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Sample records for hepatic bile acid

  1. 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....

  2. 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....

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

    Science.gov (United States)

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

    2017-08-03

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

  4. Endoplasmic Reticulum Stress Regulates Hepatic Bile Acid Metabolism in MiceSummary

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    Anne S. Henkel

    2017-03-01

    Full Text Available Background & Aims: Cholestasis promotes endoplasmic reticulum (ER stress in the liver, however, the effect of ER stress on hepatic bile acid metabolism is unknown. We aim to determine the effect of ER stress on hepatic bile acid synthesis and transport in mice. Methods: ER stress was induced pharmacologically in C57BL/6J mice and human hepatoma (HepG2 cells. The hepatic expression of genes controlling bile acid synthesis and transport was determined. To measure the activity of the primary bile acid synthetic pathway, the concentration of 7α-hydroxy-4-cholesten-3-1 was measured in plasma. Results: Induction of ER stress in mice and HepG2 cells rapidly suppressed the hepatic expression of the primary bile acid synthetic enzyme, cholesterol 7α-hydroxylase. Plasma levels of 7α-hydroxy-4-cholesten-3-1 were reduced in mice subjected to ER stress, indicating impaired bile acid synthesis. Induction of ER stress in mice and HepG2 cells increased expression of the bile salt export pump (adenosine triphosphate binding cassette [Abc]b11 and a bile salt efflux pump (Abcc3. The observed regulation of Cyp7a1, Abcb11, and Abcc3 occurred in the absence of hepatic inflammatory cytokine activation and was not dependent on activation of hepatic small heterodimer partner or intestinal fibroblast growth factor 15. Consistent with suppressed bile acid synthesis and enhanced bile acid export from hepatocytes, prolonged ER stress decreased the hepatic bile acid content in mice. Conclusions: Induction of ER stress in mice suppresses bile acid synthesis and enhances bile acid removal from hepatocytes independently of established bile acid regulatory pathways. These data show a novel function of the ER stress response in regulating bile acid metabolism. Keywords: Unfolded Protein Response, Cyp7a1, 7α-Hydroxy-4-Cholesten-3-1, Bile Acid Synthesis

  5. Dysregulated hepatic bile acids collaboratively promote liver carcinogenesis.

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    Xie, Guoxiang; Wang, Xiaoning; Huang, Fengjie; Zhao, Aihua; Chen, Wenlian; Yan, Jingyu; Zhang, Yunjing; Lei, Sha; Ge, Kun; Zheng, Xiaojiao; Liu, Jiajian; Su, Mingming; Liu, Ping; Jia, Wei

    2016-10-15

    Dysregulated bile acids (BAs) are closely associated with liver diseases and attributed to altered gut microbiota. Here, we show that the intrahepatic retention of hydrophobic BAs including deoxycholate (DCA), taurocholate (TCA), taurochenodeoxycholate (TCDCA), and taurolithocholate (TLCA) were substantially increased in a streptozotocin and high fat diet (HFD) induced nonalcoholic steatohepatitis-hepatocellular carcinoma (NASH-HCC) mouse model. Additionally chronic HFD-fed mice spontaneously developed liver tumors with significantly increased hepatic BA levels. Enhancing intestinal excretion of hydrophobic BAs in the NASH-HCC model mice by a 2% cholestyramine feeding significantly prevented HCC development. The gut microbiota alterations were closely correlated with altered BA levels in liver and feces. HFD-induced inflammation inhibited key BA transporters, resulting in sustained increases in intrahepatic BA concentrations. Our study also showed a significantly increased cell proliferation in BA treated normal human hepatic cell lines and a down-regulated expression of tumor suppressor gene CEBPα in TCDCA treated HepG2 cell line, suggesting that several hydrophobic BAs may collaboratively promote liver carcinogenesis. © 2016 UICC.

  6. Effects of feeding bile acids and a bile acid sequestrant on hepatic bile acid composition in mice[S

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    Zhang, Youcai; Klaassen, Curtis D.

    2010-01-01

    An improved ultra performance liquid chromatography-tandem mass spectrometry (UPLC/MS/MS) method was established for the simultaneous analysis of various bile acids (BA) and applied to investigate liver BA content in C57BL/6 mice fed 1% cholic acid (CA), 0.3% deoxycholic acid (DCA), 0.3% chenodeoxycholic acid (CDCA), 0.3% lithocholic acid (LCA), 3% ursodeoxycholic acid (UDCA), or 2% cholestyramine (resin). Results indicate that mice have a remarkable ability to maintain liver BA concentrations. The BA profiles in mouse livers were similar between CA and DCA feedings, as well as between CDCA and LCA feedings. The mRNA expression of Cytochrome P450 7a1 (Cyp7a1) was suppressed by all BA feedings, whereas Cyp7b1 was suppressed only by CA and UDCA feedings. Gender differences in liver BA composition were observed after feeding CA, DCA, CDCA, and LCA, but they were not prominent after feeding UDCA. Sulfation of CA and CDCA was found at the 7-OH position, and it was increased by feeding CA or CDCA more in male than female mice. In contrast, sulfation of LCA and taurolithocholic acid (TLCA) was female-predominant, and it was increased by feeding UDCA and LCA. In summary, the present systematic study on BA metabolism in mice will aid in interpreting BA-mediated gene regulation and hepatotoxicity. PMID:20671298

  7. Effects of feeding bile acids and a bile acid sequestrant on hepatic bile acid composition in mice.

    Science.gov (United States)

    Zhang, Youcai; Klaassen, Curtis D

    2010-11-01

    An improved ultra performance liquid chromatography-tandem mass spectrometry (UPLC/MS/MS) method was established for the simultaneous analysis of various bile acids (BA) and applied to investigate liver BA content in C57BL/6 mice fed 1% cholic acid (CA), 0.3% deoxycholic acid (DCA), 0.3% chenodeoxycholic acid (CDCA), 0.3% lithocholic acid (LCA), 3% ursodeoxycholic acid (UDCA), or 2% cholestyramine (resin). Results indicate that mice have a remarkable ability to maintain liver BA concentrations. The BA profiles in mouse livers were similar between CA and DCA feedings, as well as between CDCA and LCA feedings. The mRNA expression of Cytochrome P450 7a1 (Cyp7a1) was suppressed by all BA feedings, whereas Cyp7b1 was suppressed only by CA and UDCA feedings. Gender differences in liver BA composition were observed after feeding CA, DCA, CDCA, and LCA, but they were not prominent after feeding UDCA. Sulfation of CA and CDCA was found at the 7-OH position, and it was increased by feeding CA or CDCA more in male than female mice. In contrast, sulfation of LCA and taurolithocholic acid (TLCA) was female-predominant, and it was increased by feeding UDCA and LCA. In summary, the present systematic study on BA metabolism in mice will aid in interpreting BA-mediated gene regulation and hepatotoxicity.

  8. The inheritance of extra-hepatic portosystemic shunts and elevated bile acid concentrations in Maltese dogs.

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    O'Leary, C A; Parslow, A; Malik, R; Hunt, G B; Hurford, R I; Tisdall, P L C; Duffy, D L

    2014-01-01

    To determine the heritability of extra-hepatic portosystemic shunts and elevated post-prandial serum bile acid concentrations in Maltese dogs. Maltese dogs were recruited and investigated by a variable combination of procedures including dynamic bile acid testing, rectal ammonia tolerance testing, ultrasonography, portal venography, surgical inspection or necropsy. In addition, nine test matings were carried out between affected and affected dogs, and affected and unaffected dogs. In 135 variably related Maltese, shunt status could be confirmed in 113, including 19 with an extra-hepatic portosystemic shunt (17 confirmed at surgery, 2 at necropsy). Rectal ammonia tolerance testing results and post-prandial serum bile acid concentrations were retrievable for 50 and 88 dogs, respectively. Pedigree information was available for these 135 and an additional 164 related dogs. Two consecutive test matings were carried out between two affected animals (whose shunts had been attenuated), with 2 of 8 (25%) of offspring having an extra-hepatic portosystemic shunt. Six test matings were carried out between an affected and an unaffected animal, with 2 of 22 (9%) offspring affected. Heritability of extra-hepatic portosystemic shunt was 0·61 calculated using variance components analysis [95% confidence interval (CI) 0·14 to 1·0, P=0·001]. The best fitting model from segregation analysis was a common, partially penetrant, recessive model (allele frequency 0·34, penetrance 0·99, CI 0·09 to 1·0). The heritability of elevated post-prandial serum bile acid (and thus likely portal vein hypoplasia) was 0·81 (CI 0·43 to 1·0, P=0·2) after logarithmic transformation of post-prandial serum bile acid concentrations. There is strong support for extra-hepatic portosystemic shunts and elevated post-prandial serum bile acid concentrations both being inherited conditions in Maltese. © 2013 British Small Animal Veterinary Association.

  9. 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.

  10. History of Hepatic Bile Formation: Old Problems, New Approaches

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    Javitt, Norman B.

    2014-01-01

    Studies of hepatic bile formation reported in 1958 established that it was an osmotically generated water flow. Intravenous infusion of sodium taurocholate established a high correlation between hepatic bile flow and bile acid excretion. Secretin, a hormone that stimulates bicarbonate secretion, was also found to increase hepatic bile flow. The…

  11. Bile acids and sphingosine-1-phosphate receptor 2 in hepatic lipid metabolism

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    Eric Kwong

    2015-03-01

    Full Text Available The liver is the central organ involved in lipid metabolism. Dyslipidemia and its related disorders, including non-alcoholic fatty liver disease (NAFLD, obesity and other metabolic diseases, are of increasing public health concern due to their increasing prevalence in the population. Besides their well-characterized functions in cholesterol homoeostasis and nutrient absorption, bile acids are also important metabolic regulators and function as signaling hormones by activating specific nuclear receptors, G-protein coupled receptors, and multiple signaling pathways. Recent studies identified a new signaling pathway by which conjugated bile acids (CBA activate the extracellular regulated protein kinases (ERK1/2 and protein kinase B (AKT signaling pathway via sphingosine-1-phosphate receptor 2 (S1PR2. CBA-induced activation of S1PR2 is a key regulator of sphingosine kinase 2 (SphK2 and hepatic gene expression. This review focuses on recent findings related to the role of bile acids/S1PR2-mediated signaling pathways in regulating hepatic lipid metabolism.

  12. Bile acids and sphingosine-1-phosphate receptor 2 in hepatic lipid metabolism.

    Science.gov (United States)

    Kwong, Eric; Li, Yunzhou; Hylemon, Phillip B; Zhou, Huiping

    2015-03-01

    The liver is the central organ involved in lipid metabolism. Dyslipidemia and its related disorders, including non-alcoholic fatty liver disease (NAFLD), obesity and other metabolic diseases, are of increasing public health concern due to their increasing prevalence in the population. Besides their well-characterized functions in cholesterol homoeostasis and nutrient absorption, bile acids are also important metabolic regulators and function as signaling hormones by activating specific nuclear receptors, G-protein coupled receptors, and multiple signaling pathways. Recent studies identified a new signaling pathway by which conjugated bile acids (CBA) activate the extracellular regulated protein kinases (ERK1/2) and protein kinase B (AKT) signaling pathway via sphingosine-1-phosphate receptor 2 (S1PR2). CBA-induced activation of S1PR2 is a key regulator of sphingosine kinase 2 (SphK2) and hepatic gene expression. This review focuses on recent findings related to the role of bile acids/S1PR2-mediated signaling pathways in regulating hepatic lipid metabolism.

  13. Impaired uptake of conjugated bile acids and hepatitis b virus pres1-binding in na(+) -taurocholate cotransporting polypeptide knockout mice

    NARCIS (Netherlands)

    Slijepcevic, Davor; Kaufman, Christina; Wichers, Catharina G. K.; Gilglioni, Eduardo H.; Lempp, Florian A.; Duijst, Suzanne; de Waart, Dirk R.; Elferink, Ronald P. J. Oude; Mier, Walter; Stieger, Bruno; Beuers, Ulrich; Urban, Stephan; van de Graaf, Stan F. J.

    2015-01-01

    The Na(+) -taurocholate cotransporting polypeptide (NTCP) mediates uptake of conjugated bile acids (BAs) and is localized at the basolateral membrane of hepatocytes. It has recently been recognized as the receptor mediating hepatocyte-specific entry of hepatitis B virus and hepatitis delta virus.

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

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    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.

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

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    Lawlor, Megan L; Critchfield, Agatha S

    2016-01-01

    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.

