. Intriguingly, recent studies have described niacin receptor-mediated effects in macrophages. In summary, although adverse reactions in Achilles tendon xanthomas appear to be infrequent, clinicians should be aware of this phenomenon in their patients after intensifying lipid treatments, especially with the use of niacin in patients with familial hypercholesterolemia. Xanthoma responses may provide clues to new pharmacologic effects in cholesterol-infiltrated tissues.

  7. A comparative study on the hepatoprotective action of bear bile and coptidis rhizoma aqueous extract on experimental liver fibrosis in rats

    Directory of Open Access Journals (Sweden)

    Wang Ning

    2012-11-01

    Full Text Available Abstract Aim of the study Bear bile and Coptidis Rhizoma have been used in Chinese medicine with a long tradition in treating heat-diseases. Both bear bile and Coptidis Rhizoma are used to treat liver diseases in clinical practice of Chinese Medicine. Since bears are currently endangered, it raises the question whether the use of bear bile is ethical. To look for substitute for bear bile, the aim of this study is to compare the anti-fibrotic effects of Coptidis Rhizoma and its major component berberine with the actions of bear bile and its major compound tauroursodeoxycholic acid on experimental liver fibrosis in rats. Method Quality assessment was conducted with high performance liquid chromatography. The experimental liver fibrosis in rats was induced by carbon tetrachloride, alcohol, and bile duct ligation respectively. The biochemical criteria in the blood and tissue samples were measured to evaluate the anti-fibrotic properties and underlying mechanisms of the drugs. Results Coptidis Rhizoma Aqueous Extract (CRAE, berberine, and bear bile exerted anti-fibrotic properties on various liver fibrosis models in rats. CRAE and berberine significantly reduced the peroxidative stress in liver through increasing the superoxide dismutase enzyme activity. CRAE and berberine were able to excrete bilirubin products from the liver and protect hepatocytes from cholestatic damage. The effect of CRAE and berberine are comparable to that of bear bile. Conclusion Instead of using bear bile, CRAE and berberine can be potential substitutes in treating liver fibrosis.

  8. Novel potent and selective bile acid derivatives as TGR5 agonists: biological screening, structure-activity relationships, and molecular modeling studies.

    Science.gov (United States)

    Sato, Hiroyuki; Macchiarulo, Antonio; Thomas, Charles; Gioiello, Antimo; Une, Mizuho; Hofmann, Alan F; Saladin, Régis; Schoonjans, Kristina; Pellicciari, Roberto; Auwerx, Johan

    2008-03-27

    TGR5, a metabotropic receptor that is G-protein-coupled to the induction of adenylate cyclase, has been recognized as the molecular link connecting bile acids to the control of energy and glucose homeostasis. With the aim of disclosing novel selective modulators of this receptor and at the same time clarifying the molecular basis of TGR5 activation, we report herein the biological screening of a collection of natural occurring bile acids, bile acid derivatives, and some steroid hormones, which has resulted in the discovery of new potent and selective TGR5 ligands. Biological results of the tested collection of compounds were used to extend the structure-activity relationships of TGR5 agonists and to develop a binary classification model of TGR5 activity. This model in particular could unveil some hidden properties shared by the molecular shape of bile acids and steroid hormones that are relevant to TGR5 activation and may hence be used to address the design of novel selective and potent TGR5 agonists.

  9. Improved Glycemic Control with Colesevelam Treatment in Patients with Type 2 Diabetes Is Not Directly Associated with Changes in Bile Acid Metabolism

    NARCIS (Netherlands)

    Brufau Dones, Gemma; Stellaard, Frans; Prado, Kris; Bloks, Vincent W.; Jonkers, Elles; Boverhof, Renze; Kuipers, Folkert; Murphy, Elizabeth J.

    2010-01-01

    Bile acids (BAs) are essential for fat absorption and appear to modulate glucose and energy metabolism. Colesevelam, a BA sequestrant, improves glycemic control in type 2 diabetes mellitus (T2DM). We aimed to characterize the alterations in BA metabolism associated with T2DM and colesevelam treatmen

  10. Quantitative profiling of bile acids in biofluids and tissues based on accurate mass high resolution LC-FT-MS: Compound class targeting in a metabolomics workflow

    NARCIS (Netherlands)

    Bobeldijk, I.; Hekman, M.; Vries de- Weij, J.van der; Coulier, L.; Ramaker, R.; Kleemann, R.; Kooistra, T.; Rubingh, C.; Freidig, A.; Verheij, E.

    2008-01-01

    We report a sensitive, generic method for quantitative profiling of bile acids and other endogenous metabolites in small quantities of various biological fluids and tissues. The method is based on a straightforward sample preparation, separation by reversed-phase high performance liquid-chromatograp

  11. The Tissue Distribution and Urinary Excretion Study of Gallic Acid and Protocatechuic Acid after Oral Administration of Polygonum Capitatum Extract in Rats.

    Science.gov (United States)

    Ma, Feng-Wei; Deng, Qing-Fang; Zhou, Xin; Gong, Xiao-Jian; Zhao, Yang; Chen, Hua-Guo; Zhao, Chao

    2016-03-24

    In the present study, we investigated the tissue distribution and urinary excretion of gallic acid (GA) and protocatechuic acid (PCA) after rat oral administration of aqueous extract of Polygonum capitatum (P. capitatum, named Herba Polygoni Capitati in China). An UHPLC-MS/MS analytical method was developed and adopted for quantification of GA and PCA in different tissue homogenate and urine samples. Interestingly, we found that GA and PCA showed a relatively targeted distribution in kidney tissue after dosing 60 mg/kg P. capitatum extract (equivalent to 12 mg/kg of GA and 0.9 mg/kg of PCA). The concentrations of GA and PCA in the kidney tissue reached 1218.62 ng/g and 43.98 ng/g, respectively, at one hour after oral administration. The results helped explain the empirical use of P. capitatum for kidney diseases in folk medicine. Further studies on urinary excretion of P. capitatum extract indicated that GA and PCA followed a concentrated elimination over a 4-h period. The predominant metabolites were putatively identified to be 4-methylgallic acid (4-OMeGA) and 4-methylprotocatechuic acid (4-OMePCA) by analyzing their precursor ions and characteristic fragment ions using tandem mass spectrometry. However, the amount of unchanged GA and PCA that survived the metabolism were about 14.60% and 15.72% of the total intake, respectively, which is reported for the first time in this study.

  12. Modulation of fibroblast growth factor 19 expression by bile acids, meal replacement and energy drinks, milk, and coffee.

    Directory of Open Access Journals (Sweden)

    Amanda M Styer

    Full Text Available BACKGROUND: The enterohepatic pathway involving the fibroblast growth factor 19 (FGF19 and bile acids (BA has been linked with the etiology and remission of type 2 diabetes (T2D following Roux-en-Y gastric bypass (RYGB surgery. Specifically, diabetic patients had lower FGF19 circulating levels but postoperative FGF19 and BA levels were higher in diabetic patients that experience remission of T2D, as compared to non-diabetic patients and diabetic patients that do not experience remission. It has been proposed that this may be due to the direct flow of digestate-free bile acids into the ileum benefiting mostly T2D patients without severe diabetes. METHODS/RESULTS: We used a human colorectal cell line (LS174T that endogenously expresses FGF19, real time PCR, and Elisas for precise quantitation of FGF19 mRNA and secreted protein levels. We report here that BA and fractions of BA stimulated FGF19 in vitro but this effect was partially blocked when BA were pre-incubated with a lipoprotein mix which emulates digested food. In addition, we show that FGF19 mRNA was stimulated by meal replacement drinks (Ensure, Glucerna, SlimFast, non-fat milk, and coffee which has been linked with reduced risk for developing diabetes. Pure caffeine and the 5-hour Energy drink, on the other hand, decreased FGF19 mRNA. CONCLUSIONS: In summary, FGF19 expression in vitro is modifiable by popular drinks suggesting that such approaches could potentially be used for modulating FGF19 expression in humans.

  13. Organic anion-transporting polypeptide 1a4 (Oatp1a4) is important for secondary bile acid metabolism.

    Science.gov (United States)

    Zhang, Youcai; Csanaky, Iván L; Selwyn, Felcy Pavithra; Lehman-McKeeman, Lois D; Klaassen, Curtis D

    2013-08-01

    Organic anion transporting polypeptides (human: OATPs; rodent: Oatps) were thought to have important functions in bile acid (BA) transport. Oatp1a1, 1a4, and 1b2 are the three major Oatp1 family members in rodent liver. Our previous studies have characterized the BA homeostasis in Oatp1a1-null and Oatp1b2-null mice. The present study investigated the physiological role of Oatp1a4 in BA homeostasis by using Oatp1a4-null mice. Oatp1a4 expression is female-predominant in livers of mice, and thereby it was expected that female Oatp1a4-null mice will have more prominent changes than males. Interestingly, the present study demonstrated that female Oatp1a4-null mice had no significant alterations in BA concentrations in serum or liver, though they had increased mRNA of hepatic BA efflux transporters (Mrp4 and Ostα/β) and ileal BA transporters (Asbt and Ostα/β). In contrast, male Oatp1a4-null mice showed significantly altered BA homeostasis, including increased concentrations of deoxycholic acid (DCA) in serum, liver and intestinal contents. After feeding a DCA-supplemented diet, male but not female Oatp1a4-null mice had higher concentrations of DCA in serum and livers than their WT controls. This suggested that Oatp1a4 is important for intestinal absorption of secondary BAs in male mice. Furthermore, loss of Oatp1a4 function did not decrease BA accumulation in serum or livers of bile-duct-ligated mice, suggesting that Oatp1a4 is not likely a BA uptake transporter. In summary, the present study for the first time demonstrates that Oatp1a4 does not appear to mediate the hepatic uptake of BAs, but plays an important male-predominant role in secondary BA metabolism in mice.

  14. Transmembrane domain V plays a stabilizing role in the function of human bile acid transporter SLC10A2.

    Science.gov (United States)

    Moore, Robyn H; Chothe, Paresh; Swaan, Peter W

    2013-07-30

    The human apical sodium-dependent bile acid transporter (hASBT, SLC10A2), primarily expressed in the ileum, is involved in both the recycling of bile acids and cholesterol homeostasis. In this study, the structure-function relationship of transmembrane domain 5 (TM5) residues involved in transport is elucidated. Cysteine scanning mutagenesis of each consecutive residue on TM5 resulted in 96% of mutants having a significantly decreased transport activity, although each was expressed at the cell surface. Specifically, G197 and I208 were no longer functional, and G201 and G212 functioned at a level of Conservative alanine mutations of the four residues displayed a higher activity in all but G197A, indicating its functional importance. G197 and G201 form a GxxxG motif, which has been found to be important in helix-helix interactions. According to our model, G197 and G201 face transmembrane domain 4 (TM4) residues G179 and P175, respectively. Similarly, G212 faces G237, which forms part of a GxxxG domain in transmembrane domain 6 (TM6). It is possible that these GxxxG domains and their interacting partners are responsible for maintaining the structure of the helices and their interactions with one another. I205 and I208 are both in positions to anchor the GxxxG domains and direct the change in interaction of TM5 from TM4 to TM6. Combined, the results suggest that residues along TM5 are critical for ASBT function but are not directly involved in substrate translocation.

  15. Generation of reactive oxygen species by a novel berberine–bile acid analog mediates apoptosis in hepatocarcinoma SMMC-7721 cells

    Energy Technology Data Exchange (ETDEWEB)

    Li, Qingyong, E-mail: li_qingyong@126.com [Key Laboratory of Forest Plant Ecology (Northeast Forestry University), Ministry of Education (China); Zhang, Li; Zu, Yuangang; Liu, Tianyu; Zhang, Baoyou; He, Wuna [Key Laboratory of Forest Plant Ecology (Northeast Forestry University), Ministry of Education (China)

    2013-04-19

    Graphical abstract: - Highlights: • Anticancer effects of B4, a novel berberine–bile acid analog, were tested. • B4 inhibited cell proliferation in hepatocellular carcinoma cells. • It also stimulated mitochondrial ROS production and membrane depolarization. • Effects of B4 were inhibited by a non-specific ROS scavenger. • Regulation of ROS generation may be a strategy for treating hepatic carcinoma. - Abstract: 2,3-Methenedioxy-9-O-(3′α,7′α-dihydroxy-5′β-cholan-24′-propy-lester) berberine (B4) is a novel berberine–bile acid analog synthesized in our laboratory. Previously, we showed that B4 exerted greater cytotoxicity than berberine in several human cancer cell lines. Therefore, we further evaluated the mechanism governing its anticancer actions in hepatocellular carcinoma SMMC-7721 cells. B4 inhibited the proliferation of SMMC-7721 cells, and stimulated reactive oxygen species (ROS) production and mitochondrial membrane depolarization; anti-oxidant capacity was reduced. B4 also induced the release of cytochrome c from the mitochondria to the cytosol and an increase in poly ADP-ribose polymerase (PARP) cleavage products, reflective of caspase-3 activation. Moreover, B4 induced the nuclear translocation of apoptosis-inducing factor (AIF) and a rise in DNA fragmentation. Pretreatment with the anti-oxidant N-acetylcysteine (NAC) inhibited B4-mediated effects, including cytotoxicity, ROS production, mitochondrial membrane depolarization increase in intracellular Ca{sup 2+}, cytochrome c release, PARP cleavage, and AIF translocation. Our data suggest that B4 induces ROS-triggered caspase-dependent and caspase-independent apoptosis pathways in SMMC-7721 cells and that ROS production may be a specific potential strategy for treating hepatic carcinoma.

  16. Intake of rye bread ileostomists increases ileal excretion of fiber polysaccharide components and organic acids but does not increase plasma or urine lignans and isoflavonoids.

    Science.gov (United States)

    Pettersson, D; Aman, P; Knudsen, K E; Lundin, E; Zhang, J X; Hallmans, G; Härkönen, H; Adlercreutz, H

    1996-06-01

    The excretion of starch, enzyme-resistant starch, dietary fiber components and organic acids (short-chain fatty acids plus lactic acid) as well as plasma and urine lignans and isoflavonoids was studied in eight ileostomists consuming mixed diets with wheat bread (low fiber diet) or rye bread (high fiber diet) in a crossover design. Average ileal excretions of enzyme-available starch were 3.5 g/d during the low fiber period and 4.1 g/d during the high fiber period. The excretion of enzyme-resistant starch was approximately the same (2.3 g/d) in both periods. In comparison with intake, similar amounts of total fiber residues were excreted both by subjects receiving the low fiber diet (3.4 g/d) and by those receiving the high fiber diet (2.7 g/d). However, subjects excreted significantly more of certain polysaccharide residues (fucose, galactose, and uronic acids) than they ingested. On average, the excretion of organic acids was 18.6 mmol/d during the low fiber period and 30.2 mmol/d during the high fiber period. No significant differences in plasma lignans were observed between the high fiber and the low fiber dietary periods. The present findings indicate that enzyme-available starch is highly digested and that a microbial breakdown of dietary fibers and probably other carbohydrates occurs in the small intestine. However, the bacterial activity in the ileostomists was not sufficient to cause an increased level in plasma lignans even when subjects consumed the high fiber rye diet.

  17. 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

  18. Identification of urine tauro-β-muricholic acid as a promising biomarker in Polygoni Multiflori Radix-induced hepatotoxicity by targeted metabolomics of bile acids.

    Science.gov (United States)

    Zhao, Dong-Sheng; Jiang, Li-Long; Fan, Ya-Xi; Dong, Lei-Chi; Ma, Jiang; Dong, Xin; Xu, Xiao-Jun; Li, Ping; Li, Hui-Jun

    2017-02-24

    Polygoni Multiflori Radix (PMR) has been widely used as a tonic for centuries. However, hepatotoxicity cases linked to PMR have been frequently reported and appropriate biomarkers for clinical diagnosis are currently lacking. Here, an approach using UPLC-QqQ/MS-based targeted metabolomics of bile acids (BAs) complemented with biochemistry and histopathology was applied to characterize the development and recovery processes of PMR-induced hepatotoxicity in rats and to identify biomarkers. The expression of bile salt export pump (Bsep) and sodium taurocholate cotransporting polypeptide (Ntcp) were evaluated to investigate the underlying mechanism. Steatosis and inflammatory cell infiltration were observed in PMR-treated rats, which were accompanied by the elevation of serum biochemistry. The metabolic profiles of BAs were analyzed by Principal Component Analysis, hyodeoxycholic acid (HDCA) in serum and tauro-β-muricholic acid (TβMCA) in urine were identified as potential biomarkers for PMR-induced hepatotoxicity. The elevated expression of Bsep and decreased expression of Ntcp in the liver of PMRtreated rats indicated that hepatotoxicity was related to the disorders of BAs metabolism. Our study demonstrated that BAs may be used for clinical diagnosis of PMR-induced hepatotoxicity. Urine TβMCA was identified as a promising biomarker to facilitate the clinical monitoring of PMR-induced hepatotoxicity and may serve as potential therapeutic target.

  19. Bile Reflux

    Science.gov (United States)

    ... commonly used to soothe inflammation associated with GERD, gastritis, ulcers and other digestive problems. However, licorice contains ... Minn. Dec. 15, 2014. March 04, 2015 Original article: http://www.mayoclinic.org/diseases-conditions/bile-reflux/ ...

  20. Metabonomics and population studies: age-related amino acids excretion and inferring networks through the study of urine samples in two Italian isolated populations.

    Science.gov (United States)

    D'Adamo, Pio; Ulivi, Sheila; Beneduci, Amerigo; Pontoni, Gabriele; Capasso, Giovambattista; Lanzara, Carmela; Andrighetto, Gilberto; Hladnik, Uros; Nunes, Virginia; Palacin, Manuel; Gasparini, Paolo

    2010-01-01

    The study of two different Italian isolated populations was combined with a metabonomic approach to better understand tubular handling of amino acids. Levels of amino acids and metabolites have been analyzed by Nucleic Magnetic Resonance and expressed as ratio vs urinary creatinine concentration (mmol/mol). For most of the amino acids there is an age-related U shape pattern of excretion, with the peaks during childhood and old age, and a significant reduction in the adult age. Hierarchical cluster analysis has clearly identified three groups clustering the same amino acids: His, Thr and Ala (group one); Gly and Phe (group two) and a third larger one. Results have been further confirmed by factor and regression analysis, and used to confirm and, in some cases, infer new amino acids networks. As a matter of facts, the identification of strong evidences for clustering of urine excretion of several neutral amino acids suggests the predominant impact of relevant and common transporters.

  1. 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.

  2. The effect of dietary prebiotics and probiotics on body weight, large intestine indices, and fecal bile acid profile in wild type and IL10-/- mice.

    Science.gov (United States)

    Kuo, Shiu-Ming; Merhige, Patricia M; Hagey, Lee R

    2013-01-01

    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 (IL)10-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.

  3. Postprandial lipemia in relation to sterol and fat excretion in ileostomy subjects given oat-bran and wheat test meals.

    Science.gov (United States)

    Lia, A; Andersson, H; Mekki, N; Juhel, C; Senft, M; Lairon, D

    1997-08-01

    To investigate the mechanisms behind the serum cholesterol-lowering effect of oat fiber, we simultaneously measured postprandial lipid responses, serum lathosterol concentrations, and small bowel excretion of fat and sterols in ileostomy subjects given test meals high or low in oat fiber. Six ileostomy subjects (three women and three men) were served an oat-bran test meal (OB; 16.3 g fiber) and a wheat test meal (6.3 g fiber) in random order. After the postprandial 7-h period, a controlled, low-fat, cholesterol-free diet was served and ileostomy effluent was sampled throughout the 24-h period. Bile acid and fat excretion (24 h) increased by 93% and 146%, respectively (P < 0.05), and total and endogenous cholesterol excretion decreased by 14% and 19%, respectively (P < 0.05), after the OB test meal. The change in hepatic cholesterol synthesis was strongly related to the change in bile acid excretion (Spearman r = 0.89, P < 0.02). The postprandial chylomicron lipid concentration tended to be lower after the OB test meal (-43% for cholesterol, P = 0.07) whereas there was no difference in cholesterol absorption measured by isotope in five subjects. The main effect of the viscous oat beta-glucan seems to be related to increased bile acid excretion and subsequent changes in synthesis and endogenous excretion of cholesterol. An additional effect may have been a delay in the micellar lipid solubilization process and a consequent reduction in the secretion of chylomicrons into the circulation.

  4. Unraveling the impact of hydroxylation on interactions of bile acid cationic lipids with model membranes by in-depth calorimetry studies.

    Science.gov (United States)

    Singh, Manish; Bajaj, Avinash

    2014-09-28

    We used eight bile acid cationic lipids differing in the number of hydroxyl groups and performed in-depth differential scanning calorimetry studies on model membranes doped with different percentages of these cationic bile acids. These studies revealed that the number and positioning of free hydroxyl groups on bile acids modulate the phase transition and co-operativity of membranes. Lithocholic acid based cationic lipids having no free hydroxyl groups gel well with dipalmitoylphosphatidylcholine (DPPC) membranes. Chenodeoxycholic acid lipids having one free hydroxyl group at the 7'-carbon position disrupt the membranes and lower their co-operativity. Deoxycholic acid and cholic acid based cationic lipids have free hydroxyl groups at the 12'-carbon position, and at 7'- and 12'-carbon positions respectively. Doping of these lipids at high concentrations increases the co-operativity of membranes suggesting that these lipids might induce self-assembly in DPPC membranes. These different modes of interactions between cationic lipids and model membranes would help in future for exploring their use in DNA/drug delivery.

  5. 胆汁酸诱导的肠道激素与肝脏糖代谢%Bile acid induced gut hormones and hepatic glucose metabolism

    Institute of Scientific and Technical Information of China (English)

    曹宏伟; 姜崴

    2015-01-01

    [Summary] Bile acid is a main component of bile ,which plays a key role in keeping cholesterol metabolism balance in vivo and promoting lipids digestion in intestine. Recently ,more and more researches focus on bile acid for its regulating effect on glucose ,lipid and energy metabolism as a signal molecule. The reabsorbed bile acid stimulates the secretion of fibroblast growth factor 19 (FGF19) and glucagon-like peptide-1(GLP-1) in the intestine by activating a nuclear receptor farnesoid X-activated receptor (FXR) and a membrane receptor TGR5. FGF19 and GLP-1 regulate hepatic glucose metabolism through different pathways. Here ,we briefly summarize the research progress and relationship between bile acid induced gut hormones and hepatic glucose metabolism.%胆汁酸是胆汁的主要成分,其主要作用是维持体内胆固醇代谢的平衡和促进肠道脂肪的消化。近年,胆汁酸作为一种信号分子,对葡萄糖、脂质及能量代谢的调节作用日趋受到重视。胆汁酸在肠道重吸收时分别通过核受体法呢醇X受体(FXR)、膜受体TGR5促进肠道细胞分泌成纤维细胞生长因子19(FGF19)及胰升血糖素样肽-1(GLP-1)。FGF19和GLP-1通过不同的作用途径影响肝脏的糖代谢。本文就胆汁酸诱导的肠道激素与肝脏糖代谢的关系及研究进展进行综述。

  6. Effect of bile acids on glucose and lipid metabolism%胆汁酸对糖脂代谢影响的研究现状

    Institute of Scientific and Technical Information of China (English)

    孙逊; 杨刚毅

    2008-01-01

    胆汁酸是胆汁的重要成分,主要在肝脏合成,在膳食脂肪的消化吸收和胆固醇的代谢调节中发挥重要作用.近年来研究发现,胆汁酸还可激活法尼酯X受体-α、TGK5等信号分子,通过多种信号途径反馈调节自身的肠肝循环,同时还有降低血浆高密度脂蛋白和甘油三酯的作用,并且还参与糖代谢的调节,与体内糖脂代谢的动态平衡密切相关.因此,一些胆汁酸相关的信号途径很有希望成为治疗代谢性疾病的新靶点.%Bile acids,synthesized in liver,is a primary component of bile.It plays an important role in the digestion and absorption of dietary lipid as well as in cholesterol homeostasis.Recently,many studies showed that bile acids could activate several signaling molecules,such as farnesoid X receptor α and TGR5.Through these mechanisms,bile acids regulates its entero-hepatic circulation,brings down plasma levels of high density lipoprotein,triglyceride and regulates glucose metabolism.So it is closely related to glucose and lipid homeostasis.Thus,several bile acids-related pathways are promising targets of metabolic disease therapy.