  16. Sensitivity and Specificity of Plasma ALT, ALP, and Bile Acids for Hepatitis in Labrador Retrievers.

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    Dirksen, K; Burgener, I A; Rothuizen, J; van den Ingh, T S G A M; Penning, L C; Spee, B; Fieten, H

    2017-07-01

    Biochemical indicators for diagnosing liver disease are plasma alanine aminotransferase activity (ALT), alkaline phosphatase activity (ALP), and bile acid concentration (BA). To determine the sensitivity and specificity of ALT, ALP, and BA for detecting primary hepatitis (PH) in clinically healthy Labrador retrievers and investigate whether ALT and ALP can discriminate between dogs with PH and nonspecific reactive hepatitis (RH). 191 clinically healthy and 51 clinically ill Labrador retrievers with hepatic histopathology. Retrospective study. Medical records were reviewed for ALT, ALP, preprandial BA, liver histopathology, and hepatic copper concentrations. In 64% (122/191) of the clinically healthy Labrador retrievers, hepatic histology revealed inflammatory infiltrates. This frequency might be biased because part of them was included as first-line relatives of dogs with copper-associated hepatitis. Sensitivity of ALT, ALP, and BA in this population for detecting acute hepatitis was 45, 15, and 15%, respectively. For chronic hepatitis, sensitivity was 71, 35, and 13%, respectively. Specificity of ALT, ALP, and BA was >90% for AH, CH, and RH. When increased liver enzymes were present, median ALT was significantly higher in PH cases (312 U/L, range 38-1,369) compared to RH cases (91 U/L, range 39-139) (P dogs with a PH and a RH (P = .361). Histopathologic abnormalities in the liver were present in the majority of apparent clinically healthy Labrador retrievers. The sensitivity of ALT, ALP, and BA for detecting acute and chronic hepatitis in this population was low. More sensitive biomarkers are needed for early detection of liver disease in apparent clinically healthy dogs. Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

  17. Hepatic Uptake of Conjugated Bile Acids Is Mediated by Both Sodium Taurocholate Cotransporting Polypeptide and Organic Anion Transporting Polypeptides and Modulated by Intestinal Sensing of Plasma Bile Acid Levels in Mice

    NARCIS (Netherlands)

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

    2017-01-01

    The Na1-taurocholate cotransporting polypeptide (NTCP/ SLC10A1) is believed to be pivotal for hepatic uptake of conjugated bile acids. However, plasma bile acid levels are normal in a subset of NTCP knockout mice and in mice treated with myrcludex B, a specific NTCP inhibitor. Here, we elucidated

  18. Risk Factors for Development of Cholestatic Drug-Induced Liver Injury: Inhibition of Hepatic Basolateral Bile Acid Transporters Multidrug Resistance-Associated Proteins 3 and 4

    OpenAIRE

    Köck, Kathleen; Ferslew, Brian C.; Netterberg, Ida; Yang, Kyunghee; Urban, Thomas J.; Swaan, Peter W.; Stewart, Paul W.; Brouwer, Kim L. R.

    2014-01-01

    Impaired hepatic bile acid export may contribute to development of cholestatic drug-induced liver injury (DILI). The multidrug resistance-associated proteins (MRP) 3 and 4 are postulated to be compensatory hepatic basolateral bile acid efflux transporters when biliary excretion by the bile salt export pump (BSEP) is impaired. BSEP inhibition is a risk factor for cholestatic DILI. This study aimed to characterize the relationship between MRP3, MRP4, and BSEP inhibition and cholestatic potentia...

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

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

    2017-11-01

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

  20. [Phylogenetic vision of bile acids].

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    Reyes, H

    1994-08-01

    Bile acids are the most important solutes of bile: they are essential in cholesterol degradation, solubilization and excretion; they are determinants of bile flow and secretion; and their role is crucial in the intestinal absorption of lipids and lipid soluble vitamins. In amphibia and in cartilaginous fish, the 27C cholestane molecule is hydroxylated to alcohols. In birds, the terminal 27C-OH group is oxydated to cholestanoic acids. In vertebrates of a more recent evolutionary origin, the lateral chain is shortened to 24C and oxydated to cholestanoic acids. Further transformations include chemical changes in the cholestane skeleton and in the lateral chain (hydroxylations, dehydroxylations, epimerization, etc). In the intestinal lumen, the saprophytic flora provides enzymes catalysing new changes that originate "secondary" bile acids. During entero-hepatic circulation, another variety of bile acids appear, commonly termed "tertiary" bile acids. A recent study of Lee R Hagey characterized bile acid composition of over 600 species of vertebrates, showing that bile acid composition of bile has been the subject of an interesting evolutionary phenomenon and that it is a chemical marker of biodiversity in vertebrates.

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

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    Matthew McMillin

    2017-07-01

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

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

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    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.

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

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    Martin Perreault

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

  4. Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study.

    Science.gov (United States)

    Beysen, C; Murphy, E J; Deines, K; Chan, M; Tsang, E; Glass, A; Turner, S M; Protasio, J; Riiff, T; Hellerstein, M K

    2012-02-01

    The primary aim of this completed multicentre randomised, parallel, double-blind placebo-controlled study was to elucidate the mechanisms of glucose-lowering with colesevelam and secondarily to investigate its effects on lipid metabolism (hepatic de novo lipogenesis, cholesterol and bile acid synthesis). Participants with type 2 diabetes (HbA(1c) 6.7-10.0% [50-86 mmol/mol], fasting glucose 1.55 mmol/l) treated with diet and exercise, sulfonylurea, metformin or a combination thereof, were randomised by a central coordinator to either 3.75 g/day colesevelam (n = 30) or placebo (n = 30) for 12 weeks at three clinical sites in the USA. The primary measure was the change from baseline in glucose kinetics with colesevelam compared to placebo treatment. Fasting and postprandial glucose, lipid and bile acid pathways were measured at baseline and post-treatment using stable isotope techniques. Plasma glucose, insulin, total glucagon-like peptide-1 (GLP-1), total glucose-dependent insulinotropic polypeptide (GIP), glucagon and fibroblast growth factor-19 (FGF-19) concentrations were measured during the fasting state and following a meal tolerance test. Data was collected by people blinded to treatment. Compared with placebo, colesevelam improved HbA(1c) (mean change from baseline of 0.3 [SD 1.1]% for placebo [n = 28] and -0.3 [1.1]% for colesevelam [n = 26]), glucose concentrations, fasting plasma glucose clearance and glycolytic disposal of oral glucose. Colesevelam did not affect gluconeogenesis or appearance rate (absorption) of oral glucose. Fasting endogenous glucose production and glycogenolysis significantly increased with placebo but were unchanged with colesevelam (treatment effect did not reach statistical significance). Compared with placebo, colesevelam increased total GLP-1 and GIP concentrations and improved HOMA-beta cell function while insulin, glucagon and HOMA-insulin resistance were unchanged. Colesevelam increased cholesterol and bile acid synthesis and

  5. Acute caloric restriction counteracts hepatic bile acid and cholesterol deficiency in morbid obesity.

    Science.gov (United States)

    Straniero, S; Rosqvist, F; Edholm, D; Ahlström, H; Kullberg, J; Sundbom, M; Risérus, U; Rudling, M

    2017-05-01

    Bile acid (BA) synthesis is regulated by BA signalling in the liver and by fibroblast growth factor 19 (FGF19), synthesized and released from the intestine. In morbid obesity, faecal excretion and hepatic synthesis of BAs and cholesterol are strongly induced and caloric restriction reduces their faecal excretion considerably. We hypothesized that the high intestinal food mass in morbidly obese subjects promotes faecal excretion of BAs and cholesterol, thereby creating a shortage of both BAs and cholesterol in the liver. Ten morbidly obese women (BMI 42 ± 2.6 kg m-2 ) were monitored on days 0, 3, 7, 14 and 28 after beginning a low-calorie diet (800-1100 kcal day-1 ). Serum was collected and liver size and fat content determined. Synthesis of BAs and cholesterol was evaluated from serum markers, and the serum levels of lipoproteins, BAs, proprotein convertase subtilisin/kexin type 9 (PCSK9), insulin, glucose and FGF19 were monitored. Fifty-four nonobese women (BMI cholesterol and serum levels of BAs and PCSK9 were elevated in the obese group compared to controls. Already after 3 days on a low-calorie diet, BA and cholesterol synthesis and serum BA and PCSK9 levels normalized, whereas LDL cholesterol increased. FGF19 and triglyceride levels were unchanged, and liver volume was reduced by 10%. The results suggest that hepatic BAs and cholesterol are deficient in morbid obesity. Caloric restriction rapidly counteracts these deficiencies, normalizing BA and cholesterol synthesis and circulating PCSK9 levels, indicating that overproduction of cholesterol in enlarged peripheral tissues cannot explain this phenotype. We propose that excessive food intake promotes faecal loss of BAs and cholesterol contributing to their hepatic deficiencies. © 2017 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.

  6. Analysis of Bile Acids

    Science.gov (United States)

    Sjövall, Jan; Griffiths, William J.; Setchell, Kenneth D. R.; Mano, Nariyasu; Goto, Junichi

    Bile acids constitute a large family of steroids in vertebrates, normally formed from cholesterol and carrying a carboxyl group in a side-chain of variable length. Bile alcohols, also formed from cholesterol, have similar structures as bile acids, except for the absence of a carboxyl group in the steroid skeleton. The conversion of cholesterol to bile acids and/or bile alcohols is of major importance for maintenance of cholesterol homeostasis, both from quantitative and regulatory points of view (Chiang, 2004; Kalaany and Mangelsdorf, 2006; Moore, Kato, Xie, et al., 2006; Scotti, Gilardi, Godio, et al., 2007). Appropriately conjugated bile acids and bile alcohols (also referred to as bile salts) are secreted in bile and serve vital functions in the absorption of lipids and lipid-soluble compounds (Hofmann, 2007). Reliable analytical methods are required for studies of the functions and pathophysiological importance of the variety of bile acids and bile alcohols present in living organisms. When combined with genetic and proteomic studies, analysis of these small molecules (in today's terminology: metabolomics, steroidomics, sterolomics, cholanoidomics, etc.) will lead to a deeper understanding of the integrated metabolic processes in lipid metabolism.

  7. [Importance of bile acids for intra-hepatic cholestasis of pregnancy].

    Science.gov (United States)

    Favre, N; Bourdel, N; Sapin, V; Abergel, A; Gallot, D

    2010-04-01

    Intrahepatic cholestasis during pregnancy is a risk factor for prematurity, respiratory distress, fetal death in utero and exposure to meconium stained liquor. Treatment is based on ursodeoxycholic acid, which allows the pregnancy to continue until term. There is no consensus for labor induction criteria or for extraction of the fetus. We report a series of 10 patients who presented cholestasis during pregnancy and for whom we monitored the bile acid levels. These assays provided the means of confirming the diagnosis in patients suffering from pruritus. The threshold of 40 micromoles/L could be a way of defining a group at risk of complications. Proper management for monitoring this pathology has not yet been properly established, but assay of the bile acids is an important element. Copyright 2010. Published by Elsevier SAS.

  8. 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...... 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...

  9. Effect of side-chain shortening on the physiologic properties of bile acids: hepatic transport and effect on biliary secretion of 23-nor-ursodeoxycholate in rodents.

    Science.gov (United States)

    Yoon, Y B; Hagey, L R; Hofmann, A F; Gurantz, D; Michelotti, E L; Steinbach, J H

    1986-04-01

    To define whether side-chain length influences the physiologic properties of bile acids, nor-ursodeoxycholate (nor-UDC), the C23-nor derivative of ursodeoxycholate (UDC), was synthesized in both nonradioactive and radioactive forms (23-14C). Its hepatic translocation, hepatic biotransformation, and effect on bile flow, biliary bicarbonate, and biliary lipid secretion were compared with that of UDC and those of their respective glycine and taurine conjugates in anesthetized biliary fistula hamsters, rats, and guinea pigs, as well as the isolated perfused hamster liver. Hepatic uptake and biliary output of nor-UDC was slower than that of UDC or cholyltaurine in the isolated perfused hamster liver. In biliary fistula animals, nor-UDC was secreted only in bile. Biliary recovery of nor-UDC as compared to that of UDC was prolonged in the rat and hamster, although not in the guinea pig. Hepatic biotransformation, assessed by chromatography of bile, showed that conjugation of nor-UDC was inefficient, as unconjugated nor-UDC was present in bile; there was little amidation with glycine or taurine in any species, but sulfates and glucuronides, as well as other metabolites, were formed, with the pattern of biotransformation varying among species. When infused over a dosage range of 0.2-30 mumol/kg X min, nor-UDC induced a striking choleresis of canalicular origin. The bile acid-dependent flow was increased threefold in hamsters, ninefold in rats, and nearly twofold in guinea pigs when compared to that induced by UDC. The choleresis was associated with a linear increase in bicarbonate output and concentration in bile, and little phospholipid or cholesterol secretion was induced. A competition experiment in the bile fistula hamster indicated that nor-UDC or its metabolites, or both, appeared to compete for canalicular transport of ursocholyltaurine (a cholyltaurine epimer) when the latter was secreted under its Vmax conditions. Conjugates of nor-UDC and UDC were promptly and

  10. Inhibition of Human Hepatic Bile Acid Transporters by Tolvaptan and Metabolites: Contributing Factors to Drug-Induced Liver Injury?