  7. 胆汁酸的代谢、生理作用及其临床意义%Bile acids: Metabolism,physiology and clinical significance

    Institute of Scientific and Technical Information of China (English)

    尹凯歌; 冯志杰

    2012-01-01

    胆汁酸通过肠肝循环代谢,具有促进脂类消化吸收、防止胆道结石生成、增加胆汁分泌、排泄等多种生物学作用,血清胆汁酸测定可反映急性肝炎慢性化、慢性肝炎炎症和纤维化程度、肝硬化门脉高压以及重症肝炎的病情演变,是梗阻性黄疸患者梗阻解除的早期敏感指标.另外,血清胆汁酸测定对炎症性肠病、妊娠期肝内胆汁淤积、先天性胆道疾病、肝移植等疾病的诊断也有一定价值.%Enterohepatic circulation of bile acids can promote lipid digestion and absorption, prevent gallstone formation, and increase the secretion of bile. Measurement of serum bile acids can be used to predict the progression from acute hepatitis to chronic hepatitis and evaluate the degree of inflammation and fibrosis in patients with chronic hepatitis and the degree of portal hypertension and severe hepatitis. Serum bile acids are also an early and sensitive predictor of the relief of biliary obstruction in patients with obstructive jaundice. In addition, serum bile acids can be used for the diagnosis of inflammatory bowel disease, intra-hepatic cholestasis during pregnancy, congenital biliary tract disease, and liver transplantation.

  8. The effects of a single oral dose of ethyl linoleate on urinary prostaglandin E excretion in essential fatty acid-deficient rats

    DEFF Research Database (Denmark)

    Hansen, Harald S.; Jensen, B.

    1985-01-01

    The effects of a single oral dose of ethyl linoleate on urinary prostaaglandin E (PGE) excretion and urine output were investigated in essential fatty acid (EFA)-deficient rats. Weanling male rats were fed a fat-free diet. After 13 wk of feeding, eight rats received an oral dose of 400 mg of ethy...

  9. The effect of disodium cromoglycate and ketotifen on the excretion of histamine and N tau-methylimidazole acetic acid in urine of patients with mastocytosis.

    Science.gov (United States)

    Mallet, A I; Norris, P; Rendell, N B; Wong, E; Greaves, M W

    1989-01-01

    Treatment of four mastocytosis patients with the mast cell stabilising drugs, disodium cromoglycate and ketotifen failed to alter significantly the urinary excretion levels of histamine or N tau-methylimidazole acetic acid. No clinical improvement was noted in any subject after treatment by either drug. PMID:2495814

  10. Impact of low-dose acetylsalicylic acid on kidney function in type 2 diabetic patients with elevated urinary albumin excretion rate

    DEFF Research Database (Denmark)

    Gaede, Peter; Hansen, Henrik Post; Parving, Hans-Henrik

    2003-01-01

    Low-dose treatment with acetylsalicylic acid (ASA) is widely recommended to type 2 diabetic patients as primary prevention against cardiovascular disease. High-dose treatment with cyclooxygenase inhibitors reduces urinary albumin excretion rate (AER) in type 1 diabetic patients with micro...

  11. Dietary hydroxypropyl methylcellulose increases excretion of saturated and trans fats by hamsters fed fast food diets.

    Science.gov (United States)

    Yokoyama, Wallace; Anderson, William H K; Albers, David R; Hong, Yun-Jeong; Langhorst, Marsha L; Hung, Shao-Ching; Lin, Jiann-Tsyh; Young, Scott A

    2011-10-26

    In animal studies, hydroxypropyl methylcellulose (HPMC) intake results in increased fecal fat excretion; however, the effects on dietary saturated fatty acids (SATs) and trans-fatty acids (TRANS) remain unknown. This study investigated the effect of HPMC on digestion and absorption of lipids in male Golden Syrian hamsters fed either freeze-dried ground pizza (PZ), pound cake (PC), or hamburger and fries (BF) supplemented with dietary fiber from either HPMC or microcrystalline cellulose (MCC) for 3 weeks. We observed greater excretion of SATs and TRANS by both diets supplemented with HPMC or MCC as compared to the feed. SAT, TRANS, and unsaturated fatty acids (UNSAT) contents of feces of the PZ diet supplemented with HPMC were 5-8 times higher than diets supplemented with MCC and tended to be higher in the PC- and BF-HPMC supplemented diets as well. We also observed significant increases in fecal excretion of bile acids (2.6-3-fold; P fat excretion in a biased manner with preferential fecal excretion of both TRANS and SAT in hamsters fed fast food diets.

  12. Cystathionine γ-lyase, a H2S-generating enzyme, is a GPBAR1-regulated gene and contributes to vasodilation caused by secondary bile acids.

    Science.gov (United States)

    Renga, Barbara; Bucci, Mariarosaria; Cipriani, Sabrina; Carino, Adriana; Monti, Maria Chiara; Zampella, Angela; Gargiulo, Antonella; d'Emmanuele di Villa Bianca, Roberta; Distrutti, Eleonora; Fiorucci, Stefano

    2015-07-01

    GPBAR1 is a bile acid-activated receptor (BAR) for secondary bile acids, lithocholic (LCA) and deoxycholic acid (DCA), expressed in the enterohepatic tissues and in the vasculature by endothelial and smooth muscle cells. Despite that bile acids cause vasodilation, it is unclear why these effects involve GPBAR1, and the vascular phenotype of GPBAR1 deficient mice remains poorly defined. Previous studies have suggested a role for nitric oxide (NO) in regulatory activity exerted by GPBAR1 in liver endothelial cells. Hydrogen sulfide (H2S) is a vasodilatory agent generated in endothelial cells by cystathionine-γ-lyase (CSE). Here we demonstrate that GPBAR1 null mice had increased levels of primary and secondary bile acids and impaired vasoconstriction to phenylephrine. In aortic ring preparations, vasodilation caused by chenodeoxycholic acid (CDCA), a weak GPBAR1 ligand and farnesoid-x-receptor agonist (FXR), was iberiotoxin-dependent and GPBAR1-independent. In contrast, vasodilation caused by LCA was GPBAR1 dependent and abrogated by propargyl-glycine, a CSE inhibitor, and by 5β-cholanic acid, a GPBAR1 antagonist, but not by N(5)-(1-iminoethyl)-l-ornithine (l-NIO), an endothelial NO synthase inhibitor, or iberiotoxin, a large-conductance calcium-activated potassium (BKCa) channels antagonist. In venular and aortic endothelial (HUVEC and HAEC) cells GPBAR1 activation increases CSE expression/activity and H2S production. Two cAMP response element binding protein (CREB) sites (CREs) were identified in the CSE promoter. In addition, TLCA stimulates CSE phosphorylation on serine residues. In conclusion we demonstrate that GPBAR1 mediates the vasodilatory activity of LCA and regulates the expression/activity of CSE. Vasodilation caused by CDCA involves BKCa channels. The GPBAR1/CSE pathway might contribute to endothelial dysfunction and hyperdynamic circulation in liver cirrhosis.

  13. Grape Seed Procyanidins and Cholestyramine Differentially Alter Bile Acid and Cholesterol Homeostatic Gene Expression in Mouse Intestine and Liver.

    Directory of Open Access Journals (Sweden)

    Rebecca M Heidker

    Full Text Available Bile acid (BA sequestrants, lipid-lowering agents, may be prescribed as a monotherapy or combination therapy to reduce the risk of coronary artery disease. Over 33% of adults in the United States use complementary and alternative medicine strategies, and we recently reported that grape seed procyanidin extract (GSPE reduces enterohepatic BA recirculation as a means to reduce serum triglyceride (TG levels. The current study was therefore designed to assess the effects on BA, cholesterol and TG homeostatic gene expression following co-administration with GSPE and the BA sequestrant, cholestyramine (CHY. Eight-week old male C57BL/6 mice were treated for 4 weeks with either a control or 2% CHY-supplemented diet, after which, they were administered vehicle or GSPE for 14 hours. Liver and intestines were harvested and gene expression was analyzed. BA, cholesterol, non-esterified fatty acid and TG levels were also analyzed in serum and feces. Results reveal that GSPE treatment alone, and co-administration with CHY, regulates BA, cholesterol and TG metabolism differently than CHY administration alone. Notably, GSPE decreased intestinal apical sodium-dependent bile acid transporter (Asbt gene expression, while CHY significantly induced expression. Administration with GSPE or CHY robustly induced hepatic BA biosynthetic gene expression, especially cholesterol 7α-hydroxylase (Cyp7a1, compared to control, while co-administration further enhanced expression. Treatment with CHY induced both intestinal and hepatic cholesterologenic gene expression, while co-administration with GSPE attenuated the CHY-induced increase in the liver but not intestine. CHY also induced hepatic lipogenic gene expression, which was attenuated by co-administration with GSPE. Consequently, a 25% decrease in serum TG levels was observed in the CHY+GSPE group, compared to the CHY group. Collectively, this study presents novel evidence demonstrating that GSPE provides additive and

  14. Dietary cholesterol supplementation to a plant-based diet suppresses the complete pathway of cholesterol synthesis and induces bile acid production in Atlantic salmon (Salmo salar L.).

    Science.gov (United States)

    Kortner, Trond M; Björkhem, Ingemar; Krasnov, Aleksei; Timmerhaus, Gerrit; Krogdahl, Åshild

    2014-06-28

    Plants now supply more than 50 % of protein in Norwegian salmon aquafeeds. The inclusion of plant protein in aquafeeds may be associated with decreased lipid digestibility and cholesterol and bile salt levels, indicating that the replacement of fishmeal with plant protein could result in inadequate supplies of cholesterol in fish. A reduction in feed efficiency, fish growth and pathogen resistance is often observed in parallel to alterations in sterol metabolism. Previous studies have indicated that the negative effects induced by plant components can be attenuated when diets are supplemented with cholesterol. The present study evaluated the effects of dietary cholesterol supplementation (1·5 %) in Atlantic salmon fed a plant-based diet for 77 d. The weights of body, intestines and liver were recorded and blood, tissues, faeces, chyme and bile were sampled for the evaluation of effects on growth, nutrient utilisation and metabolism, and transcriptome and metabolite levels, with particular emphasis on sterol metabolism and organ structure and function. Cholesterol supplementation did not affect the growth or organ weights of Atlantic salmon, but seemed to promote the induction of cholesterol and plant sterol efflux in the intestine while suppressing sterol uptake. Cholesterol biosynthesis decreased correspondingly and conversion into bile acids increased. The marked effect of cholesterol supplementation on bile acid synthesis suggests that dietary cholesterol can be used to increase bile acid synthesis in fish. The present study clearly demonstrated how Atlantic salmon adjusted their metabolic functions in response to the dietary load of cholesterol. It has also expanded our understanding of sterol metabolism and turnover, adding to the existing, rather sparse, knowledge of these processes in fish.

  15. Bile acid malabsorption or disturbed intestinal permeability in patients treated with enzyme substitution for exocrine pancreatic insufficiency is not caused by bacterial overgrowth

    DEFF Research Database (Denmark)

    Madsen, Jan Lysgård; Graff, Jesper; Philipsen, Else Kirstine;

    2003-01-01

    enzyme replacement therapy, were studied. The prevalence of bacterial overgrowth was evaluated by means of a hydrogen and methane breath test with glucose. Gamma camera scintigraphy after intake of 75Se-homocholic acid taurine (75Se-HCAT) was used to evaluate bile acid absorption capacity. Intestinal......INTRODUCTION: In some patients with severe exocrine pancreatic insufficiency, enzyme replacement therapy will not lead to clinical improvement or reduction of steatorrhea. Therefore, other mechanisms separately or in interplay with reduced enzyme secretion might be responsible for malabsorption...... in these patients. AIMS: To evaluate the prevalence of bacterial overgrowth, bile acid absorption capacity, and intestinal permeability in a group of patients with well-characterized exocrine pancreatic insufficiency. METHODOLOGY: Eleven men with severe exocrine pancreatic insufficiency, of whom 10 were receiving...

  16. Formation of Short-Chain Fatty Acids, Excretion of Anthocyanins, and Microbial Diversity in Rats Fed Blackcurrants, Blackberries, and Raspberries

    Directory of Open Access Journals (Sweden)

    Greta Jakobsdottir

    2013-01-01

    Full Text Available Introduction. Berries contain high amounts of dietary fibre and flavonoids and have been associated with improved metabolic health. The mechanisms are not clear but the formation of SCFAs, especially propionic and butyric acids, could be important. The potent antioxidant and antimicrobial properties of flavonoids could also be a factor, but little is known about their fate in the gastrointestinal tract. Aim. To compare how blackcurrants, blackberries, raspberries, and Lactobacillus plantarum HEAL19 affect formation of SCFAs, inflammatory status, caecal microbial diversity, and flavonoids. Results and Conclusions. Degradation of the dietary fibre, formation of SCFAs including propionic and butyric acids, the weight of the caecal content and tissue, and the faecal wet and dry weight were all higher in rats fed blackcurrants rather than blackberries or raspberries. However, the microbial diversity of the gut microbiota was higher in rats fed raspberries. The high content of soluble fibre in blackcurrants and the high proportion of mannose-containing polymers might explain these effects. Anthocyanins could only be detected in urine of rats fed blackcurrants, and the excretion was lower with HEAL19. No anthocyanins or anthocyanidins were detected in caecal content or blood. This may indicate uptake in the stomach or small intestine.

  17. Urinary total flavonoid excretion but not 4-pyridoxic acid or potassium can be used as a biomarker for the intake of fruits and vegetables

    DEFF Research Database (Denmark)

    Krogholm, Kirstine Suszkiewicz; Haraldsdottir, J.; Knuthsen, Pia;

    2004-01-01

    in fruit and vegetable consumption. Furthermore, the urinary excretions of 4-pyridoxic acid (4-PA) and potassium were investigated as other potential biomarkers of fruit and vegetable intake. The study was designed as a 5-d randomized, controlled crossover study. On d 1-3, the men (n = 12) consumed a self......To gain better insight into the potential health effects of fruits and vegetables, reliable biomarkers of intake are needed. The main purpose of this study was to investigate the ability of flavonoid excretion in both 24-h and morning urine samples to reflect a low intake and moderate changes......-restricted flavonoid-free diet. On d 4, they were provided a strictly controlled diet containing no fruits or vegetables (basic diet). On d 5, they consumed the basic diet supplemented with 300 or 600 g of fruits and vegetables. The total excretion of flavonoids in 24-h urine samples increased linearly with increasing...

  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. Urinary excretion of fatty acid-binding proteins in idiopathic membranous nephropathy.

    NARCIS (Netherlands)

    Hofstra, J.M.; Deegens, J.K.J.; Steenbergen, E.J.; Wetzels, J.F.M.

    2008-01-01

    BACKGROUND: It is suggested that proteinuria contributes to progressive renal failure by inducing tubular cell injury. The site of injury is unknown. Most studies have used markers of proximal tubular cell damage. Fatty acid-binding proteins (FABPs) are intracellular carrier proteins with different

  20. 复合全谷豆粗杂粮的活性成分及其对胆汁酸代谢的调控%Active constituents in compound whole grain and its regulation on bile acids metabolism

    Institute of Scientific and Technical Information of China (English)

    谭琴; 翟成凯; 郭延波; 韩淑芬; 迟静; 邢花

    2012-01-01

    目的 分析比较复合全谷豆粗杂粮中膳食纤维(dietary fiber,DF)、抗性淀粉(resistant starch,RS)、总黄酮和总皂甙等活性成分,了解其对大鼠粪胆汁酸(fecal bile acid,FBA)排出的影响及其调控机制.方法 按国家标准及文献方法测定复合全谷豆粗杂粮中DF、RS、总黄酮和总皂甙的含量.44只SPF级SD大鼠随机分为阴性对照组、高脂模型组、米面组和复合全谷豆粗杂粮组,分别给予相应饲料连续喂养8周.实验开始前和结束后,代谢笼收集大鼠粪便,磷钼酸法测定FBA.RT-PCR法测定大鼠肝脏组织中胆固醇7α-羟化酶(cholesterol 7α-hydroxylase,CYP7Al) mRNA和肝X受体α(Liver X receptorα,LXRα) mRNA的表达.结果 复合全谷豆粗杂粮中每100g含DF 15.3g、RS 9.03g、总黄酮0.45g和总皂甙0.24g.复合全谷豆粗杂粮组大鼠FBA排出量显著升高(P<0.05);CYP7A1 mRNA和LXRα mRNA表达比其他3组显著增加(P<0.05).结论 复合全谷豆粗杂粮比面粉大米富含UF、RS、黄酮和皂甙等活性物质.可以促使胆汁酸合成经典途径中限速酶CYP7Al和其上游受体LXRα mRNA表达的上调,有效地增加大鼠FBA的排出量,起到改善脂代谢紊乱的作用.%Objective To analyze and compare the contents of dietary fiber, resistant starch,flavonoid and total saponins in the compound whole grain,to observe the effects of compound whole grain on the excretion of bile acid and its regulation mechanisms. Methods The contents of dietary fiber, resistant starch, flavonoid and saponins in compound whole grain were determined according to the national standard methods and other methods in literatures. Forty-four SPF grade SD rats were allocated randomly into four groups:the negative control group,hyperlipemia model group,rice-flour group and compound whole grain group,and each group was provided with corresponding diet for 8 consecutive weeks. The excrements of rats were collected at the beginning and the ending of the

  1. Urinary, biliary and faecal excretion of rocuronium in humans

    NARCIS (Netherlands)

    Proost, JH; Eriksson, LI; Mirakhur, RK; Wierda, JMKH

    2000-01-01

    The excretion of rocuronium and its potential metabolites was studied in 38 anaesthetized patients, ASA I-III and 21-69 yr old. Rocuronium bromide was administered as an i.v. bolus dose of 0.3 or 0.9 mg kg(-1). in Part A of the study, the excretion into urine and bile, and the liver content were stu

  2. 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.

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

    Science.gov (United States)

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

    2016-03-01

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

  4. Diurnal variations of mouse plasma and hepatic bile acid concentrations as well as expression of biosynthetic enzymes and transporters.

    Directory of Open Access Journals (Sweden)

    Yu-Kun Jennifer Zhang

    Full Text Available BACKGROUND: Diurnal fluctuation of bile acid (BA concentrations in the enterohepatic system of mammals has been known for a long time. Recently, BAs have been recognized as signaling molecules beyond their well-established roles in dietary lipid absorption and cholesterol homeostasis. METHODS AND RESULTS: The current study depicted diurnal variations of individual BAs detected by ultra-performance liquid chromatography/mass spectrometry (UPLC/MS in serum and livers collected from C57BL/6 mice fed a regular chow or a chow containing cholestyramine (resin. Circadian rhythms of mRNA of vital BA-related nuclear receptors, enzymes, and transporters in livers and ilea were determined in control- and resin-fed mice, as well as in farnesoid X receptor (FXR null mice. The circadian profiles of BAs showed enhanced bacterial dehydroxylation during the fasting phase and efficient hepatic reconjugation of BAs in the fed phase. The resin removed more than 90% of BAs with β-hydroxy groups, such as muricholic acids and ursodeoxycholic acid, from serum and livers, but did not exert as significant influence on CA and CDCA in both compartments. Both resin-fed and FXR-null mouse models indicate that BAs regulate their own biosynthesis through the FXR-regulated ileal fibroblast growth factor 15. BA flux also influences the daily mRNA levels of multiple BA transporters. CONCLUSION: BA concentration and composition exhibit circadian variations in mouse liver and serum, which influences the circadian rhythms of BA metabolizing genes in liver and ileum. The diurnal variations of BAs appear to serve as a signal that coordinates daily nutrient metabolism in mammals.

  5. Biotransformations of Bile Acids with Bacteria from Cayambe Slaughterhouse (Ecuador): Synthesis of Bendigoles.

    Science.gov (United States)

    Costa, Stefania; Maldonado Rodriguez, Maria Elena; Rugiero, Irene; De Bastiani, Morena; Medici, Alessandro; Tamburini, Elena; Pedrini, Paola

    2016-08-01

    The biotransformations of cholic acid (1a), deoxycholic acid (1b), and hyodeoxycholic acid (1c) to bendigoles and other metabolites with bacteria isolated from the rural slaughterhouse of Cayambe (Pichincha Province, Ecuador) were reported. The more active strains were characterized, and belong to the genera Pseudomonas and Rhodococcus. Various biotransformation products were obtained depending on bacteria and substrates. Cholic acid (1a) afforded the 3-oxo and 3-oxo-4-ene derivatives 2a and 3a (45% and 45%, resp.) with P. mendocina ECS10, 3,12-dioxo-4-ene derivative 4a (60%) with Rh. erythropolis ECS25, and 9,10-secosteroid 6 (15%) with Rh. erythropolis ECS12. Bendigole F (5a) was obtained in 20% with P. fragi ECS22. Deoxycholic acid (1b) gave 3-oxo derivative 2b with P. prosekii ECS1 and Rh. erythropolis ECS25 (20% and 61%, resp.), while 3-oxo-4-ene derivative 3b was obtained with P. prosekii ECS1 and P. mendocina ECS10 (22% and 95%, resp.). Moreover, P. fragi ECS9 afforded bendigole A (8b; 80%). Finally, P. mendocina ECS10 biotransformed hyodeoxycholic acid (1c) to 3-oxo derivative 2c (50%) and Rh. erythropolis ECS12 to 6α-hydroxy-3-oxo-23,24-dinor-5β-cholan-22-oic acid (9c, 66%). Bendigole G (5c; 13%) with P. prosekii ECS1 and bendigole H (8c) with P. prosekii ECS1 and Rh. erythropolis ECS12 (20% and 16%, resp.) were obtained.

  6. Critical role of RanBP2-mediated SUMOylation of Small Heterodimer Partner in maintaining bile acid homeostasis.

    Science.gov (United States)

    Kim, Dong-Hyun; Kwon, Sanghoon; Byun, Sangwon; Xiao, Zhen; Park, Sean; Wu, Shwu-Yuan; Chiang, Cheng-Ming; Kemper, Byron; Kemper, Jongsook Kim

    2016-07-14

    Bile acids (BAs) are recently recognized signalling molecules that profoundly affect metabolism. Because of detergent-like toxicity, BA levels must be tightly regulated. An orphan nuclear receptor, Small Heterodimer Partner (SHP), plays a key role in this regulation, but how SHP senses the BA signal for feedback transcriptional responses is not clearly understood. We show an unexpected function of a nucleoporin, RanBP2, in maintaining BA homoeostasis through SUMOylation of SHP. Upon BA signalling, RanBP2 co-localizes with SHP at the nuclear envelope region and mediates SUMO2 modification at K68, which facilitates nuclear transport of SHP and its interaction with repressive histone modifiers to inhibit BA synthetic genes. Mice expressing a SUMO-defective K68R SHP mutant have increased liver BA levels, and upon BA- or drug-induced biliary insults, these mice exhibit exacerbated cholestatic pathologies. These results demonstrate a function of RanBP2-mediated SUMOylation of SHP in maintaining BA homoeostasis and protecting from the BA hepatotoxicity.

  7. Tris(2-butoxyethyl)phosphate and triethyl phosphate alter embryonic development, hepatic mRNA expression, thyroid hormone levels, and circulating bile acid concentrations in chicken embryos

    Energy Technology Data Exchange (ETDEWEB)

    Egloff, Caroline [National Wildlife Research Centre, Environment Canada, Ottawa, ON K1A 0H3 (Canada); Crump, Doug, E-mail: doug.crump@ec.gc.ca [National Wildlife Research Centre, Environment Canada, Ottawa, ON K1A 0H3 (Canada); Porter, Emily; Williams, Kim L.; Letcher, Robert J.; Gauthier, Lewis T. [National Wildlife Research Centre, Environment Canada, Ottawa, ON K1A 0H3 (Canada); Kennedy, Sean W. [National Wildlife Research Centre, Environment Canada, Ottawa, ON K1A 0H3 (Canada); Department of Biology, University of Ottawa, Ottawa, ON K1N 6N5 (Canada)

    2014-09-15

    The organophosphate flame retardants tris(2-butoxyethyl) phosphate (TBOEP) and triethyl phosphate (TEP) are used in a wide range of applications to suppress or delay the ignition and spread of fire. Both compounds have been detected in the environment and TBOEP was recently measured in free-living avian species. In this study, TBOEP and TEP were injected into the air cell of chicken embryos at concentrations ranging from 0 to 45,400 ng/g and 0 to 241,500 ng/g egg, respectively. Pipping success, development, hepatic mRNA expression of 9 target genes, thyroid hormone levels, and circulating bile acid concentrations were determined. Exposure to the highest doses of TBOEP and TEP resulted in negligible detection of the parent compounds in embryonic contents at pipping indicating their complete metabolic degradation. TBOEP exposure had limited effects on chicken embryos, with the exception of hepatic CYP3A37 mRNA induction. TEP exposure decreased pipping success to 68%, altered growth, increased liver somatic index (LSI) and plasma bile acids, and modulated genes associated with xenobiotic and lipid metabolism and the thyroid hormone pathway. Plasma thyroxine levels were decreased at all TEP doses, including an environmentally-relevant concentration (8 ng/g), and gallbladder hypotrophy was evident at ≥ 43,200 ng/g. Tarsus length and circulating thyroxine concentration emerged as potential phenotypic anchors for the modulation of transthyretin mRNA. The increase in plasma bile acids and LSI, gallbladder hypotrophy, and discoloration of liver tissue represented potential phenotypic outcomes associated with modulation of hepatic genes involved with xenobiotic and lipid metabolism. - Highlights: • TBOEP is not embryolethal to chicken embryos. • TEP affected embryonic viability, morphometric endpoints, and thyroid hormone levels. • TEP altered mRNA levels of xenobiotic and lipid metabolism genes. • TEP increased plasma bile acids and caused gallbladder hypotrophy