    Science.gov (United States)

    Slizgi, Jason R; Lu, Yang; Brouwer, Kenneth R; St Claire, Robert L; Freeman, Kimberly M; Pan, Maxwell; Brock, William J; Brouwer, Kim L R

    2016-01-01

    Tolvaptan is a vasopressin V(2)-receptor antagonist that has shown promise in treating Autosomal Dominant Polycystic Kidney Disease (ADPKD). Tolvaptan was, however, associated with liver injury in some ADPKD patients. Inhibition of bile acid transporters may be contributing factors to drug-induced liver injury. In this study, the ability of tolvaptan and two metabolites, DM-4103 and DM-4107, to inhibit human hepatic transporters (NTCP, BSEP, MRP2, MRP3, and MRP4) and bile acid transport in sandwich-cultured human hepatocytes (SCHH) was explored. IC(50) values were determined for tolvaptan, DM-4103 and DM-4107 inhibition of NTCP (∼41.5, 16.3, and 95.6 μM, respectively), BSEP (31.6, 4.15, and 119 μM, respectively), MRP2 (>50, ∼51.0, and >200 μM, respectively), MRP3 (>50, ∼44.6, and 61.2 μM, respectively), and MRP4 (>50, 4.26, and 37.9 μM, respectively). At the therapeutic dose of tolvaptan (90 mg), DM-4103 exhibited a C(max)/IC(50) value >0.1 for NTCP, BSEP, MRP2, MRP3, and MRP4. Tolvaptan accumulation in SCHH was extensive and not sodium-dependent; intracellular concentrations were ∼500 μM after a 10-min incubation duration with tolvaptan (15 μM). The biliary clearance of taurocholic acid (TCA) decreased by 43% when SCHH were co-incubated with tolvaptan (15 μM) and TCA (2.5 μM). When tolvaptan (15 μM) was co-incubated with 2.5 μM of chenodeoxycholic acid, taurochenodeoxycholic acid, or glycochenodeoxycholic acid in separate studies, the cellular accumulation of these bile acids increased by 1.30-, 1.68-, and 2.16-fold, respectively. Based on these data, inhibition of hepatic bile acid transport may be one of the biological mechanisms underlying tolvaptan-associated liver injury in patients with ADPKD. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  11. Bile Acid Physiology.

    Science.gov (United States)

    Di Ciaula, Agostino; Garruti, Gabriella; Baccetto, Raquel Lunardi; Molina-Molina, Emilio; Bonfrate, Leonilde; Wang, David Q-H; Portincasa, Piero

    2017-10-28

    The primary bile acids (BAs) are synthetized from colesterol in the liver, conjugated to glycine or taurine to increase their solubility, secreted into bile, concentrated in the gallbladder during fasting, and expelled in the intestine in response to dietary fat, as well as bio-transformed in the colon to the secondary BAs by the gut microbiota, reabsorbed in the ileum and colon back to the liver, and minimally lost in the feces. BAs in the intestine not only regulate the digestion and absorption of cholesterol, triglycerides, and fat-soluble vitamins, but also play a key role as signaling molecules in modulating epithelial cell proliferation, gene expression, and lipid and glucose metabolism by activating farnesoid X receptor (FXR) and G-protein-coupled bile acid receptor-1 (GPBAR-1, also known as TGR5) in the liver, intestine, muscle and brown adipose tissue. Recent studies have revealed the metabolic pathways of FXR and GPBAR-1 involved in the biosynthesis and enterohepatic circulation of BAs and their functions as signaling molecules on lipid and glucose metabolism.

  12. Bile acids in health and disease

    DEFF Research Database (Denmark)

    Krag, E; Thaysen, E H

    1996-01-01

    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...... 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...

  13. Farnesoid X receptor induces Takeda G-protein receptor 5 cross-talk to regulate bile acid synthesis and hepatic metabolism.

    Science.gov (United States)

    Pathak, Preeti; Liu, Hailiang; Boehme, Shannon; Xie, Cen; Krausz, Kristopher W; Gonzalez, Frank; Chiang, John Y L

    2017-06-30

    The bile acid-activated receptors, nuclear farnesoid X receptor (FXR) and the membrane Takeda G-protein receptor 5 (TGR5), are known to improve glucose and insulin sensitivity in obese and diabetic mice. However, the metabolic roles of these two receptors and the underlying mechanisms are incompletely understood. Here, we studied the effects of the dual FXR and TGR5 agonist INT-767 on hepatic bile acid synthesis and intestinal secretion of glucagon-like peptide-1 (GLP-1) in wild-type, Fxr-/-, and Tgr5-/- mice. INT-767 efficaciously stimulated intracellular Ca2+ levels, cAMP activity, and GLP-1 secretion and improved glucose and lipid metabolism more than did the FXR-selective obeticholic acid and TGR5-selective INT-777 agonists. Interestingly, INT-767 reduced expression of the genes in the classic bile acid synthesis pathway but induced those in the alternative pathway, which is consistent with decreased taurocholic acid and increased tauromuricholic acids in bile. Furthermore, FXR activation induced expression of FXR target genes, including fibroblast growth factor 15, and unexpectedly Tgr5 and prohormone convertase 1/3 gene expression in the ileum. We identified an FXR-responsive element on the Tgr5 gene promoter. Fxr-/- and Tgr5-/- mice exhibited reduced GLP-1 secretion, which was stimulated by INT-767 in the Tgr5-/- mice but not in the Fxr-/- mice. Our findings uncovered a novel mechanism in which INT-767 activation of FXR induces Tgr5 gene expression and increases Ca2+ levels and cAMP activity to stimulate GLP-1 secretion and improve hepatic glucose and lipid metabolism in high-fat diet-induced obese mice. Activation of both FXR and TGR5 may therefore represent an effective therapy for managing hepatic steatosis, obesity, and diabetes. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  14. Binding of hepatitis B virus to its cellular receptor alters the expression profile of genes of bile acid metabolism.

    Science.gov (United States)

    Oehler, Nicola; Volz, Tassilo; Bhadra, Oliver D; Kah, Janine; Allweiss, Lena; Giersch, Katja; Bierwolf, Jeanette; Riecken, Kristoffer; Pollok, Jörg M; Lohse, Ansgar W; Fehse, Boris; Petersen, Joerg; Urban, Stephan; Lütgehetmann, Marc; Heeren, Joerg; Dandri, Maura

    2014-11-01

    Chronic hepatitis B virus (HBV) infection has been associated with alterations in lipid metabolism. Moreover, the Na+-taurocholate cotransporting polypeptide (NTCP), responsible for bile acid (BA) uptake into hepatocytes, was identified as the functional cellular receptor mediating HBV entry. The aim of the study was to determine whether HBV alters the liver metabolic profile by employing HBV-infected and uninfected human liver chimeric mice. Humanized urokinase plasminogen activator/severe combined immunodeficiency mice were used to establish chronic HBV infection. Gene expression profiles were determined by real-time polymerase chain reaction using primers specifically recognizing transcripts of either human or murine origin. Liver biopsy samples obtained from HBV-chronic individuals were used to validate changes determined in mice. Besides modest changes in lipid metabolism, HBV-infected mice displayed a significant enhancement of human cholesterol 7α-hydroxylase (human [h]CYP7A1; median 12-fold induction; Pmetabolic alterations. Binding of HBV to NTCP limits its function, thus promoting compensatory BA synthesis and cholesterol provision. The intimate link determined between HBV and liver metabolism underlines the importance to exploit further metabolic pathways, as well as possible NTCP-related viral-drug interactions. © 2014 by the American Association for the Study of Liver Diseases.

  15. Inhibition of hepatic cytochrome P450 enzymes and sodium/bile acid cotransporter exacerbates leflunomide-induced hepatotoxicity

    Science.gov (United States)

    Ma, Lei-lei; Wu, Zhi-tao; Wang, Le; Zhang, Xue-feng; Wang, Jing; Chen, Chen; Ni, Xuan; Lin, Yun-fei; Cao, Yi-yi; Luan, Yang; Pan, Guo-yu

    2016-01-01

    Aim: Leflunomide is an immunosuppressive agent marketed as a disease-modifying antirheumatic drug. But it causes severe side effects, including fatal hepatitis and liver failure. In this study we investigated the contributions of hepatic metabolism and transport of leflunomide and its major metabolite teriflunomide to leflunomide induced hepatotoxicity in vitro and in vivo. Methods: The metabolism and toxicity of leflunomide and teriflunomide were evaluated in primary rat hepatocytes in vitro. Hepatic cytochrome P450 reductase null (HRN) mice were used to examine the PK profiling and hepatotoxicity of leflunomide in vivo. The expression and function of sodium/bile acid cotransporter (NTCP) were assessed in rat and human hepatocytes and NTCP-transfected HEK293 cells. After Male Sprague-Dawley (SD) rats were administered teriflunomide (1,6, 12 mg·kg−1·d−1, ig) for 4 weeks, their blood samples were analyzed. Results: A nonspecific CYPs inhibitor aminobenzotriazole (ABT, 1 mmol/L) decreased the IC50 value of leflunomide in rat hepatocytes from 409 to 216 μmol/L, whereas another nonspecific CYPs inhibitor proadifen (SKF, 30 μmol/L) increased the cellular accumulation of leflunomide to 3.68-fold at 4 h. After oral dosing (15 mg/kg), the plasma exposure (AUC0-t) of leflunomide increased to 3-fold in HRN mice compared with wild type mice. Administration of leflunomide (25 mg·kg−1·d−1) for 7 d significantly increased serum ALT and AST levels in HRN mice; when the dose was increased to 50 mg·kg−1·d−1, all HRN mice died on d 6. Teriflunomide significantly decreased the expression of NTCP in human hepatocytes, as well as the function of NTCP in rat hepatocytes and NTCP-transfected HEK293 cells. Four-week administration of teriflunomide significantly increased serum total bilirubin and direct bilirubin levels in female rats, but not in male rats. Conclusion: Hepatic CYPs play a critical role in detoxification process of leflunomide, whereas the major

  16. 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

  17. Overexpression of cholesterol 7α‐hydroxylase promotes hepatic bile acid synthesis and secretion and maintains cholesterol homeostasis

    National Research Council Canada - National Science Library

    Li, Tiangang; Matozel, Michelle; Boehme, Shannon; Kong, Bo; Nilsson, Lisa‐Mari; Guo, Grace; Ellis, Ewa; Chiang, John Y. L

    2011-01-01

    ...–induced hypercholesterolemia, obesity, and insulin resistance. Here, we investigated the underlying mechanism of bile acid signaling in maintaining cholesterol homeostasis in Cyp7a1‐tg mice. Cyp7a1‐tg mice had two...

  18. 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 ...

  19. Risk factors for development of cholestatic drug-induced liver injury: inhibition of hepatic basolateral bile acid transporters multidrug resistance-associated proteins 3 and 4.

    Science.gov (United States)

    Köck, Kathleen; Ferslew, Brian C; Netterberg, Ida; Yang, Kyunghee; Urban, Thomas J; Swaan, Peter W; Stewart, Paul W; Brouwer, Kim L R

    2014-04-01

    Impaired hepatic bile acid export may contribute to development of cholestatic drug-induced liver injury (DILI). The multidrug resistance-associated proteins (MRP) 3 and 4 are postulated to be compensatory hepatic basolateral bile acid efflux transporters when biliary excretion by the bile salt export pump (BSEP) is impaired. BSEP inhibition is a risk factor for cholestatic DILI. This study aimed to characterize the relationship between MRP3, MRP4, and BSEP inhibition and cholestatic potential of drugs. The inhibitory effect of 88 drugs (100 μM) on MRP3- and MRP4-mediated substrate transport was measured in membrane vesicles. Drugs selected for investigation included 50 BSEP non-inhibitors (24 non-cholestatic; 26 cholestatic) and 38 BSEP inhibitors (16 non-cholestatic; 22 cholestatic). MRP4 inhibition was associated with an increased risk of cholestatic potential among BSEP non-inhibitors. In this group, for each 1% increase in MRP4 inhibition, the odds of the drug being cholestatic increased by 3.1%. Using an inhibition cutoff of 21%, which predicted a 50% chance of cholestasis, 62% of cholestatic drugs inhibited MRP4 (P drugs were MRP4 inhibitors. Among BSEP inhibitors, MRP4 inhibition did not provide additional predictive value of cholestatic potential; almost all BSEP inhibitors were also MRP4 inhibitors. Inclusion of pharmacokinetic predictor variables (e.g., maximal unbound concentration in plasma) in addition to percent MRP4 inhibition in logistic regression models did not improve cholestasis prediction. Association of cholestasis with percent MRP3 inhibition was not statistically significant, regardless of BSEP-inhibition status. Inhibition of MRP4, in addition to BSEP, may be a risk factor for the development of cholestatic DILI.