  8. The effect of acetaminophen on the expression of BCRP in trophoblast cells impairs the placental barrier to bile acids during maternal cholestasis

    Energy Technology Data Exchange (ETDEWEB)

    Blazquez, Alba G., E-mail: albamgb@usal.es [Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca (Spain); CIBERehd, Instituto de Salud Carlos III, Madrid (Spain); Briz, Oscar, E-mail: obriz@usal.es [Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca (Spain); CIBERehd, Instituto de Salud Carlos III, Madrid (Spain); Gonzalez-Sanchez, Ester, E-mail: u60343@usal.es [Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca (Spain); Perez, Maria J., E-mail: mjperez@usal.es [Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca (Spain); University Hospital of Salamanca, IECSCYL-IBSAL, Salamanca (Spain); CIBERehd, Instituto de Salud Carlos III, Madrid (Spain); Ghanem, Carolina I., E-mail: cghanem@ffyb.uba.ar [Instituto de Investigaciones Farmacologicas, Facultad de Farmacia y Bioquimica, CONICET, Universidad de Buenos Aires, Buenos Aires (Argentina); Marin, Jose J.G., E-mail: jjgmarin@usal.es [Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca (Spain); CIBERehd, Instituto de Salud Carlos III, Madrid (Spain)

    2014-05-15

    Acetaminophen is used as first-choice drug for pain relief during pregnancy. Here we have investigated the effect of acetaminophen at subtoxic doses on the expression of ABC export pumps in trophoblast cells and its functional repercussion on the placental barrier during maternal cholestasis. The incubation of human choriocarcinoma cells (JAr, JEG-3 and BeWo) with acetaminophen for 48 h resulted in no significant changes in the expression and/or activity of MDR1 and MRPs. In contrast, in JEG-3 cells, BCRP mRNA, protein, and transport activity were reduced. In rat placenta, collected at term, acetaminophen administration for the last three days of pregnancy resulted in enhanced mRNA, but not protein, levels of Mrp1 and Bcrp. In fact, a decrease in Bcrp protein was found. Using in situ perfused rat placenta, a reduction in the Bcrp-dependent fetal-to-maternal bile acid transport after treating the dams with acetaminophen was found. Complete biliary obstruction in pregnant rats induced a significant bile acid accumulation in fetal serum and tissues, which was further enhanced when the mothers were treated with acetaminophen. This drug induced increased ROS production in JEG-3 cells and decreased the total glutathione content in rat placenta. Moreover, the NRF2 pathway was activated in JEG-3 cells as shown by an increase in nuclear NRF2 levels and an up-regulation of NRF2 target genes, NQO1 and HMOX-1, which was not observed in rat placenta. In conclusion, acetaminophen induces in placenta oxidative stress and a down-regulation of BCRP/Bcrp, which may impair the placental barrier to bile acids during maternal cholestasis. - Highlights: • Acetaminophen induces changes in placental BCRP expression in vitro. • This drug reduces the ability of placental cells to export BCRP substrates. • Acetaminophen induces changes in Bcrp expression in rat placenta. • Placental barrier to bile acids is impaired in rats treated with this drug.

  9. Molecular Properties of Guar Gum and Pectin Modify Cecal Bile Acids, Microbiota, and Plasma Lipopolysaccharide-Binding Protein in Rats.

    Science.gov (United States)

    Ghaffarzadegan, Tannaz; Marungruang, Nittaya; Fåk, Frida; Nyman, Margareta

    2016-01-01

    Bile acids (BAs) act as signaling molecules in various physiological processes, and are related to colonic microbiota composition as well as to different types of dietary fat and fiber. This study investigated whether guar gum and pectin-two fibers with distinct functional characteristics-affect BA profiles, microbiota composition, and gut metabolites in rats. Low- (LM) or high-methoxylated (HM) pectin, and low-, medium-, or high-molecular-weight (MW) guar gum were administered to rats that were fed either low- or high-fat diets. Cecal BAs, short-chain fatty acids (SCFA) and microbiota composition, and plasma lipopolysaccharide-binding protein (LBP) levels were analyzed, by using novel methodologies based on gas chromatography (BAs and SCFAs) and 16S rRNA gene sequencing on the Illumina MiSeq platform. Strong correlations were observed between cecal BA and SCFA levels, microbiota composition, and portal plasma LBP levels in rats on a high-fat diet. Notably, guar gum consumption with medium-MW increased the cecal amounts of cholic-, chenodeoxycholic-, and ursodeoxycholic acids as well as α-, β-, and ω-muricholic acids to a greater extent than other types of guar gum or the fiber-free control diet. In contrast, the amounts of cecal deoxycholic- and hyodeoxycholic acid were reduced with all types of guar gum independent of chain length. Differences in BA composition between pectin groups were less obvious, but cecal levels of α- and ω-muricholic acids were higher in rats fed LM as compared to HM pectin or the control diet. The inflammatory marker LBP was downregulated in rats fed medium-MW guar gum and HM pectin; these two fibers decreased the cecal abundance of Oscillospira and an unclassified genus in Ruminococcaceae, and increased that of an unclassified family in RF32. These results indicate that the molecular properties of guar gum and pectin are important for their ability to modulate cecal BA formation, gut microbiota composition, and high-fat diet induced

  10. Effect of potential renal acid load of foods on urinary citrate excretion in calcium renal stone formers.

    Science.gov (United States)

    Trinchieri, Alberto; Lizzano, Renata; Marchesotti, Federica; Zanetti, Giampaolo

    2006-02-01

    The aim of this study was to investigate the influence of the potential renal acid load (PRAL) of the diet on the urinary risk factors for renal stone formation. The present series comprises 187 consecutive renal calcium stone patients (114 males, 73 females) who were studied in our stone clinic. Each patient was subjected to an investigation including a 24-h dietary record and 24-h urine sample taken over the same period. Nutrients and calories were calculated by means of food composition tables using a computerized procedure. Daily PRAL was calculated considering the mineral and protein composition of foods, the mean intestinal absorption rate for each nutrient and the metabolism of sulfur-containing amino acids. Sodium, potassium, calcium, magnesium, phosphate, oxalate, urate, citrate, and creatinine levels were measured in the urine. The mean daily PRAL was higher in male than in female patients (24.1+/-24.0 vs 16.1+/-20.1 mEq/day, P=0.000). A significantly (P=0.01) negative correlation (R=-0.18) was found between daily PRAL and daily urinary citrate, but no correlation between PRAL and urinary calcium, oxalate, and urate was shown. Daily urinary calcium (R=0.186, P=0.011) and uric acid (R=0.157, P=0.033) were significantly related to the dietary intake of protein. Daily urinary citrate was significantly related to the intakes of copper (R=0.178, P=0.015), riboflavin (R=0.20, P=0.006), piridoxine (R=0.169, P=0.021) and biotin (R=0.196, P=0.007). The regression analysis by stepwise selection confirmed the significant negative correlation between PRAL and urinary citrate (P=0.002) and the significant positive correlation between riboflavin and urinary citrate (P=0.000). Urinary citrate excretion of renal stone formers (RSFs) is highly dependent from dietary acid load. The computation of the renal acid load is advisable to investigate the role of diet in the pathogenesis of calcium stone disease and it is also a useful tool to evaluate the lithogenic potential of

  11. Simultaneous quantification of the major bile acids in artificial Calculus bovis by high-performance liquid chromatography with precolumn derivatization and its application in quality control.

    Science.gov (United States)

    Shi, Yan; Xiong, Jing; Sun, Dongmei; Liu, Wei; Wei, Feng; Ma, Shuangcheng; Lin, Ruichao

    2015-08-01

    An accurate and sensitive high-performance liquid chromatography method coupled with ultralviolet detection and precolumn derivatization was developed for the simultaneous quantification of the major bile acids in Artificial Calculus bovis, including cholic acid, hyodeoxycholic acid, chenodeoxycholic acid, and deoxycholic acid. The extraction, derivatization, chromatographic separation, and detection parameters were fully optimized. The samples were extracted with methanol by ultrasonic extraction. Then, 2-bromine-4'-nitroacetophenone and 18-crown ether-6 were used for derivatization. The chromatographic separation was performed on an Agilent SB-C18 column (250 × 4.6 mm id, 5 μm) at a column temperature of 30°C and liquid flow rate of 1.0 mL/min using water and methanol as the mobile phase with a gradient elution. The detection wavelength was 263 nm. The method was extensively validated by evaluating the linearity (r(2) ≥ 0.9980), recovery (94.24-98.91%), limits of detection (0.25-0.31 ng) and limits of quantification (0.83-1.02 ng). Seventeen samples were analyzed using the developed and validated method. Then, the amounts of bile acids were analyzed by hierarchical agglomerative clustering analysis and principal component analysis. The results of the chemometric analysis showed that the contents of these compounds reflect the intrinsic quality of artificial Calculus bovis, and two compounds (hyodeoxycholic acid and chenodeoxycholic acid) were the most important markers for quality evaluating.

  12. Bile Acid Look-Alike Controls Life Span in C. elegans

    NARCIS (Netherlands)

    Groen, Albert K.; Kuipers, Folkert

    2013-01-01

    Extensive transcriptional networks maintain sterol homeostasis across species, underscoring the importance of sterol balance for healthy life. Magner et al. (2013) now show that, in C. elegans, the nuclear receptor NHR-8 is key in regulation of cholesterol balance and production of dafachronic acid,

  13. BILE SECRETION OF SULFATED GLYCOLITHOCHOLIC ACID IS REQUIRED FOR ITS CHOLESTATIC ACTION IN RATS

    NARCIS (Netherlands)

    KUIPERS, F; HARDONK, MJ; VONK, RJ; VANDERMEER, R

    1992-01-01

    To test our hypothesis that the cholestatic action of sulfated glycolithocholic acid (SGLC) in the rat is related to its interaction with calcium in the biliary tree [R. van der Meer, R. J. Vonk, and F. Kuipers. Am. J. Physiol. 254 (Gastrointest. Liver Physiol. 17): G644-G649, 1988], we have now com

  14. 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

    signalling are other important regulators of similar secretory mechanisms in pancreas. The aim of our study was to elucidate whether there is interplay between ATP and BA signalling. RESULTS: Here we show that CDCA (chenodeoxycholic acid) caused fast and concentration-dependent ATP release from acini (AR42J...

  15. Quantification of 15 bile acids in lake charr feces by ultra-high performance liquid chromatography–tandem mass spectrometry

    Science.gov (United States)

    Li, Ke; Buchinger, Tyler J.; Bussy, Ugo; Fissette, Skye D; Johnson, Nicholas; Li, Weiming

    2015-01-01

    Many fishes are hypothesized to use bile acids (BAs) as chemical cues, yet quantification of BAs in biological samples and the required methods remain limited. Here, we present an UHPLC–MS/MS method for simultaneous, sensitive, and rapid quantification of 15 BAs, including free, taurine, and glycine conjugated BAs, and application of the method to fecal samples from lake charr (Salvelinus namaycush). The analytes were separated on a C18 column with acetonitrile–water (containing 7.5 mM ammonium acetate and 0.1% formic acid) as mobile phase at a flow rate of 0.25 mL/min for 12 min. BAs were monitored with a negative electrospray triple quadrupole mass spectrometer (Xevo TQ-S™). Calibration curves of 15 BAs were linear over the concentration range of 1.00–5,000 ng/mL. Validation revealed that the method was specific, accurate, and precise. The method was applied to quantitative analysis of feces extract of fry lake charr and the food they were eating. The concentrations of analytes CA, TCDCA, TCA, and CDCA were 242.3, 81.2, 60.7, and 36.2 ng/mg, respectively. However, other taurine conjugated BAs, TUDCA, TDCA, and THDCA, were not detected in feces of lake charr. Interestingly, TCA and TCDCA were detected at high concentrations in food pellets, at 71.9 and 38.2 ng/mg, respectively. Application of the method to feces samples from lake charr supported a role of BAs as chemical cues, and will enhance further investigation of BAs as chemical cues in other fish species.