  20. 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....

  1. Cholesterol and bile acid biodynamics after total small bowel resection and bile diversion in humans.

    Science.gov (United States)

    Férézou, J; Beau, P; Parquet, M; Champarnaud, G; Lutton, C; Matuchansky, C

    1993-06-01

    In humans, the patterns of cholesterol and bile acid biodynamics in the absence of the small intestine are not yet known. They are described in two parenterally fed patients several months after total enterectomy and bile diversion. After an intravenous pulse of [3H]cholesterol, a long-term study involved the analysis of both the decay in the specific activity of plasma cholesterol and the biliary outputs of sterols and bile acids. Plasma cholesterol input reached 2-3 g/day (vs. 1 g/day in healthy patients), mostly from synthesis. As assessed by sterol balance, whole body cholesterol synthesis approximated 6 g/day (vs. 0.6-0.8 g/day). Unusually, about 60% of the newly synthesized cholesterol was eliminated, without prior transit into the bloodstream, from the liver into the bile. Bile acid conversion concerned over 90% (vs. 40%-50%) of the cholesterol meant to be excreted, issued from plasma or hepatic synthesis. In addition to cholic and chenodeoxycholic acids, one patient secreted up to 1 g/day of 7-epicholic acid. The stimulation (up to 10-fold) of the cholesterol and bile acid synthesis, stronger than that observed following ileal bypass or resection or complete bile diversion, could well be partially linked to the absence of small bowel tissue per se.

  2. Biodynamics of cholesterol and bile acids in the lithiasic hamster.

    Science.gov (United States)

    Khallou, J; Riottot, M; Parquet, M; Verneau, C; Lutton, C

    1991-11-01

    By using the isotopic equilibrium method in the young male Syrian hamster, the rates of cholesterol turnover processes, i.e. dietary cholesterol absorption, cholesterol synthesis, cholesterol excretion in the faeces and urine and cholesterol transformation into bile acids, were determined in the hamster receiving a control (C) or a lithogenic diet (L) for 7 weeks. At the end of this period the gall bladder of all animals in group L contained cholesterol gallstones. The coefficient of dietary cholesterol absorption was reduced by 26%, cholesterol synthesis and cholesterol faecal excretion were twofold higher in group L than in group C. Bile acid content in the small intestine was diminished in group L, but bile acid composition was similar in the two groups. The increase in cholesterogenesis in lithiasic animals essentially took place in the liver. Bile acid biosynthesis did not significantly differ in the two groups, but represented only 35% of total cholesterol input (dietary absorption + internal secretion) in group L v. 52% in group C. Thus, in the lithiasic hamster, hepatic synthesis of cholesterol and bile acids are not coupled. The molar percentage of cholesterol in bile was twofold higher in group L than in group C but those of bile acids and of phospholipids were not modified. In the lithiasic hamster the specific activity of biliary cholesterol was similar to that in plasma and liver. Consequently, biliary cholesterol does not derive directly from cholesterol newly synthesized in the liver but from hepatic cholesterol rapidly exchangeable with plasma cholesterol.

  3. Ursodeoxycholic acid, 7-ketolithocholic acid, and chenodeoxycholic acid are primary bile acids of the nutria (Myocastor coypus).

    Science.gov (United States)

    Tint, G S; Bullock, J; Batta, A K; Shefer, S; Salen, G

    1986-03-01

    Because ursodeoxycholic and chenodeoxycholic acids are interconverted in humans via 7-ketolithocholic acid, bile acid metabolism was studied in the nutria (Myocastor coypus), the bile of which is known to contain these three bile acids. Relative concentrations of ursodeoxycholic (37% +/- 20%), 7-ketolithocholic (33% +/- 17%), and chenodeoxycholic (17% +/- 9%) acids in gallbladder bile were unchanged by 5-20 h of complete biliary diversion (n = 7). Injection of either [14C]cholesterol, [14C]ursodeoxycholic, [14C]7-ketolithocholic acid, or a mixture of [7 beta-3H]chenodeoxycholic acid and [14C]chenodeoxycholic acid into bile fistula nutria demonstrated that all three bile acids can be synthesized hepatically from cholesterol, that they are interconverted sparingly (2%-5%) by the liver, but that 7-ketolithocholic acid is an intermediate in the hepatic transformation of chenodeoxycholic acid to ursodeoxycholic acid. An animal that had been fed antibiotics showed an unusually elevated concentration of ursodeoxycholic acid in gallbladder and hepatic bile, suggesting that bacterial transformation of ursodeoxycholic acid in the intestine may be a source of some biliary chenodeoxycholic acid and 7-ketolithocholic acid.

  4. 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.

  5. Biosynthesis and biotransformation of bile acids

    Directory of Open Access Journals (Sweden)

    Šarenac Tanja M.

    2017-01-01

    Full Text Available Bile acids are steroidal compounds, which contain 24 carbon atoms. They can be classified into two major groups: primary and secondary. The most abundant bile acids: The primary bile acids include cholic acid and chenodeoxycholic acid, while the major secondary bile acids are deoxycholic acid and litocholic acid. Bile acids are important physiological agents for intestinal absorption of nutrients and are used for biliary lipid secretion, toxic metabolites and xenobiotics. The aim of this paper is to analyze biosynthesis and biotransformation of bile acids, as preparation for practical usage in laboratory and clinical conditions. Topic: Biosynthesis and biotransformation of bile acids: The biosynthesis of bile acids is the dominant metabolic pathway for catabolism of cholesterol in humans. The classical route of biosynthesis of bile acids is embarking on the conversion of cholesterol into 7α-hydroxycholesterol using enzyme 7α-cholesterol hydroxylase (CYP7A1. This enzyme is one of the microsomal cytochrome P450 enzyme is localized exclusively in the liver. Classical road is the main road in the biosynthesis of bile acids, and its total contribution amounts to 90% for people, and 75% in mice. CYP 7A1 enzyme is considered to be sensitive to the inhibition of carbon monoxide, and the condition for the effect of NADPH, the oxygen, lecithin, and the NADPH-cytochrome P450 reductase. Bile acids are important signaling molecules and metabolic controls which activate the nuclear receptor and the G protein-coupled receptors (GPCR, a signaling lipid regulation of the liver, glucose and energy homeostasis. Also, bile acids maintain metabolic homeostasis. Biotransformation of bile acids: The conversion of cholesterol into bile acids just important for maintenance of cholesterol homeostasis, but also to prevent the accumulation of cholesterol, triglycerides and toxic metabolites as well as violations of the liver and other organs. Enterohepatic circulation of

  6. Targeting the Enterohepatic Bile Acid Signaling Induces Hepatic Autophagy via a CYP7A1–AKT–mTOR Axis in MiceSummary

    Directory of Open Access Journals (Sweden)

    Yifeng Wang

    2017-03-01

    Full Text Available Background & Aims: Hepatic cholesterol accumulation and autophagy defects contribute to hepatocyte injury in fatty liver disease. Bile acid synthesis is a major pathway for cholesterol catabolism in the liver. This study aims to understand the molecular link between cholesterol and bile acid metabolism and hepatic autophagy activity. Methods: The effects of cholesterol and cholesterol 7α-hydroxylase (CYP7A1 expression on autophagy and lysosome function were studied in cell models. The effects and mechanism of disrupting enterohepatic bile acid circulation on hepatic autophagy were studied in mice. Results: The results first showed differential regulation of hepatic autophagy by free cholesterol and cholesterol ester, whereby a modest increase of cellular free cholesterol, but not cholesterol ester, impaired lysosome function and caused marked autolysosome accumulation. We found that CYP7A1 induction, either by cholestyramine feeding in mice or adenovirus-mediated CYP7A1 expression in hepatocytes, caused strong autophagy induction. Mechanistically, we showed that CYP7A1 expression markedly attenuated growth factor/AKT signaling activation of mechanistic target of rapamycin (mTOR, but not amino acid signaling to mTOR in vitro and in vivo. Metabolomics analysis further found that CYP7A1 induction not only decreased hepatic cholesterol but also altered phospholipid and sphingolipid compositions. Collectively, these results suggest that CYP7A1 induction interferes with growth factor activation of AKT/mTOR signaling possibly by altering membrane lipid composition. Finally, we showed that cholestyramine feeding restored impaired hepatic autophagy and improved metabolic homeostasis in Western diet–fed mice. Conclusions: This study identified a novel CYP7A1–AKT–mTOR signaling axis that selectively induces hepatic autophagy, which helps improve hepatocellular integrity and metabolic homeostasis. Keywords: Cholesterol

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

    Science.gov (United States)

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

    2018-01-06

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

  8. Simple resection of the lesion bile duct branch for treatment of regional hepatic bile duct stones.

    Science.gov (United States)

    Enliang, Li; Rongshou, Wu; Shidai, Shi; Jingling, Zhang; Qian, Feng; Wenjun, Liao; Linquan, Wu

    2017-07-01

    To evaluate the effectiveness and safety of simple resections of bile duct branch lesions for the treatment of regional hepatic bile duct stones.A retrospective analysis of the clinical data from patients in our hospital from November 2008 to November 2015, who only underwent a simple resection of the lesion bile duct branch. The patients' clinical characteristics, surgical features, postoperative complications, stone clear rate, residual stone rate, and recurrence stone rate were analyzed.This study of 32 patients included 13 males and 19 females with intrahepatic bile duct stones confined to the right hepatic bile duct branch. The intraoperative blood loss, operation time, and postoperative hospital stay were 478.0 ± 86.5, 210.7 ± 6.6, and 10.8 ± 3.5, respectively. Postoperative complications occurred in 6 patients (18.8%), all of whom recovered with conservative management. There were no deaths during hospitalization. The intraoperative stone clearance rate was 95.8%. Three patients had a recurrence of stones at a mean of 22 months of follow-up (range, 4-36 months).Simple resection of bile duct branch lesions is safe and feasible for patients who have regional hepatic bile duct stones limited to the right hepatic bile duct branches.

  9. 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...

  10. Bile acid sequestrants : more than simple resins

    NARCIS (Netherlands)

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

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

  11. 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.

  12. Enterobacteria modulate intestinal bile acid transport and homeostasis through apical sodium-dependent bile acid transporter (SLC10A2) expression.

    Science.gov (United States)

    Miyata, Masaaki; Yamakawa, Hiroki; Hamatsu, Mayumi; Kuribayashi, Hideaki; Takamatsu, Yuki; Yamazoe, Yasushi

    2011-01-01

    In our study, ampicillin (AMP)-mediated decrease of enterobacteria caused increases in hepatic bile acid concentration through (at least in part) elevation of bile acid synthesis in C57BL/6N mice. We investigated the involvement of enterobacteria on intestinal bile acid absorption in AMP-treated mice in the present study. Fecal enterobacterial levels and fecal bile acid excretion rates were markedly decreased in mice treated with AMP (100 mg/kg) for 3 days, whereas bile acid concentrations in portal blood were significantly increased compared with those in mice treated with a vehicle. Ileal apical sodium-dependent bile acid transporter (SLC10A2) mRNA levels and ileal SLC10A2 protein levels in brush-border membranes were significantly increased compared with those in mice treated with the vehicle. In AMP-treated mice, total bile acid levels were increased, whereas levels of enterobacteria-biotransformed bile acid, taurodeoxycholic acid, and cholic acid were decreased in intestinal lumen. These phenomena were also observed in farnesoid X receptor-null mice treated with AMP for 3 days. Discontinuation of AMP administration after 3 days (vehicle administration for 4 days) increased levels of fecal enterobacteria, fecal bile acid excretion, and taurodeoxycholic acid and cholic acid in the intestinal lumen, whereas the discontinuation decreased ileal SLC10A2 expression and bile acid concentrations in the portal blood. Coadministration of taurodeoxycholic acid or cholic acid decreased ileal SLC10A2 expression in mice treated with AMP. These results suggest that enterobacteria-mediated bile acid biotransformation modulates intestinal bile acid transport and homeostasis through down-regulation of ileal SLC10A2 expression.

  13. Metformin impairs systemic bile acid homeostasis through regulating SIRT1 protein levels.

    Science.gov (United States)

    Chen, Qi; Yang, Xiaoying; Zhang, Huabing; Kong, Xingxing; Yao, Lu; Cui, Xiaona; Zou, Yongkang; Fang, Fude; Yang, Jichun; Chang, Yongsheng

    2017-01-01

    Metformin is widely used to treat hyperglycemia. However, metformin treatment may induce intrahepatic cholestasis and liver injury in a few patients with type II diabetes through an unknown mechanism. Here we show that metformin decreases SIRT1 protein levels in primary hepatocytes and liver. Both metformin-treated wild-type C57 mice and hepatic SIRT1-mutant mice had increased hepatic and serum bile acid levels. However, metformin failed to change systemic bile acid levels in hepatic SIRT1-mutant mice. Molecular mechanism study indicates that SIRT1 directly interacts with and deacetylates Foxa2 to inhibit its transcriptional activity on expression of genes involved in bile acids synthesis and transport. Hepatic SIRT1 mutation elevates Foxa2 acetylation levels, which promotes Foxa2 binding to and activating genes involved in bile acids metabolism, impairing hepatic and systemic bile acid homeostasis. Our data clearly suggest that hepatic SIRT1 mediates metformin effects on systemic bile acid metabolism and modulation of SIRT1 activity in liver may be an attractive approach for treatment of bile acid-related diseases such as cholestasis. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Interactions between bile salts, gut microbiota, and hepatic innate immunity.

    Science.gov (United States)

    Schubert, Kristin; Olde Damink, Steven W M; von Bergen, Martin; Schaap, Frank G

    2017-09-01

    Bile salts are the water-soluble end products of hepatic cholesterol catabolism that are released into the duodenum and solubilize lipids due to their amphipathic structure. Bile salts also act as endogenous ligands for dedicated nuclear receptors that exert a plethora of biological processes, mostly related to metabolism. Bile salts are actively reclaimed in the distal part of the small intestine, released into the portal system, and subsequently extracted by the liver. This enterohepatic cycle is critically dependent on dedicated bile salt transporters. In the intestinal lumen, bile salts exert direct antimicrobial activity based on their detergent property and shape the gut microbiota. Bile salt metabolism by gut microbiota serves as a mechanism to counteract this toxicity and generates bile salt species that are distinct from those of the host. Innate immune cells of the liver play an important role in the early recognition and effector response to invading microbes. Bile salts signal primarily via the membrane receptor TGR5 and the intracellular farnesoid-x receptor, both present in innate immune cells. In this review, the interactions between bile salts, gut microbiota, and hepatic innate immunity are discussed. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  15. Bile acids for liver-transplanted patients

    DEFF Research Database (Denmark)

    Poropat, Goran; Giljaca, Vanja; Stimac, Davor

    2010-01-01

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

  16. Bile acid receptor agonists. INT747 and INT777 decrease oestrogen deficiency-related postmenopausal obesity and hepatic steatosis in mice

    NARCIS (Netherlands)

    de Oliveira, Monique C.; Gilglioni, Eduardo H.; de Boer, Bouke A.; Runge, Jurgen H.; de Waart, Dirk R.; Salgueiro, Clairce L.; Ishii-Iwamoto, Emy L.; Oude Elferink, Ronald P. J.; Gaemers, Ingrid C.

    2016-01-01

    Menopause is often followed by obesity and, related to this, non-alcoholic fatty liver disease (NAFLD). Two bile acid (BA) receptors, farnesoid X receptor (FXR) and G-protein-coupled receptor TGR5, have emerged as putative therapeutic targets for obesity and NAFLD. Aim of this study: to evaluate the

  17. Preference of Conjugated Bile Acids over Unconjugated Bile Acids as Substrates for OATP1B1 and OATP1B3.

    Science.gov (United States)

    Suga, Takahiro; Yamaguchi, Hiroaki; Sato, Toshihiro; Maekawa, Masamitsu; Goto, Junichi; Mano, Nariyasu

    2017-01-01

    Bile acids, the metabolites of cholesterol, are signaling molecules that play critical role in many physiological functions. They undergo enterohepatic circulation through various transporters expressed in intestine and liver. Human organic anion-transporting polypeptides (OATP) 1B1 and OATP1B3 contribute to hepatic uptake of bile acids such as taurocholic acid. However, the transport properties of individual bile acids are not well understood. Therefore, we selected HEK293 cells overexpressing OATP1B1 and OATP1B3 to evaluate the transport of five major human bile acids (cholic acid, chenodeoxycholic acid, deoxycholic acid, ursodeoxycholic acid, lithocholic acid) together withtheir glycine and taurine conjugates via OATP1B1 and OATP1B3. The bile acids were quantified by liquid chromatography-tandem mass spectrometry. The present study revealed that cholic acid, chenodeoxyxcholic acid, and deoxycholic acid were transported by OATP1B1 and OATP1B3, while ursodeoxycholic acid and lithocholic acid were not significantly transported by OATPs. However, all the conjugated bile acids were taken up rapidly by OATP1B1 and OATP1B3. Kinetic analyses revealed the involvement of saturable OATP1B1- and OATP1B3-mediated transport of bile acids. The apparent Km values for OATP1B1 and OATP1B3 of the conjugated bile acids were similar (0.74-14.7 μM for OATP1B1 and 0.47-15.3 μM for OATP1B3). They exhibited higher affinity than cholic acid (47.1 μM for OATP1B1 and 42.2 μM for OATP1B3). Our results suggest that conjugated bile acids (glycine and taurine) are preferred to unconjugated bile acids as substrates for OATP1B1 and OATP1B3.

  18. Protection of live bacteria from bile acid toxicity using bile acid adsorbing resins.

    Science.gov (United States)

    Edwards, Alexander D; Slater, Nigel K H

    2009-06-12

    We previously demonstrated that a dry, room temperature stable formulation of a live bacterial vaccine was highly susceptible to bile, and suggested that this will lead to significant loss of viability of any live bacterial formulation released into the intestine using an enteric coating or capsule. We found that bile and acid tolerance is very rapidly recovered after rehydration with buffer or water, raising the possibility that rehydration in the absence of bile prior to release into the intestine might solve the problem of bile toxicity to dried cells. We describe here a novel formulation that combines extensively studied bile acid adsorbent resins with the dried bacteria, to temporarily adsorb bile acids and allow rehydration and recovery of bile resistance of bacteria in the intestine before release. Tablets containing the bile acid adsorbent cholestyramine release 250-fold more live bacteria when dissolved in a bile solution, compared to control tablets without cholestyramine or with a control resin that does not bind bile acids. We propose that a simple enteric coated oral dosage form containing bile acid adsorbent resins will allow improved live bacterial delivery to the intestine via the oral route, a major step towards room temperature stable, easily administered and distributed vaccine pills and other bacterial therapeutics.

  19. Mouse organic solute transporter alpha deficiency enhances renal excretion of bile acids and attenuates cholestasis.

    Science.gov (United States)

    Soroka, Carol J; Mennone, Albert; Hagey, Lee R; Ballatori, Nazzareno; Boyer, James L

    2010-01-01

    Organic solute transporter alpha-beta (Ostalpha-Ostbeta) is a heteromeric bile acid and sterol transporter that facilitates the enterohepatic and renal-hepatic circulation of bile acids. Hepatic expression of this basolateral membrane protein is increased in cholestasis, presumably to facilitate removal of toxic bile acids from the liver. In this study, we show that the cholestatic phenotype induced by common bile duct ligation (BDL) is reduced in mice genetically deficient in Ostalpha. Although Ostalpha(-/-) mice have a smaller bile acid pool size, which could explain lower serum and hepatic levels of bile acids after BDL, gallbladder bilirubin and urinary bile acid concentrations were significantly greater in Ostalpha(-/-) BDL mice, suggesting additional alternative adaptive responses. Livers of Ostalpha(-/-) mice had higher messenger RNA levels of constitutive androstane receptor (Car) than wild-type BDL mice and increased expression of Phase I enzymes (Cyp7a1, Cyp2b10, Cyp3a11), Phase II enzymes (Sult2a1, Ugt1a1), and Phase III transporters (Mrp2, Mrp3). Following BDL, the bile acid pool size increased in Ostalpha(-/-) mice and protein levels for the hepatic basolateral membrane export transporters, multidrug resistance-associated protein 3 (Mrp3) and Mrp4, and for the apical bilirubin transporter, Mrp2, were all increased. In the kidney of Ostalpha(-/-) mice after BDL, the apical bile acid uptake transporter Asbt is further reduced, whereas the apical export transporters Mrp2 and Mrp4 are increased, resulting in a significant increase in urinary bile acid excretion. These findings indicate that loss of Ostalpha provides protection from liver injury in obstructive cholestasis through adaptive responses in both the kidney and liver that enhance clearance of bile acids into urine and through detoxification pathways most likely mediated by the nuclear receptor Car.

  20. Mouse organic solute transporter α deficiency enhances renal excretion of bile acids and attenuates cholestasis

    Science.gov (United States)

    Soroka, Carol J.; Mennone, Albert; Hagey, Lee R.; Ballatori, Nazzareno; Boyer, James L.

    2010-01-01

    Organic solute transporter alpha-beta (Ostα-Ostβ) is a heteromeric bile acid and sterol transporter that facilitates the entero- and renal-hepatic circulation of bile acids. Hepatic expression of this basolateral membrane protein is increased in cholestasis, presumably to facilitate removal of toxic bile acids from the liver. In this study we show that the cholestatic phenotype induced by common bile duct ligation (BDL) is reduced in mice genetically deficient in Ostα. Although Ostα−/− mice have a smaller bile acid pool size which could explain lower serum and hepatic levels of bile acids after BDL, gallbladder bilirubin and urinary bile acid concentrations were significantly greater in Ostα−/− BDL mice, suggesting additional alternative adaptive responses. Livers of Ostα−/− mice had higher mRNA levels of constitutive androstane receptor (Car) than wild-type BDL mice and increased expression of Phase I enzymes (Cyp7a1, Cyp2b10, Cyp3a11), Phase II enzymes (Sult2a1, Ugt1a1) and Phase III transporters (Mrp2, Mrp3). Following BDL, the bile acid pool size increased in Ostα−/− mice and protein levels for the hepatic basolateral membrane export transporters, Mrp3 and Mrp4, and for the apical bilirubin transporter, Mrp2, were all increased. In the kidney of Ostα−/− mice after BDL the apical bile acid uptake transporter, Asbt, is further reduced, while apical export transporters, Mrp2 and Mrp4, are increased, resulting in a significant increase in urinary bile acid excretion. Conclusions: These findings indicate that loss of Ostα provides protection from liver injury in obstructive cholestasis through adaptive responses in both the kidney and liver that enhance clearance of bile acids into urine and through detoxification pathways most likely mediated by the nuclear receptor, Car. PMID:19902485

  1. Impact of parenteral nutrition versus fasting on hepatic bile acid production and transport in a rabbit model of prolonged critical illness.

    Science.gov (United States)

    Vanwijngaerden, Yoo-Mee; Langouche, Lies; Derde, Sarah; Liddle, Christopher; Coulter, Sally; van den Berghe, Greet; Mesotten, Dieter

    2014-01-01

    Cholestatic liver dysfunction frequently occurs during critical illness. Administration of parenteral nutrition (PN) is thought to aggravate this. Underlying mechanisms are not clear. In a burn model of prolonged critical illness, rabbits were randomized to a nutritional strategy either accepting caloric deficits (fasted, n = 11) or covering caloric needs by PN (fed, n = 10). At baseline and after 7 days of critical illness, markers of hepatotoxicity, circulating bile acids, and the hepatobiliary transport system were studied. Fasted animals had lower circulating alanine aminotransferase/aspartate aminotransferase levels than did the fed animals at day 7. Compared with baseline values, fed animals displayed lower serum unconjugated cholic acid (CA) and deoxycholic acid (DCA) levels. Unconjugated DCA remained unaltered in fasted animals. Unconjugated lithocholic acid was increased comparably in all animals, whereas hyodeoxycholic acid was not altered. In contrast, fasting induced a shift from unconjugated CA and DCA to glyco-CA and glyco-DCA. Total bile acids did not correlate with the bile acid-producing enzyme CYP7A1, but with the basolateral efflux transporter MRP3. Fasting increased protein expression of the basolateral (MRP3) and the canalicular (BSEP) transporter, whereas the canalicular efflux pump MRP2 was suppressed. Gene expression levels of the nuclear receptor farnesoid X receptor were lower with fasting and correlated inversely with MRP3. The heterodimer partner of farnesoid X receptor, retinoid X receptor α, was increased with fasting and correlated positively with MRP3. During prolonged critical illness, withholding PN improved markers for hepatocyte injury and accentuated bile acid transport toward the blood. This suggests that the latter is an adaptive rather than a dysfunctional feedback to illness.

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

    Science.gov (United States)

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

    2014-02-01

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

  3. 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.