  16. Pharmacological activation of the bile acid nuclear farnesoid X receptor is feasible in patients with quiescent Crohn's colitis.

    Directory of Open Access Journals (Sweden)

    Fiona D M van Schaik

    Full Text Available BACKGROUND: The bile acid-activated nuclear receptor Farnesoid X Receptor (FXR is critical in maintaining intestinal barrier integrity and preventing bacterial overgrowth. Patients with Crohn's colitis (CC exhibit reduced ileal FXR target gene expression. FXR agonists have been shown to ameliorate inflammation in murine colitis models. We here explore the feasibility of pharmacological FXR activation in CC. METHODS: Nine patients with quiescent CC and 12 disease controls were treated with the FXR ligand chenodeoxycholic acid (CDCA; 15 mg/kg/day for 8 days. Ileal FXR activation was assessed in the fasting state during 6 hrs after the first CDCA dose and on day 8, by quantification of serum levels of fibroblast growth factor (FGF 19. Since FGF19 induces gallbladder (GB refilling in murine models, we also determined concurrent GB volumes by ultrasound. On day 8 ileal and cecal biopsies were obtained and FXR target gene expression was determined. RESULTS: At baseline, FGF19 levels were not different between CC and disease controls. After the first CDCA dose, there were progressive increases of FGF19 levels and GB volumes during the next 6 hours in CC patients and disease controls (FGF19: 576 resp. 537% of basal; GB volumes: 190 resp. 178% of basal without differences between both groups, and a further increase at day 8. In comparison with a separate untreated control group, CDCA affected FXR target gene expression in both CC and disease controls, without differences between both groups. CONCLUSIONS: Pharmacological activation of FXR is feasible in patients with CC. These data provide a rationale to explore the anti-inflammatory properties of pharmacological activation of FXR in these patients. TRIAL REGISTRATION: TrialRegister.nl NTR2009.

  17. LONG-TERM EFFECTS OF LINOLEIC-ACID-ENRICHED DIET ON ALBUMINURIA AND LIPID-LEVELS IN TYPE-1 (INSULIN-DEPENDENT) DIABETIC-PATIENTS WITH ELEVATED URINARY ALBUMIN EXCRETION

    NARCIS (Netherlands)

    DULLAART, RPF; BEUSEKAMP, BJ; MEIJER, S; HOOGENBERG, K; VANDOORMAAL, JJ; SLUITER, WJ

    1992-01-01

    We conducted a 2-year prospective randomised study to investigate the effects of a linoleic-acid-enriched diet on albuminuria and lipid levels in Type 1 (insulin-dependent) diabetic patients with elevated urinary albumin excretion (overnight urinary albumin excretion rate between 10 and 200-mu-g/min

  18. Effect of lacking intestinal bile acid on liver regeneration in rats%肠道缺乏胆汁酸对大鼠肝再生的影响

    Institute of Scientific and Technical Information of China (English)

    董秀山; 赵浩亮

    2010-01-01

    Objective To investigate the effect of the lack of intestinal bile on liver regeneration after hepatectomy.Methods The model of interference with intestinal bile acid metabolism in rats was established by feeding rats with 0.2% cholic acid(cholic acid loading group), 2% cholestyramine resin(lack of bile group)and feeding the standard diet as the control group.Liver regeneration was compared among the 3 groups at 0, 1, 2, 3, and 7 d after 70% partial hepatectomy(PH)in rats and mRNA expression of the rate-limiting enzyme of bile acid biosynthesis(CYP7a1)and farnesoid X receptor (FXR)were detected.Results The rate of liver regeneration was significantly lower on days 3 and 7after PH in the lack of bile group than in the other groups(P<0.05).On day 1, the labeling indices of PCNA and Ki-67 in the lack of bile group(22.21% ±2.31%、 17.25 % ± 6.50 %)were lower than those in the cholic acid loading group(44.4%±4.92%、 30.83% ± 3.91%)and control group (38.74% ±6.42% 、27.04% ±7.22%)and the peaking of labeling indices was delayed.After PH, the mRNA expression of FXR was significantly lower in the lack of bile group than in other groups.However, CYP7al mRNA had a trend towards increase after PH and was higher than that in other groups.Conclusion Lack of intestinal bile results in delayed liver regeneration of normal rat liver accompanied by decreased expression of FXR mRNA after hepatectomy.%目的 探索肠道缺乏胆汁酸对肝再生的影响.方法 通过喂养大鼠0.2%胆酸(胆酸负荷组)、2%考来烯胺(胆酸缺乏组)建立干扰肠道胆汁酸代谢的动物模型,以喂养标准饲料作为对照组,所有大鼠均行70%肝部分切除术(PH).比较PH后0、1、2、3、7 d三组大鼠的肝脏再生情况,并检测法尼酯衍生物X受体FXR及其靶基因胆汁酸合成限速酶CYP7a1的mRNA表达.结果 胆酸缺乏组的肝再生率在PH后3、7 d显著低于胆酸负荷组和对照组(P<0.05),1 d时PCNA和Ki-67标记指数(22.21%±2.31%、17

  19. Bile acid mediated effects on gut integrity and performance of early-weaned piglets

    DEFF Research Database (Denmark)

    de Diego-Cabero, Nuria; Mereu, Alessandro; Menoyo, David;

    2015-01-01

    of the study on day 35. On days 1, 7 and 14 blood samples were collected from 6 pigs per treatment to measure plasma GLP-2. On day 15, 6 pigs per treatment were euthanized to obtain intestinal tissue samples for later histological and gene expression analyses. Results Supplementing the diet with CDC tended...... small intestine. Conclusions This study showed that the oral administration of CDC to early-weaned pigs has the potential to improve the protection......Background Early weaning (EW) results in a transient period of impaired integrity of the intestinal mucosa that may be associated with reduced plasma concentration of glucagon-like peptide-(GLP) 2. We have previously shown that intragastric infusion of chenodeoxycholic acid (CDC) increases...

  20. Bile acid sequestration reduces plasma glucose levels in db/db mice by increasing its metabolic clearance rate.

    Directory of Open Access Journals (Sweden)

    Maxi Meissner

    Full Text Available AIMS/HYPOTHESIS: Bile acid sequestrants (BAS reduce plasma glucose levels in type II diabetics and in murine models of diabetes but the mechanism herein is unknown. We hypothesized that sequestrant-induced changes in hepatic glucose metabolism would underlie reduced plasma glucose levels. Therefore, in vivo glucose metabolism was assessed in db/db mice on and off BAS using tracer methodology. METHODS: Lean and diabetic db/db mice were treated with 2% (wt/wt in diet Colesevelam HCl (BAS for 2 weeks. Parameters of in vivo glucose metabolism were assessed by infusing [U-(13C]-glucose, [2-(13C]-glycerol, [1-(2H]-galactose and paracetamol for 6 hours, followed by mass isotopologue distribution analysis, and related to metabolic parameters as well as gene expression patterns. RESULTS: Compared to lean mice, db/db mice displayed an almost 3-fold lower metabolic clearance rate of glucose (p = 0.0001, a ∼300% increased glucokinase flux (p = 0.001 and a ∼200% increased total hepatic glucose production rate (p = 0.0002. BAS treatment increased glucose metabolic clearance rate by ∼37% but had no effects on glucokinase flux nor total hepatic or endogenous glucose production. Strikingly, BAS-treated db/db mice displayed reduced long-chain acylcarnitine content in skeletal muscle (p = 0.0317 but not in liver (p = 0.189. Unexpectedly, BAS treatment increased hepatic FGF21 mRNA expression 2-fold in lean mice (p = 0.030 and 3-fold in db/db mice (p = 0.002. CONCLUSIONS/INTERPRETATION: BAS induced plasma glucose lowering in db/db mice by increasing metabolic clearance rate of glucose in peripheral tissues, which coincided with decreased skeletal muscle long-chain acylcarnitine content.

  1. Bile acid metabolites in serum: intraindividual variation and associations with coronary heart disease, metabolic syndrome and diabetes mellitus.

    Directory of Open Access Journals (Sweden)

    Carine Steiner

    Full Text Available Bile acids (BAs regulate glucose and lipid metabolism. In longitudinal and case-control-studies, we investigated the diurnal variation of serum concentrations of the 15 major BAs as well as the biosynthetic precursor 7α-hydroxy-4-cholesten-3-one (C4 and their associations, respectively, with coronary artery disease (CAD, diabetes mellitus type 2 (T2DM, and non-diabetic metabolic syndrome (MetS. In hourly taken blood samples of four healthy probands, the intraindividual 24 h variation of C4, conjugated and unconjugated BAs ranged from 42% to 72%, from 23% to 91%, and from 49% to 90%, respectively. Conjugated BA concentrations mainly increased following food intake. Serum levels of C4 and unconjugated BAs changed with daytime with maxima varying interindividually between 20h00 and 1h00 and between 3h00 and 8h00, respectively. Comparisons of data from 75 CAD patients with 75 CAD-free controls revealed no statistically significant association of CAD with BAs or C4. Comparisons of data from 50 controls free of T2DM or MetS, 50 MetS patients, and 50 T2DM patients revealed significantly increased fasting serum levels of C4 in patients with MetS and T2DM. Multiple regression analysis revealed body mass index (BMI and plasma levels of triglycerides (TG as independent determinants of C4 levels. Upon multivariate and principle component analyses the association of C4 with T2DM and/or MetS was not independent of or superior to the canonical MetS components. In conclusion, despite large intra- and interindividual variation, serum levels of C4 are significantly increased in patients with MetS and T2DM but confounded with BMI and TG.

  2. Mineral phosphate solubilization by Streptomyces sp. CTM396 involves the excretion of gluconic acid and is stimulated by humic acids.

    Science.gov (United States)

    Farhat, Mounira Ben; Boukhris, Ines; Chouayekh, Hichem

    2015-03-01

    The actinomycetes isolates (128) which were taken from agricultural soil samples and collected near a rock phosphate processing unit were screened for mineral phosphate-solubilizing (MPS) ability. A significant MPS activity was observed for 30 isolates on various phosphate sources when grown in the National Botanical Research Institute's phosphate broth. CTM396 and CTM397 strains which showed the highest MPS abilities were identified by 16S rDNA sequencing as members of the genus Streptomyces. Their MPS activity was proved to be concomitant with a drop in pH due to the secretion of gluconic acid (GA). This was correlated with the simultaneous detection by PCR of genes gdh [encoding the glucose dehydrogenase (GDH) responsible for GA production from glucose] and pqq (involved in biosynthesis of the pyrroloquinoline quinone cofactor of GDH), as well as the highlighting of GHD enzyme activity, for the first time in a Streptomyces sp. strain producing GA. Furthermore, the 0.05% of humic acids proved to have a stimulatory effect on the growth and the ability of CTM396 to solubilize Gafsa rock phosphate. According to this study, it is possible to use humic acids and Gafsa rock phosphate in association with spores of ad hoc Streptomyces strains as natural and efficient amendments to improve plant growth with no need of costly and pollutant transformation of Gafsa rock phosphate.

  3. Postprandial response and tissue distribution of the bile acid synthesis-related genes, cyp7a1, cyp8b1 and shp, in rainbow trout Oncorhynchus mykiss.

    Science.gov (United States)

    Murashita, Koji; Yoshiura, Yasutoshi; Chisada, Shin-ichi; Furuita, Hirofumi; Sugita, Tsuyoshi; Matsunari, Hiroyuki; Yamamoto, Takeshi

    2013-10-01

    In mammals, cholesterol 7α-hydroxylase (CYP7A1) and sterol 12α-hydroxylase (CYP8B1) are rate-limiting enzymes in bile acid synthesis. In addition, a small heterodimer partner (SHP) is also known to inhibit bile acid synthesis via the suppression of CYP7A1 and CYP8B1 expression. However, little information is currently available regarding primary structure of the genes involved in bile acid synthesis in fish. We therefore cloned cyp7a1, cyp8b1 and shp genes from rainbow trout and obtained cDNAs encoding two isoforms each of Cyp7a1 (-1 and -2), Cyp8b1 (-1 and -2) and Shp (-1 and -2). Both cyp7a1-1 and -2 encoded proteins of 512 amino acids. Trout cyp7a1-1 was expressed not only primarily in the kidney, pyloric caecum and mid-gut, but also weakly in the liver, eye, gill and ovary. cyp7a1-2 was highly expressed in the liver, pyloric caecum and mid-gut. cyp8b1-1 and -2, which encoded proteins of 512 and 509 amino acids, respectively, were principally expressed in the liver. Both shp-1 and -2, which encoded proteins of 288 and 290 amino acids, respectively, were strongly expressed in the liver, but shp-2 was also highly expressed in the gallbladder and digestive tract. The temporal changes in the expression of cyp7a1-1/-2, cyp8b1-1/-2 and shp-1/-2 in the liver were assessed after consumption of a single meal. Expression of cyp7a1-1/-2 and cyp8b1-1/-2 increased within 3h post feeding (hpf) when the stomach was still approximately 84% full and the gallbladder was almost completely empty. Although the expression of shp-1 did not change after feeding, the expression pattern of shp-2 was inversely related to the expression patterns of cyp7a1-1/-2 and cyp8b1-1/-2. Specifically, shp-2 expression decreased until 3 hpf before returning to initial levels at 24 hpf. These findings suggest that Cyp7a1s/8b1s and Shp-2 function antagonistically in bile acid synthesis in rainbow trout.