  4. Bile Acid-Induced Suicidal Erythrocyte Death

    Directory of Open Access Journals (Sweden)

    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.

  5. Protection of live bacteria from bile acid toxicity using bile acid adsorbing resins

    OpenAIRE

    Edwards, Alexander D.; Slater, Nigel K. H.

    2009-01-01

    We previously demonstrated that a dry, room temperature stable formulation of a live bacterial vaccine was highly susceptible to bile, and suggested that this will lead to significant loss of viability of any live bacterial formulation released into the intestine using an enteric coating or capsule. We found that bile and acid tolerance is very rapidly recovered after rehydration with buffer or water, raising the possibility that rehydration in the absence of bile prior to release into the in...

  6. Organochloride pesticides modulated gut microbiota and influenced bile acid metabolism in mice.

    Science.gov (United States)

    Liu, Qian; Shao, Wentao; Zhang, Chunlan; Xu, Cheng; Wang, Qihan; Liu, Hui; Sun, Haidong; Jiang, Zhaoyan; Gu, Aihua

    2017-07-01

    Organochlorine pesticides (OCPs) can persistently accumulate in body and threaten human health. Bile acids and intestinal microbial metabolism have emerged as important signaling molecules in the host. However, knowledge on which intestinal microbiota and bile acids are modified by OCPs remains unclear. In this study, adult male C57BL/6 mice were exposed to p, p'-dichlorodiphenyldichloroethylene (p, p'-DDE) and β-hexachlorocyclohexane (β-HCH) for 8 weeks. The relative abundance and composition of various bacterial species were analyzed by 16S rRNA gene sequencing. Bile acid composition was analyzed by metabolomic analysis using UPLC-MS. The expression of genes involved in hepatic and enteric bile acids metabolism was measured by real-time PCR. Expression of genes in bile acids synthesis and transportation were measured in HepG2 cells incubated with p, p'-DDE and β-HCH. Our findings showed OCPs changed relative abundance and composition of intestinal microbiota, especially in enhanced Lactobacillus with bile salt hydrolase (BSH) activity. OCPs affected bile acid composition, enhanced hydrophobicity, decreased expression of genes on bile acid reabsorption in the terminal ileum and compensatory increased expression of genes on synthesis of bile acids in the liver. We demonstrated that chronic exposure of OCPs could impair intestinal microbiota; as a result, hepatic and enteric bile acid profiles and metabolism were influenced. The findings in this study draw our attention to the hazards of chronic OCPs exposure in modulating bile acid metabolism that might cause metabolic disorders and their potential to cause related diseases in human. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

    African Journals Online (AJOL)

    (CDCA), deoxycholic acid (DCA), and lithocholic acid. (LCA) 1. The homeostasis of bile acids can be tightly regulated through feed-back and feed-forward regula- tion pathways. Bile acids exert their toxicity towards cells at high concentrations, and the accumulation of bile acids can induce the severe damage towards liver.

  8. Dietary Karaya Saponin and Rhodobacter capsulatus Exert Hypocholesterolemic Effects by Suppression of Hepatic Cholesterol Synthesis and Promotion of Bile Acid Synthesis in Laying Hens

    Directory of Open Access Journals (Sweden)

    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.

  9. Effect of bile acids on digestion

    Directory of Open Access Journals (Sweden)

    O. O. Stremoukhov

    2013-12-01

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

  10. Bile acids and cardiovascular function in cirrhosis

    DEFF Research Database (Denmark)

    Voiosu, Andrei; Wiese, Signe; Voiosu, Theodor

    2017-01-01

    identified in cardiomyocytes, vascular endothelial cells and smooth muscle cellswhere theyseem to play an important role in cellular metabolism. Chronic cholestasis leading to abnormal levels of circulating bile acids alters the normal signaling pathways and contributes to the development of profound......Cirrhotic cardiomyopathy and the hyperdynamic syndrome are clinically important complications of cirrhosis but their exact pathogenesis is still partly unknown. Experimental models have proven the cardiotoxic effects of bile acidsand recent studies of their varied receptor-mediated functions offer...... cardiovascular disturbances. This review summarizes the evidence regarding the role of bile acids and their receptors in the generation of cardiovascular dysfunction in cirrhosis. This article is protected by copyright. All rights reserved....

  11. 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...

  12. FXR-dependent reduction of hepatic steatosis in a bile salt deficient mouse model

    NARCIS (Netherlands)

    Kunne, Cindy; Acco, Alexandra; Duijst, Suzanne; de Waart, Dirk R.; Paulusma, Coen C.; Gaemers, Ingrid; Oude Elferink, Ronald P. J.

    2014-01-01

    It has been established that bile salts play a role in the regulation of hepatic lipid metabolism. Accordingly, overt signs of steatosis have been observed in mice with reduced bile salt synthesis. The aim of this study was to identify the mechanism of hepatic steatosis in mice with bile salt

  13. Inhibition of ileal apical but not basolateral bile acid transport reduces atherosclerosis in apoE⁻/⁻ mice.

    Science.gov (United States)

    Lan, Tian; Haywood, Jamie; Dawson, Paul A

    2013-08-01

    Interruption of the enterohepatic circulation of bile acids induces hepatic bile acid synthesis, increases hepatic cholesterol demand, and increases clearance of apoB-containing lipoproteins in plasma. Based on these effects, bile acid sequestrants have been used for many years to treat hypercholesterolemia and the associated atherosclerosis. The objective of this study was to determine the effect of blocking ileal apical versus basolateral membrane bile acid transport on the development of hypercholesterolemia and atherosclerosis in mouse models. ApoE(-/-) and Ldlr(-/-) mice deficient in the apical sodium-dependent bile acid transporter (Asbt) or apoE(-/-) mice deficient in the basolateral bile acid transporter (Ostα) were fed an atherogenic diet for 16 weeks. Bile acid metabolism, cholesterol metabolism, gene expression, and development of atherosclerosis were examined. Mice deficient in Asbt exhibited the classic response to interruption of the enterohepatic circulation of bile acids, including significant reductions in hepatic and plasma cholesterol levels, and reduced aortic cholesteryl ester content. Ileal Fibroblast Growth Factor-15 (FGF15) expression was significantly reduced in Asbt(-/-)apoE(-/-) mice and was inversely correlated with expression of hepatic cholesterol 7-hydroxylase (Cyp7a1). Ileal FGF15 expression was directly correlated with plasma cholesterol levels and aortic cholesterol content. In contrast, plasma and hepatic cholesterol levels and atherosclerosis development were not reduced in apoE(-/-) mice deficient in Ostα. Decreases in ileal FGF15, with subsequent increases in hepatic Cyp7a1 expression and bile acid synthesis appear to be necessary for the plasma cholesterol-lowering and atheroprotective effects associated with blocking intestinal bile acid absorption. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  14. 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. Copyright © 2011 S. Karger AG, Basel.

  15. Beyond intestinal soap-bile acids in metabolic control

    NARCIS (Netherlands)

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

    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

  16. Diet-dependent effects of insulin infusion on the hepatic lipoprotein receptors and the key enzymes of bile acid synthesis in the hamster.

    Science.gov (United States)

    Dubrac, S; Parquet, M; Gripois, D; Blouquit, M F; Sérougne, C; Loison, C; Lutton, C

    2001-10-12

    The effects of an induced hyperinsulinemia on both the cholesterol and bile acid metabolisms were analyzed in the hamster. The role of dietary sucrose as modulator of these effects was evaluated by feeding the animals with two semi-synthetic diets containing a low (SD, 20%) and a high (LD, 62.5%) sucrose proportion. Hamsters fed under basal nutritional conditions (chow diet, CD) were also used. LD enabled the consequences of an insulin infusion on cholesterol gallstone formation to be evaluated. Subcutaneous osmotic pumps were implanted in all the animals and delivered either 3 IU/day of insulin (insulin groups: CDI, SDI, LDI) or saline (control groups: CDC, SDC, LDC). Several parameters bound to lipid metabolism were measured. The plasma cholesterol concentration remained constant in all the insulin treated groups compared to the controls. Phospholipid and triglyceride concentrations decreased in both the plasma and liver in the CDI and SDI groups. A lower SR-BI mass (around 50%) was found in the liver of CDI and SDI hamsters with concomitant higher hydroxy-methyl-glutaryl coenzyme A reductase activity. The LDL-receptor mass and cholesterol 7alpha-hydroxylase activity in the LDI group were both decreased (-47%, -71% respectively). No variations in the cholesterol gallstone incidence were observed. In conclusion, chronic insulin infusion in growing hamsters induced similar effects on cholesterol metabolism in the CD and SD groups but different ones, between diets containing a low (SD) and a high (LD) sucrose proportion. The distribution of triglycerides and phospholipids in the plasma, liver and bile was also affected by the insulin infusion.

  17. 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...... with cheese intake. Conclusion We were not able to confirm the hypothesis that calcium from cheese increases the excretion of fecal bile acids. Therefore, the mechanisms responsible for the lowering of cholesterol concentrations with cheese compared to butter intake remains unresolved....

  18. 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

  19. Diverticular bile duct lesion in chronic active hepatitis

    DEFF Research Database (Denmark)

    Vyberg, M

    1989-01-01

    of a not previously described diverticular type were revealed. The diverticuli were of varying shape with a diameter of 30 to 110 microns and a length of 75 to 150 microns budding from small (12 to 25 microns), slightly ectatic bile ducts. The diverticular epithelium was disordered. Some cells appeared as bile duct...... cells, but most were larger, with rounded nuclei, prominent nucleoli and abundant eosinophilic cytoplasm, sometimes with periodic acid-Schiff-positive, diastase-resistant granules. The lesions were only partly surrounded by a basement membrane. They were all embedded in a tight mononuclear inflammatory...

  20. Increased hepatic blood flow during enteral immune-enhancing diet gavage requires intact enterohepatic bile cycling.

    Science.gov (United States)

    Nagengast, Andrea K; Hurt, Ryan T; Downard, Cynthia D; Smith, Jason W; Garrison, R Neal; Matheson, Paul J

    2014-03-01

    Total hepatic blood flow (HBF) via the hepatic artery and portal vein is highly dependent on gastrointestinal perfusion. During postprandial hyperemia, intestinal blood flow depends on nutrient composition, gastrointestinal location, and time. Immune-enhancing diets (IEDs) containing n-3 polyunsaturated fatty acids (PUFAs) selectively augment blood flow in the ileum at 60-120 min via a bile-dependent mechanism. My colleagues and I hypothesized that liver blood flow would be similarly affected by IEDs containing n-3 PUFAs. Mean arterial blood pressure, heart rate, and effective HBF (galactose clearance) were measured in anesthetized male Sprague-Dawley rats after gastric gavage of either a control diet (CD, Boost, Novartis) or an IED (Impact, Nestle Nutrition), with or without bile-duct ligation (BDL), and with or without supplemental bile (bovine, dried, unfractionated). Significance was assessed by 2-way ANOVA for repeated measures with the Tukey-Kramer honestly significant difference test. Compared with baseline levels, a CD increased HBF (peak at 40 min , *P < 0.05) whereas an IED increased HBF in two distinct peaks at 40 min (*P < 0.05) and 120 min (*P < 0.05), but BDL prevented both the early (CD and IED, †P < 0.05) and late peaks (IED, †P < 0.05). Bile supplementation in the CD + BDL or IED + BDL groups restored neither the CD peak nor the early or late IED peaks. HBF during absorptive intestinal hyperemia is modulated by a mechanism that requires an intact enterohepatic circulation. The early peaks at 40 min (CD or IED) were prevented by BDL, even though fat absorption in the proximal gut occurs by bile-independent direct absorption. Bile supplementation with the diet (CD + BDL or IED + BDL) was insufficient to restore HBF hyperemia, which implies that a relationship exists between intestinal and hepatic blood flow that is not solely dependent on bile-mediated intestinal fat absorption and bile recirculation. Copyright © 2014 Elsevier Inc. All rights

  1. Identity of hepatic membrane transport systems for bile salts, phalloidin, and antamanide by photoaffinity labeling.

    Science.gov (United States)

    Wieland, T; Nassal, M; Kramer, W; Fricker, G; Bickel, U; Kurz, G

    1984-08-01

    Phalloidin, a bicyclic heptapeptide, and antamanide, a monocyclic decapeptide from the poisonous mushroom Amanita phalloides, interact with bile-salt-binding polypeptides of the hepatocyte membrane, as demonstrated by photoaffinity labeling using the photolabile bile salt derivative 7,7,-azo-3 alpha, 12 alpha-dihydroxy-5 beta-cholan-24-oic acid, either unconjugated or taurine conjugated. With the photolabile derivatives of phalloidin, N-delta-(4-[(1-azi-2,2,2-trifluoroethyl) benzoyl]-beta-alanyl)-delta-aminophalloin, (N epsilon-[4-(1-azi-2,2,2-trifluoroethyl)benzoyl]lys6)-anta manide, the same membrane polypeptides with apparent MrS of 54,000 and 48,000 were labeled as with the photolabile derivatives of unconjugated and conjugated bile salts. The presence of bile salts decreased markedly the extent of labeling of these phalloidin- and antamanide-binding polypeptides. These results indicate that hepatic uptake systems for bile salts, phallotoxins, and the cycloamanide antamanide are identical, thus explaining the organotropism of phallotoxins.

  2. 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...

  3. ABC transporters, bile acids, and inflammatory stress in liver cancer.

    Science.gov (United States)

    Wang, Renxue; Sheps, Jonathan A; Ling, Victor

    2011-04-01

    The biliary secretion of bile acids is critical for multiple liver functions including digesting fatty nutrients and driving bile flow. When this process is impaired, the accumulating bile acids cause inflammatory liver injury. Multiple ABC transporters in the liver are key players to safeguard the hepatocyte and avoid toxicity due to bile acid over-accumulation. BSEP provides for efficient secretion of bile acids across the canalicular membrane against a steep concentration gradient. MDR3/Mdr2 and ABCG5/G8 secrete phosphatidylcholine and cholesterol, respectively, in coordination with BSEP-mediated bile acid secretion to mask the detergent/toxic effects of bile acids in the bile ductular space. Several lines of evidence indicate that when these critical steps are compromised, bile acid toxicity in vivo leads to inflammatory liver injury and liver cancer. In bsep-/- mice, liver cancer is rare. These mice display greatly increased expression of alternative bile acid transporters, such as Mdr1a/1b, Mrp3 and Mrp4. We believe these alternative transport systems provide an additional safeguard to avoid bile acid overload in liver. Such backup systems appear to be under-utilized in humans, as defects in BSEP and MDR3 lead to severe, often fatal childhood diseases. It is possible, therefore, that targeting ABC transporters and modulating the toxicity of the bile acid pool could be vital interventions to alleviate chronic inflammation and reduce the incidence of liver cancer in high-risk populations. The combination of an alternative ABC transporter with a novel substrate may prove an effective chemo-preventive or therapeutic strategy.

  4. 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.

  5. Organic Solute Transporter, OSTα-OSTβ: Its Role In Bile Acid Transport and Cholestasis

    Science.gov (United States)

    Soroka, Carol J.; Ballatori, Nazzareno; Boyer, James L.

    2013-01-01

    Organic solute transporter α-beta (OSTα-OSTβ) is a unique heteromeric transporter localized to the basolateral membrane of epithelial cells involved in sterol transport. It is believed to be the primary bile acid efflux transporter in the intestine of mammals and is therefore essential to bile acid homeostasis and the enterohepatic circulation. First described in the evolutionarily primitive small skate, Leucoraja erinacea, this facilitated transporter requires expression of both subunits for its function. It can transport a variety of bile acids, as well as estrone 3-sulfate, dehydroepiandrosterone 3-sulfate, digoxin and prostaglandin E2. Expression of both subunits is variable between species and tissues; in humans high expression is noted in the liver, small intestine, kidney, testis, and adrenal gland. OSTα-OSTβ is directly regulated by the bile acid sensing nuclear receptor, farnesoid X receptor (FXR). Furthermore, it is part of the complex regulatory pathway that controls bile acid synthesis and homeostasis. Hepatic OSTα-OSTβ is up-regulated in cholestasis in both humans and rodents, where it appears to play a protective role. Additional studies are necessary to determine its role in liver injury, bile acid malabsorption, and lipid and glucose metabolism, as well as a potential protective role for kidney OSTα-OSTβ in cholestasis. PMID:20422499

  6. Organic solute transporter, OSTalpha-OSTbeta: its role in bile acid transport and cholestasis.

    Science.gov (United States)

    Soroka, Carol J; Ballatori, Nazzareno; Boyer, James L

    2010-05-01

    Organic solute transporter alpha-beta (OSTalpha-OSTbeta) is a unique heteromeric transporter localized to the basolateral membrane of epithelial cells involved in sterol transport. It is believed to be the primary bile acid efflux transporter in the intestine of mammals and is therefore essential to bile acid homeostasis and the enterohepatic circulation. First described in the evolutionarily primitive small skate, LEUCORAJA ERINACEA, this facilitated transporter requires expression of both subunits for its function. It can transport a variety of bile acids, as well as estrone 3-sulfate, dehydroepiandrosterone 3-sulfate, digoxin, and prostaglandin E (2). Expression of both subunits is variable between species and tissues; in humans high expression is noted in the liver, small intestine, kidney, testis, and adrenal gland. OSTalpha-OSTbeta is directly regulated by the bile acid sensing nuclear receptor, farnesoid X receptor (FXR). Furthermore, it is part of the complex regulatory pathway that controls bile acid synthesis and homeostasis. Hepatic OSTalpha-OSTbeta is upregulated in cholestasis in both humans and rodents, where it appears to play a protective role. Additional studies are necessary to determine its role in liver injury, bile acid malabsorption, and lipid and glucose metabolism, as well as a potential protective role for kidney OSTalpha-OSTbeta in cholestasis.

  7. Bile acid nephropathy in a bodybuilder abusing an anabolic androgenic steroid.

    Science.gov (United States)

    Luciano, Randy L; Castano, Ekaterina; Moeckel, Gilbert; Perazella, Mark A

    2014-09-01

    Bile acid nephropathy, also known as cholemic nephrosis or nephropathy, is an entity that can be seen in patients with severe cholestatic liver disease. It typically is associated with acute kidney injury (AKI) with various forms of hepatic disease. Most often, patients with severe obstructive jaundice develop this lesion, which is thought to occur due to direct bile acid injury to tubular cells, as well as obstructing bile acid casts. Patients with end-stage liver disease also can develop AKI, in which case a more heterogeneous lesion occurs that includes hepatorenal syndrome and acute tubular injury/necrosis. In this circumstance, acute tubular injury develops from a combination of hemodynamic changes with some contribution from direct bile acid-related tubular toxicity and obstructive bile casts. We present a case of AKI due to bile acid nephropathy in a bodybuilder who developed severe cholestatic liver disease in the setting of anabolic androgenic steroid use. Copyright © 2014 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  8. Hydrophobic bile acids, genomic instability, Darwinian selection, and colon carcinogenesis

    Directory of Open Access Journals (Sweden)

    Claire M Payne

    2008-12-01

    Full Text Available Claire M Payne, Carol Bernstein, Katerina Dvorak, Harris BernsteinDepartment of Cell Biology and Anatomy, College of Medicine, University of Arizona, Tucson, Arizona, USAAbstract: Sporadic colon cancer is caused predominantly by dietary factors. We have selected bile acids as a focus of this review since high levels of hydrophobic bile acids accompany a Western-style diet, and play a key role in colon carcinogenesis. We describe how bile acid-induced stresses cause cell death in susceptible cells, contribute to genomic instability in surviving cells, impose Darwinian selection on survivors and enhance initiation and progression to colon cancer. The most likely major mechanisms by which hydrophobic bile acids induce stresses on cells (DNA damage, endoplasmic reticulum stress, mitochondrial damage are described. Persistent exposure of colon epithelial cells to hydrophobic bile acids can result in the activation of pro-survival stress-response pathways, and the modulation of numerous genes/proteins associated with chromosome maintenance and mitosis. The multiple mechanisms by which hydrophobic bile acids contribute to genomic instability are discussed, and include oxidative DNA damage, p53 and other mutations, micronuclei formation and aneuploidy. Since bile acids and oxidative stress decrease DNA repair proteins, an increase in DNA damage and increased genomic instability through this mechanism is also described. This review provides a mechanistic explanation for the important link between a Western-style diet and associated increased levels of colon cancer.Keywords: bile acids, genomic instability, colon cancer

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

    African Journals Online (AJOL)

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

  10. Characterization of bile acid metabolism in man using bile acids labeled with stable isotopes. [/sup 13/C

    Energy Technology Data Exchange (ETDEWEB)

    Hofmann, A.F. Klein, P.D.

    1977-01-01

    Bile acids labeled with stable isotopes in the steroid moiety can be used to characterize bile acid metabolism in man. Isotope dilution studies give information on pool size and input. Biotransformations are easily characterized. Stable isotopically labeled bile acids offer the advantage of freedom from radiation hazard, and also offer the possibility of monitoring all pools simultaneously, since all bile acids are separated by gas chromatography before isotope measurements are made. Further, since the proportion of the pool labeled with stable isotopes is greater than that achieved when radioactive isotopes are used, stable isotopes may permit isotope dilution studies to be done on serum samples in which the absolute concentration of bile acids is very low. A major disadvantage is the complex technology required for stable isotope measurement which often makes remote processing necessary. Bile acid labeled with /sup 13/C in the amino acid moiety, e.g. cholylglycine-1-/sup 13/C can be used for detection of increased bile acid deconjugation by intestinal bacteria, since the glycine-/sup 13/C, when liberated, is rapidly converted to /sup 13/CO/sub 2/, which is expired in breath. Bile acids labeled with stable isotopes may also be used for quantitation by inverse isotope dilution, but the technique is still in the development stage and seems unlikely to compete successfully with radioimmunoassay.

  11. 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

  12. 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

    -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...

  13. The effect of prostanoids on hepatic bile flow in dogs with normal liver and bile duct cell hyperplasia.

    Science.gov (United States)

    Solomon, H; Contis, J; Li, A P; Kaminski, D L

    1996-04-01

    Bile flow rates and composition are subject to a wide variety of neural, endocrine and paracrine influences. The effects of these multiple factors may be different in the diseased liver compared to the response produced in the normal liver. As prostanoids may have a therapeutic role in liver disease it was intended to evaluate the effects of two principal therapeutic prostanoids, prostaglandin E2 and prostacyclin, on bile flow in dogs with a normal liver and in dogs with hepatotoxin-induced liver injury. Initially, in awake animals with chronic biliary and gastric fistulas the bile flow response to prostaglandin E2 and prostacyclin was evaluated and compared to the response produced by bile salt infusion alone and to that produced by the standard choleretic hormones, secretin and glucagon. The animals were then fed alpha-naphthylisothiocyanate (ANIT) and the studies repeated. ANIT is a hepatoxin that produces bile duct cell hyperplasia which was confirmed in dogs by demonstrating that ANIT increased [3H]thymidine incorporation by isolated canine bile duct cells. In normal dogs, the prostanoids, secretin, and glucagon increased hepatic bile flow. 10 days of ANIT feeding produced a hypercholeresis. While secretin was able to stimulate the hyperplastic biliary epithelium and increase bile flow over values produced by the hyperplastic biliary epithelium alone, neither prostaglandin E2, prostacyclin, or glucagon appeared to stimulate the hyperplastic biliary epithelium. As ANIT produced evidence of cholestasis and hepatocellular damage, only secretin would seem to have a potential therapeutic role in increasing bile flow in cholestatic liver disorders associated with bile duct cell hyperplasia.

  14. Recent advances in understanding bile acid homeostasis [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    John YL Chiang

    2017-11-01

    Full Text Available Bile acids are derived from cholesterol to facilitate intestinal nutrient absorption and biliary secretion of cholesterol. Recent studies have identified bile acids as signaling molecules that activate nuclear farnesoid X receptor (FXR and membrane G protein-coupled bile acid receptor-1 (Gpbar-1, also known as TGR5 to maintain metabolic homeostasis and protect liver and other tissues and cells from bile acid toxicity. Bile acid homeostasis is regulated by a complex mechanism of feedback and feedforward regulation that is not completely understood. This review will cover recent advances in bile acid signaling and emerging concepts about the classic and alternative bile acid synthesis pathway, bile acid composition and bile acid pool size, and intestinal bile acid signaling and gut microbiome in regulation of bile acid homeostasis.

  15. Chenodeoxycholic acid stimulated fibroblast growth factor 19 response - a potential biochemical test for bile acid diarrhoea

    DEFF Research Database (Denmark)

    Borup, Christian; Wildt, S; Rumessen, J J

    2017-01-01

    BACKGROUND: Bile acid diarrhoea (BAD) is underdiagnosed and better diagnostic tests are needed. Fasting serum fibroblast growth factor-19 (FGF19) has insufficient diagnostic value, but this may be improved by stimulation. AIM: To explore if an impaired FGF19 response identifies primary bile acid ...... response following chenodeoxycholic acid plus meal is impaired in primary bile acid diarrhoea. This may provide a biochemical diagnostic test.......BACKGROUND: Bile acid diarrhoea (BAD) is underdiagnosed and better diagnostic tests are needed. Fasting serum fibroblast growth factor-19 (FGF19) has insufficient diagnostic value, but this may be improved by stimulation. AIM: To explore if an impaired FGF19 response identifies primary bile acid...