  4. Tissue distribution and excretion of 125I-lidamycin in mice and rats

    Institute of Scientific and Technical Information of China (English)

    You-Ping Liu; Quan-Sheng Li; Yu-Rong Huang; Chang-Xiao Liu

    2005-01-01

    AIM: To investigate the tissue distribution, urinary and fecal excretions of 125I-lidamycin (125I-C-1027) in mice and its biliary excretion in rats.METHODS: The total radioactivity assay (RA method) and the radioactivity assay after precipitation with 200 mL/L trichloroacetic acid (TCA-RA method) were used to dete-rmine the tissue distribution, and the urinary and fecal excretions of 125I-C-1027 in mice and its biliary excretion in rats.RESULTS: Tissue concentrations reached the peak at the fifth minute after administration of 125I-C-1027 to mice. The highest concentration was in kidney, and the lowest in brain at all test-time points. The organs of the concentrations of 125I-C-1027 from high to low were kidney, lung, liver, stomach, spleen, uterus, ovary, intestine, muscle, heart, testis, fat, and brain in mice. The accumulative excretionamounts of 0-24 h, and 0-96 h after administration of125I-C-1027 were 68.36 and 71.64% in urine, and 2.60 and 3.21% in feces of mice, respectively, and the accumulative excretion amount of 0-24 h was 3.57% in bile in rats.CONCLUSION: Our results reflect the characteristics of the tissue distribution, urinary and fecal excretions of 125IC-1027 in mice and the biliary excretion of 125I-C-1027and its metabolites in rats, and indicate that 125I-C-1027and its metabolites are mainly distributed in kidney, and excreted in urine.

  5. Effect of various antidotes on biliary excretion of arsenic in isolated perfused livers of guinea pigs after acute experimental poisoning with As2O3.

    Science.gov (United States)

    Reichl, F X; Mückter, H; Kreppel, H; Forth, W

    1992-05-01

    The effect of the dithiols British Anti-Kewisite (BAL), dimercaptopropanesulfonic acid (DMPS), dimercaptosuccinic acid (DMSA) and a new metal binding agent 2,3-bis-(acetylthio)- propanesulfonamide (BAPSA) on the biliary excretion of arsenic in perfused livers of guinea pigs after acute experimental poisoning with As2O3 was investigated. Guinea pigs received As2O3, 10.0 mg/kg subcutaneously at 9 a.m. as a single injection. One hour after the injection the livers were perfused (2.5 ml x min.-1 x g-1 liver) with Krebs-Henseleit buffer and glucose for 80 min. After 40 min. of saline perfusion (control) 0.1 or 0.7 mmol/l BAL, DMSA, DMPS, or BAPSA were added to the perfusate and arsenic elimination in the bile and effluent perfusate was measured. The biliary excretion of arsenic in control livers between 40 and 80 min. was 0.7% of the total arsenic liver content before perfusion (= arsenic liver content after perfusion + portion excreted in the bile+perfusate). After antidote addition (0.1 mmol/l) the excretion was 0.2% for livers perfused with BAL, 6.8% for DMSA, 10.6% for DMPS, and 11.1% for BAPSA, respectively. After 0.7 mmol/l antidote the excretion of arsenic was 0.1% in livers perfused with BAL, 9.6% for DMSA, 12.3% for DMPS, and 13.3% for BAPSA, respectively. Except BAL, all compounds and most effectively BAPSA increased biliary excretion of arsenic. This indicates that excretion of arsenic which normally is mainly renal is shifted towards faecal excretion by the dithiols.

  6. Impact of physiological levels of chenodeoxycholic acid supplementation on intestinal and hepatic bile acid and cholesterol metabolism in Cyp7a1-deficient mice.

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    Jones, Ryan D; Lopez, Adam M; Tong, Ernest Y; Posey, Kenneth S; Chuang, Jen-Chieh; Repa, Joyce J; Turley, Stephen D

    2015-01-01

    Mice deficient in cholesterol 7α-hydroxylase (Cyp7a1) have a diminished bile acid pool (BAP) and therefore represent a useful model for investigating the metabolic effects of restoring the pool with a specific BA. Previously we carried out such studies in Cyp7a1(-/-) mice fed physiological levels of cholic acid (CA) and achieved BAP restoration, along with an increased CA enrichment, at a dietary level of just 0.03% (w/w). Here we demonstrate that in Cyp7a1(-/-) mice fed chenodeoxycholic acid (CDCA) at a level of 0.06% (w/w), the BAP was restored to normal size and became substantially enriched with muricholic acid (MCA) (>70%), leaving the combined contribution of CA and CDCA to be Cyp7a1 deficiency such as an elevated rate of intestinal sterol synthesis, an enhanced level of mRNA for Cyp8b1 in the liver, and depressed mRNA levels for Ibabp, Shp and Fgf15 in the distal small intestine. When Cyp7a1(-/-) and matching Cyp7a1(+/+) mice were fed a diet with added cholesterol (0.2%) (w/w), either alone, or also containing CDCA (0.06%) (w/w) or CA (0.03%) (w/w) for 18days, the hepatic total cholesterol concentrations (mg/g) in the Cyp7a1(-/-) mice were 26.9±3.7, 16.4±0.9 and 47.6±1.9, respectively, vs. 4.9±0.4, 5.0±0.7 and 6.4±1.9, respectively in the corresponding Cyp7a1(+/+) controls. These data affirm the importance of using moderate levels of dietary BA supplementation to elicit changes in hepatic cholesterol metabolism through shifts in BAP size and composition.

  7. Krill protein hydrolysate reduces plasma triacylglycerol level with concurrent increase in plasma bile acid level and hepatic fatty acid catabolism in high-fat fed mice

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    Marie S. Ramsvik

    2013-11-01

    Full Text Available Background: Krill powder, consisting of both lipids and proteins, has been reported to modulate hepatic lipid catabolism in animals. Fish protein hydrolysate diets have also been reported to affect lipid metabolism and to elevate bile acid (BA level in plasma. BA interacts with a number of nuclear receptors and thus affects a variety of signaling pathways, including very low density lipoprotein (VLDL secretion. The aim of the present study was to investigate whether a krill protein hydrolysate (KPH could affect lipid and BA metabolism in mice. Method: C57BL/6 mice were fed a high-fat (21%, w/w diet containing 20% crude protein (w/w as casein (control group or KPH for 6 weeks. Lipids and fatty acid composition were measured from plasma, enzyme activity and gene expression were analyzed from liver samples, and BA was measured from plasma. Results: The effect of dietary treatment with KPH resulted in reduced levels of plasma triacylglycerols (TAG and non-esterified fatty acids (NEFAs. The KPH treated mice had also a marked increased plasma BA concentration. The increased plasma BA level was associated with induction of genes related to membrane canalicular exporter proteins (Abcc2, Abcb4 and to BA exporters to blood (Abcc3 and Abcc4. Of note, we observed a 2-fold increased nuclear farnesoid X receptor (Fxr mRNA levels in the liver of mice fed KPH. We also observed increased activity of the nuclear peroxiosme proliferator-activated receptor alpha (PPARα target gene carnitine plamitoyltransferase 2 (CPT-2. Conclusion: The KPH diet showed to influence lipid and BA metabolism in high-fat fed mice. Moreover, increased mitochondrial fatty acid oxidation and elevation of BA concentration may regulate the plasma level of TAGs and NEFAs.

  8. Inhibition of intestinal bile acid transporter Slc10a2 improves triglyceride metabolism and normalizes elevated plasma glucose levels in mice.

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    Thomas Lundåsen

    Full Text Available Interruption of the enterohepatic circulation of bile acids increases cholesterol catabolism, thereby stimulating hepatic cholesterol synthesis from acetate. We hypothesized that such treatment should lower the hepatic acetate pool which may alter triglyceride and glucose metabolism. We explored this using mice deficient of the ileal sodium-dependent BA transporter (Slc10a2 and ob/ob mice treated with a specific inhibitor of Slc10a2. Plasma TG levels were reduced in Slc10a2-deficient mice, and when challenged with a sucrose-rich diet, they displayed a reduced response in hepatic TG production as observed from the mRNA levels of several key enzymes in fatty acid synthesis. This effect was paralleled by a diminished induction of mature sterol regulatory element-binding protein 1c (Srebp1c. Unexpectedly, the SR-diet induced intestinal fibroblast growth factor (FGF 15 mRNA and normalized bile acid synthesis in Slc10a2-/- mice. Pharmacologic inhibition of Slc10a2 in diabetic ob/ob mice reduced serum glucose, insulin and TGs, as well as hepatic mRNA levels of Srebp1c and its target genes. These responses are contrary to those reported following treatment of mice with a bile acid binding resin. Moreover, when key metabolic signal transduction pathways in the liver were investigated, those of Mek1/2-Erk1/2 and Akt were blunted after treatment of ob/ob mice with the Slc10a2 inhibitor. It is concluded that abrogation of Slc10a2 reduces hepatic Srebp1c activity and serum TGs, and in the diabetic ob/ob model it also reduces glucose and insulin levels. Hence, targeting of Slc10a2 may be a promising strategy to treat hypertriglyceridemia and diabetes.

  9. Pertussis toxin, an inhibitor of G(αi PCR, inhibits bile acid- and cytokine-induced apoptosis in primary rat hepatocytes.

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    Golnar Karimian

    Full Text Available Excessive hepatocyte apoptosis is a common event in acute and chronic liver diseases leading to loss of functional liver tissue. Approaches to prevent apoptosis have therefore high potential for the treatment of liver disease. G-protein coupled receptors (GPCR play crucial roles in cell fate (proliferation, cell death and act through heterotrimeric G-proteins. G(αiPCRs have been shown to regulate lipoapoptosis in hepatocytes, but their role in inflammation- or bile acid-induced apoptosis is unknown. Here, we analyzed the effect of inhibiting G(αiPCR function, using pertussis toxin (PT, on bile acid- and cytokine-induced apoptosis in hepatocytes. Primary rat hepatocytes, HepG2-rNtcp cells (human hepatocellular carcinoma cells or H-4-II-E cells (rat hepatoma cells were exposed to glycochenodeoxycholic acid (GCDCA or tumor necrosis factor-α (TNFα/actinomycin D (ActD. PT (50-200 nmol/L was added 30 minutes prior to the apoptotic stimulus. Apoptosis (caspase-3 activity, acridine orange staining and necrosis (sytox green staining were assessed. PT significantly reduced GCDCA- and TNFα/ActD-induced apoptosis in rat hepatocytes (-60%, p<0.05 in a dose-dependent manner (with no shift to necrosis, but not in HepG2-rNtcp cells or rat H-4-II-E cells. The protective effect of pertussis toxin was independent of the activation of selected cell survival signal transduction pathways, including ERK, p38 MAPK, PI3K and PKC pathways, as specific protein kinase inhibitors did not reverse the protective effects of pertussis toxin in GCDCA-exposed hepatocytes.Pertussis toxin, an inhibitor of G(αiPCRs, protects hepatocytes, but not hepatocellular carcinoma cells, against bile acid- and cytokine-induced apoptosis and has therapeutic potential as primary hepatoprotective drug, as well as adjuvant in anti-cancer therapy.

  10. Biliary bile acids in birds of the Cotingidae family: taurine-conjugated (24R,25R)-3α,7α,24-trihydroxy-5β-cholestan-27-oic acid and two epimers (25R and 25S) of 3α,7α-dihydroxy-5β-cholestan-27-oic acid.

    Science.gov (United States)

    Hagey, Lee R; Iida, Takashi; Ogawa, Shoujiro; Adachi, Yuuki; Une, Mizuho; Mushiake, Kumiko; Maekawa, Masamitsu; Shimada, Miki; Mano, Nariyasu; Hofmann, Alan F

    2011-01-01

    Three C(27) bile acids were found to be major biliary bile acids in the capuchinbird (Perissocephalus tricolor) and bare-throated bellbird (Procnias nudicollis), both members of the Cotingidae family of the order Passeriformes. The individual bile acids were isolated by preparative RP-HPLC, and their structures were established by RP-HPLC, LC/ESI-MS/MS and NMR as well as by a comparison of their chromatographic properties with those of authentic reference standards of their 12α-hydroxy derivatives. The most abundant bile acid present in the capuchinbird bile was the taurine conjugate of C(27) (24R,25R)-3α,7α,24-trihydroxy-5β-cholestan-27-oic acid, a diastereomer not previously identified as a natural bile acid. The four diastereomers of taurine-conjugated (24ξ,25ξ)-3α,7α,24-trihydroxy-5β-cholestan-27-oic acid could be distinguished by NMR and were resolved by RP-HPLC. The RRT of the diastereomers (with taurocholic acid as 1.0) were found to be increased in the following order: (24R,25R)taurine conjugates) in both bird species. Epimers of the two compounds could be distinguished by their NMR spectra and resolved by RP-HPLC with the (25S)-epimer eluting before the (25R)-epimer. Characterization of the taurine-conjugated (24R,25R)-3α,7α,24-trihydroxy-5β-cholestan-27-oic acid and two epimers (25R and 25S) of 3α,7α-dihydroxy-5β-cholestan-27-oic acid should facilitate their detection in peroxisomal disease and inborn errors of bile acid biosynthesis.

  11. Glucagon and cAMP inhibit cholesterol 7alpha-hydroxylase (CYP7A1) gene expression in human hepatocytes: discordant regulation of bile acid synthesis and gluconeogenesis.

    Science.gov (United States)

    Song, Kwang-Hoon; Chiang, John Y L

    2006-01-01

    The gene encoding cholesterol 7alpha-hydroxylase (CYP7A1) is tightly regulated to control bile acid synthesis and maintain lipid homeostasis. Recent studies in mice suggest that bile acid synthesis is regulated by the fasted-to-fed cycle, and fasting induces CYP7A1 gene expression in parallel to the induction of peroxisome proliferators-activated receptor gamma co-activator 1alpha (PGC-1alpha) and phosphoenolpyruvate carboxykinase (PEPCK). How glucagon regulates CYP7A1 gene expression in the human liver is not clear. Here we show that glucagon and cyclic adenosine monophosphate (cAMP) strongly repressed CYP7A1 mRNA expression in human primary hepatocytes. Reporter assays confirmed that cAMP and protein kinase A (PKA) inhibited human CYP7A1 gene transcription, in contrast to their stimulation of the PEPCK gene. Mutagenesis analysis identified a PKA-responsive region located within the previously identified HNF4alpha binding site in the human CYP7A1 promoter. Glucagon and cAMP increased HNF4alpha phosphorylation and reduced the amount of HNF4alpha present in CYP7A1 chromatin. Our findings suggest that glucagon inhibited CYP7A1 gene expression via PKA phosphorylation of HNF4alpha, which lost its ability to bind the CYP7A1 gene and resulted in inhibition of human CYP7A1 gene transcription. In conclusion, this study unveils a species difference in nutrient regulation of the human and mouse CYP7A1 gene and suggests a discordant regulation of bile acid synthesis and gluconeogenesis by glucagon in human livers during fasting.

  12. Hypocholesterolemia of Rhizoma Coptidis alkaloids is related to the bile acid by up-regulated CYP7A1 in hyperlipidemic rats.

    Science.gov (United States)

    Cao, Yang; Bei, Weijian; Hu, Yinming; Cao, Le; Huang, Lihua; Wang, Laiyou; Luo, Duosheng; Chen, Yuanyuan; Yao, Xi; He, Wei; Liu, Xiaobo; Guo, Jiao

    2012-06-15

    This study is to investigate the cholesterol-lowering effect and the new mode of action of coptis alkaloids on high lipid diet-induced hyperlipidemic rats. Coptis alkaloids extract (CAE) was prepared by alcohol extraction from Rhizoma Coptidis that have been quality-controlled according to the protocol. The cholesterol-lowering effect of CAE was evaluated on SD rats fed with high-lipid diet. Serum level of lipid, Bile acid and cholesterol in the liver and feces of the rats were measured using colorimetric assay kit. RT-PCR and Western blot were used to analyze the mRNA and protein expression of cholesterol metabolism-related genes including cholesterol 7α-hydroxylase (CYP7A1), peroxisome proliferator-activated receptor-alpha (PPARα) and farnesoid X receptor (FXR) in the livers of the rats. A HPLC analysis was used to assess the activity of CYP7A1. The results showed that CAE reduced the levels of serum total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C). CYP7A1 gene expression and its activity was up-regulated dose-dependently accompanying with the increased level of bile acid and the reduced cholesterol level in the livers of the CAE treated hyperlipidemic rats. Meanwhile, the mRNA expression of PPARα was also up-regulated in dose-dependent way accompanying the down-modulation of the FXR mRNA expression in the livers of the CAE treated hyperlipidemic rats. The results indicate that the cholesterol-lowering effect of coptis alkaloid extract is at least partly attributed to its promoting the cholesterol conversion into bile acids by up-regulating the gene expression of CYP7A1 and thus increasing its activity in the liver of the hyperlipidemic rats, which might related to the positive regulation of PPARα and the negative modulation of FXR.

  13. Absorption, distribution, metabolism and excretion of novel phosphodiesterase type 4 inhibitor ASP3258 in rats.

    Science.gov (United States)

    Ohtsu, Yoshiaki; Sonoda, Takuya; Susaki, Yoko; Tohda, Toshifumi; Fukunaga, Yasuhisa; Iwatsubo, Takafumi; Noguchi, Kiyoshi

    2015-01-01

    The potent and selective phosphodiesterase 4 inhibitor ASP3258 is a novel therapeutic agent for asthma and chronic obstructive pulmonary disease (COPD). After a single oral administration to rats, ASP3258 is rapidly absorbed with a bioavailability of 106%. In situ absorption data indicated that ASP3258 is mainly absorbed in the small intestine. Tissue distribution data after oral administration of (14)C-ASP3258 showed rapid and extensive distribution to various tissues. Excluding the gastrointestinal tract, the tissues with the highest concentrations were liver, heart and plasma. Liquid chromatography-nuclear magnetic resonance spectroscopy data revealed that O-glucuronidation of the carboxylic acid moiety of ASP3258 (formation of an acyl glucuronide) plays a key role in metabolism. No indication was found that the acyl glucuronide reacted with proteins in plasma or tissues. When (14)C-ASP3258 was orally administered to intact rats, urinary and fecal excretion accounted for 1.3% and 100.6% of the administered radioactivity, respectively. After a single oral administration of (14)C-ASP3258 to bile-cannulated rats, urinary and biliary excretion accounted for 0.7% and 93.8% of the administered radioactivity, respectively. These findings suggest that fecal excretion via bile plays an important role in the elimination of ASP3258-derived radioactivity. In vitro metabolic profiles were relatively similar among the species examined, suggesting that our findings in rats may help us to understand pharmacokinetics, efficacy and safety profiles in humans and other species.

  14. Field study of the urinary excretion of ethoxyacetic acid during repeated daily exposure to the ethyl ether of ethylene glycol and the ethyl ether of ethylene glycol acetate.

    Science.gov (United States)

    Veulemans, H; Groeseneken, D; Masschelein, R; Van Vlem, E

    1987-06-01

    The urinary excretion of ethoxyacetic acid (EAA) was studied in a group of five women daily exposed to the ethyl ether of ethylene glycol (EGEE) and the ethyl ether of ethylene glycol acetate (EGEE-Ac) during 5 d of normal production and 7 d after a 12-d production stop. The mean combined exposure concentration of EGEE and EGEE-Ac (expressed in equivalent weight of EGEE) was 14.0 mg/m3 with occasional slight excursions above the current Belgian occupational exposure limit. The daily combined exposure profiles for EGEE and EGEE-Ac were rather constant during the first observation period, but they tended to decrease during the last week. The urinary EAA excretion clearly increased during the work week. Over the weekends the elimination was far from complete, and even after a prolonged nonexposure period of 12 d traces of the metabolite were still detectable. Based on the observations from the first period, a good linear correlation (r = 0.92) was found between the average exposure over 5 d (14.4 mg/m3) and the EAA excretion at the end of the week (105.7 mg/g creatinine). An EAA estimate of 150 +/- 35 mg/g was found to correspond with repeated 5-d full-shift exposures to the respective occupational exposure limit of EGEE (19 mg/m3) or EGEE-Ac (27 mg/m3).

  15. Dietary Karaya Saponin and Rhodobacter capsulatus Exert Hypocholesterolemic Effects by Suppression of Hepatic Cholesterol Synthesis and Promotion of Bile Acid Synthesis in Laying Hens

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    Sadia Afrose

    2010-01-01

    Full Text Available This study was conducted to elucidate the mechanism underlying the hypolipidemic action of karaya saponin or Rhodobacter (R. capsulatus. A total of 40 laying hens (20-week-old were assigned into four dietary treatment groups and fed a basal diet (as a control or basal diets supplemented with either karaya saponin, R. capsulatus, or both for 60 days. The level of serum low-density-lipoprotein cholesterol and the levels of cholesterol and triglycerides in the serum, liver, and egg yolk were reduced by all the supplementations (<.05. Liver bile acid concentration and fecal concentrations of cholesterol, triacylglycerol, and bile acid were simultaneously increased by the supplementation of karaya saponin, R. capsulatus, and the combination of karaya saponin and R. capsulatus (<.05. The supplementation of karaya saponin, R. capsulatus, and the combination of karaya saponin and R. capsulatus suppressed the incorporation of 14C from 1-14C-palmitic acid into the fractions of total lipids, phospholipids, triacylglycerol, and cholesterol in the liver in vitro (<.05. These findings suggest that the hypocholesterolemic effects of karaya saponin and R. capsulatus are caused by the suppression of the cholesterol synthesis and the promotion of cholesterol catabolism in the liver.

  16. CLA-enriched diet containing t10,c12-CLA alters bile acid homeostasis and increases the risk of cholelithiasis in mice.

    Science.gov (United States)

    Letona, Amaia Zabala; Niot, Isabelle; Laugerette, Fabienne; Athias, Anne; Monnot, Marie-Claude; Portillo, Maria P; Besnard, Philippe; Poirier, Hélène

    2011-08-01

    Mice fed a mixture of CLA containing t10,c12-CLA lose fat mass and develop hyperinsulinemia and hepatic steatosis due to an accumulation of TG and cholesterol. Because cholesterol is the precursor in bile acid (BA) synthesis, we investigated whether t10,c12-CLA alters BA metabolism. In Expt. 1, female C57Bl/6J mice were fed a standard diet for 28 d supplemented with a CLA mixture (1 g/100 g) or not (controls). In Expt. 2, the feeding period was reduced to 4, 6, and 10 d. In Expt. 3, mice were fed a diet supplemented with linoleic acid, c9,t11-CLA, or t10,c12-CLA (0.4 g/100 g) for 28 d. In Expt. 1, the BA pool size was greater in CLA-fed mice than in controls and the entero-hepatic circulation of BA was altered due to greater BA synthesis and ileal reclamation. This resulted from higher hepatic cholesterol 7α-hydroxylase (CYP7A1) and ileal apical sodium BA transporter expressions in CLA-fed mice. Furthermore, hepatic Na(+)/taurocholate co-transporting polypeptide (NTCP) (-52%) and bile salt export pump (BSEP) (-77%) protein levels were lower in CLA-fed mice than in controls, leading to a greater accumulation of BA in the plasma (+500%); also, the cholesterol saturation index and the concentration of hydrophobic BA in the bile were greater in CLA-fed mice, changes associated with the presence of cholesterol crystals. Expt. 2 suggests that CLA-mediated changes were caused by hyperinsulinemia, which occurred after 6 d of the CLA diet before NTCP and BSEP mRNA downregulation (10 d). Expt. 3 demonstrated that only t10,c12-CLA altered NTCP and BSEP mRNA levels. In conclusion, t10,c12-CLA alters BA homeostasis and increases the risk of cholelithiasis in mice.

  17. Urinary excretion of the acrylonitrile metabolite 2-cyanoethylmercapturic acid is correlated with a variety of biomarkers of tobacco smoke exposure and consumption