  16. In vitro bile acid adsorption by bismuth subsalicylate and montmorillonite.

    Science.gov (United States)

    Kocoshis, S A; Ghent, C N; Gryboski, J D

    1984-12-01

    We investigated the capability of Pepto-Bismol and its components (Veegum and bismuth subsalicylate) to sequester bile acids from aqueous solution in vitro and compared it to that of cholestyramine. Through a pH range of 3-9, all substances tested sequestered free and conjugated bile acids in quantities directly related to the concentration of the sequestering agent within the incubation mixture. Veegum was more effective gram for gram than bismuth subsalicylate. Pepto-Bismol, whose sequestering capacity approximated cholestyramine's, absorbed more than either of its components alone. The relationship between Pepto-Bismol's in vitro bile acid binding and its in vivo antidiarrheal properties is unknown.

  17. Conjugated bile acids in gallbladder bile and serum as potential biomarkers for cholesterol polyps and adenomatous polyps.

    Science.gov (United States)

    Zhao, Mei-Fen; Huang, Peng; Ge, Chun-Lin; Sun, Tao; Ma, Zhi-Gang; Ye, Fei-Fei

    2016-02-28

    To identify conjugated bile acids in gallbladder bile and serum as possible biomarkers for cholesterol polyps (CPs) and adenomatous polyps (APs). Gallbladder bile samples and serum samples were collected from 18 patients with CPs (CP group), 9 patients with APs (AP group), and 20 patients with gallstones (control group) from March to November, 2013. High performance liquid chromatography (HPLC) assay with ultraviolent detection was used to detect the concentration of 8 conjugated bile acids (glycocholic acid, GCA; taurocholic acid, TCA; glycochenodeoxycholic acid, GCDCA; taurochenodeoxycholic acid, TCDCA; glycodeoxycholic acid, GDCA; taurodeoxycholic acid, TDCA; taurolithocholic acid, TLCA; tauroursodeoxycholic acid, TUDCA) in bile samples and serum samples. The diagnostic efficacy of serum GCA, GCDCA and TCDCA was evaluated. These 8 conjugated bile acids in gallbladder bile and serum were completely identified within 10 minutes with good linearity (correlation coefficient: R>0.9900; linearity range: 3.91-500 µg/mL). Among these conjugated bile acids, the levels of gallbladder bile GCDCA and TCDCA in the CP group were significantly higher than those in the AP group (p<0.05). Furthermore, serum GCDCA and TCDCA as well as GCA were significantly higher in the AP group than the CP group (p<0.05). Serum GCDCA alone (≤12 µg/mL) had relatively better diagnostic efficacy than the other conjugated bile acids. The levels of serum GCA, GCDCA and TCDCA may be valuable for differentiation of APs and CPs.

  18. Effect of ursodeoxycholic acid administration on bile duct proliferation and cholestasis in bile duct ligated rat.

    Science.gov (United States)

    Frezza, E E; Gerunda, G E; Plebani, M; Galligioni, A; Giacomini, A; Neri, D; Faccioli, A M; Tiribelli, C

    1993-07-01

    The origin, mechanism, and significance of the bile duct proliferation (BDP) associated with cholestasis remain unexplained. This study examined the effect of oral administration of ursodeoxycholic acid (UDCA) on both BDP and cholestasis in the rat. After bile duct ligation, male Sprague-Dawley rats were treated for 30 days with either UDCA (5 mg/day) (group A) or saline solution (group B). Animals were sacrificed at day 30. The serum activity of aminotransferase (ALT, AST), alkaline phosphatase, and gamma-glutamyltransferase (GGT) was significantly lower (P acids were lower (P animals (33 +/- 11 vs 64 +/- 22 per 1000 cells; P acid and lithocolate and increase periductular bile acid recirculation.(ABSTRACT TRUNCATED AT 250 WORDS)

  19. Olfactory sensitivity of Pacific Lampreys to lamprey bile acids

    Science.gov (United States)

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

    2009-01-01

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

  20. Matrix metalloproteinase-14 mediates formation of bile ducts and hepatic maturation of fetal hepatic progenitor cells

    Energy Technology Data Exchange (ETDEWEB)

    Otani, Satoshi [Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo (Japan); Kakinuma, Sei, E-mail: skakinuma.gast@tmd.ac.jp [Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo (Japan); Department for Liver Disease Control, Tokyo Medical and Dental University, Tokyo (Japan); Kamiya, Akihide [Institute of Innovative Science and Technology, Tokai University, Isehara (Japan); Goto, Fumio; Kaneko, Shun; Miyoshi, Masato; Tsunoda, Tomoyuki; Asano, Yu; Kawai-Kitahata, Fukiko; Nitta, Sayuri; Nakata, Toru; Okamoto, Ryuichi; Itsui, Yasuhiro; Nakagawa, Mina; Azuma, Seishin [Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo (Japan); Asahina, Yasuhiro [Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo (Japan); Department for Liver Disease Control, Tokyo Medical and Dental University, Tokyo (Japan); Yamaguchi, Tomoyuki [Division of Stem Cell Therapy, Institute of Medical Science, The University of Tokyo, Tokyo (Japan); Koshikawa, Naohiko [Division of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, Tokyo (Japan); Seiki, Motoharu [Medical School, Kanazawa University, Kanazawa (Japan); Nakauchi, Hiromitsu [Division of Stem Cell Therapy, Institute of Medical Science, The University of Tokyo, Tokyo (Japan); and others

    2016-01-22

    Fetal hepatic stem/progenitor cells, called hepatoblasts, play central roles in liver development; however, the molecular mechanisms regulating the phenotype of these cells have not been completely elucidated. Matrix metalloproteinase (MMP)-14 is a type I transmembrane proteinase regulating pericellular proteolysis of the extracellular matrix and is essential for the activation of several MMPs and cytokines. However, the physiological functions of MMP-14 in liver development are unknown. Here we describe a functional role for MMP-14 in hepatic and biliary differentiation of mouse hepatoblasts. MMP-14 was upregulated in cells around the portal vein in perinatal stage liver. Formation of bile duct-like structures in MMP-14–deficient livers was significantly delayed compared with wild-type livers in vivo. In vitro biliary differentiation assays showed that formation of cholangiocytic cysts derived from MMP-14–deficient hepatoblasts was completely impaired, and that overexpression of MMP-14 in hepatoblasts promoted the formation of bile duct-like cysts. In contrast, the expression of molecules associated with metabolic functions in hepatocytes, including hepatic nuclear factor 4α and tryptophan 2,3-dioxygenase, were significantly increased in MMP-14–deficient livers. Expression of the epidermal growth factor receptor and phosphorylation of mitogen-activated protein kinases were significantly upregulated in MMP-14–deficient livers. We demonstrate that MMP-14–mediated signaling in fetal hepatic progenitor cells promotes biliary luminal formation around the portal vein and negatively controls the maturation of hepatocytes. - Highlights: • Loss of MMP-14 delayed formation of bile duct-like structures in perinatal liver. • Overexpression of MMP-14 in hepatobalsts promoted the biliary formation in vitro. • Loss of MMP-14 promoted hepatocyte maturation of hepatoblasts in vivo. • MMP-14–mediated signaling regulates terminal differentiation of

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

    African Journals Online (AJOL)

    Yomi

    2012-01-16

    Jan 16, 2012 ... properties of dominant lactic acid bacteria isolated from traditional ... spontaneous and alkaline fermentation of baobab ... leaching ashes with water is added, resulting in an .... Table 4 shows the effect of bile on the growth of.

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

    African Journals Online (AJOL)

    2014-12-31

    Dec 31, 2014 ... bacteria in the colon is to promote the biotransforma- tion of primary bile acids ... tant role in the pathogenesis of obesity and diabetes7. The pathogenesis ... tion, gut dysbiosis, and gastrointestinal cancer. Exp Biol. Med 2014 ...

  3. Explanation of colon cancer pathophysiology through analyzing the disrupted homeostasis of bile acids.

    Science.gov (United States)

    Dongfeng, Duan; An, Chen; Shujia, Peng; Jikai, Yin; Tao, Yang; Rui, Dong; Kai, Tan; Yafeng, Chen; Jianguo, Lu; Xilin, Du

    2014-12-01

    The colon plays a key role in regulating the homeostasis of bile acids. The present study aims to evaluate the influence of colon cancer towards the homeostasis of bile acids. The free and conjugated bile acids were determined using ultraperformance LC (UPLC) coupled with ABI 4000 QTRAP triple quadrupole instruments. The results showed that the free bile acids in serum of patients with colon cancers tend to increase, and the conjugated bile acids tended to decrease, especially for taurolithocholate (TLCA) (p<0.001). The alteration of bile acids balance in colon cancers indicated the possibility of complicated diseases due to the disrupted balance of bile acids.

  4. Refractory anastomotic bile leaks after orthotopic liver transplantation are associated with hepatic artery disease.

    Science.gov (United States)

    DaVee, Tomas; Geevarghese, Sunil K; Slaughter, James C; Yachimski, Patrick S

    2017-05-01

    Anastomotic bile leaks are common after orthotopic liver transplant (OLT), and standard treatment consists of placement of a biliary endoprosthesis. The objectives of this study were to identify risk factors for refractory anastomotic bile leaks and to determine the morbidity associated with refractory bile leaks after OLT. Consecutive adult patients who underwent ERCP for treatment of post-OLT biliary adverse events between 2009 and 2014 at a high-volume transplant center were retrospectively identified. A refractory leak was defined as a bile leak that persisted after placement of a plastic biliary endoprosthesis and required repeat endoscopic or surgical intervention. Forty-three subjects met study inclusion criteria. Median age was 57 years, and 36 (84%) subjects were men. Refractory bile leaks were diagnosed in 40% of subjects (17/43). Time-to-event analysis revealed an association between refractory bile leaks and the combined outcome of death, repeat transplant, or surgical biliary revision (hazard ratio, 3.78; 95% confidence interval, 1.25-11.45; P = .01). Hepatic artery disease was more common with refractory compared with treatment-responsive bile leaks (53% vs 8%, P = .001). Refractory anastomotic bile leaks after liver transplantation are associated with decreased event-free survival. Hepatic artery disease is associated with refractory leaks. Large-scale prospective studies should be performed to define the optimal management of patients at risk for refractory bile leaks. Copyright © 2017 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.

  5. Bile ductal injury and ductular reaction are frequent phenomena with different significance in autoimmune hepatitis

    NARCIS (Netherlands)

    Verdonk, Robert C.; Lozano, Mallaki F.; Berg, van den Aad P.; Gouw, Annette S. H.

    BACKGROUND & AIMS: The significance of bile duct injury and ductular reaction in biopsies from autoimmune hepatitis patients is not clear. We aim to establish the prevalence and clinical relevance of both phenomena in autoimmune hepatitis. METHODS: Cases of newly diagnosed, untreated autoimmune

  6. 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.

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

    NARCIS (Netherlands)

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

    1990-01-01

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

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

    Science.gov (United States)

    Martinez, María del Carmen; Ruspini, Silvina Fernanda; Afonso, Susana Graciela; Meiss, Roberto; Buzaleh, Ana Maria

    2015-01-01

    The effect of bile acids administration to an experimental mice model of Protoporphyria produced by griseofulvin (Gris) was investigated. The aim was to assess whether porphyrin excretion could be accelerated by bile acids treatment in an attempt to diminish liver damage induced by Gris. Liver damage markers, heme metabolism, and oxidative stress parameters were analyzed in mice treated with Gris and deoxycholic (DXA), dehydrocholic (DHA), chenodeoxycholic, or ursodeoxycholic (URSO). The administration of Gris alone increased the activities of glutathione reductase (GRed), superoxide dismutase (SOD), alkaline phosphatase (AP), gamma glutamyl transpeptidase (GGT), and glutathione-S-transferase (GST), as well as total porphyrins, glutathione (GSH), and cytochrome P450 (CYP) levels in liver. Among the bile acids studied, DXA and DHA increased PROTO IX excretion, DXA also abolished the action of Gris, reducing lipid peroxidation and hepatic GSH and CYP levels, and the activities of GGT, AP, SOD, and GST returned to control values. However, porphyrin accumulation was not prevented by URSO; instead this bile acid reduced ALA-S and the antioxidant defense enzymes system activities. In conclusion, we postulate that DXA acid would be more effective to prevent liver damage induced by Gris. PMID:25945334

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

    Directory of Open Access Journals (Sweden)

    María del Carmen Martinez

    2015-01-01

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

  10. Experimental protoporphyria: effect of bile acids on liver damage induced by griseofulvin.

    Science.gov (United States)

    Martinez, María Del Carmen; Ruspini, Silvina Fernanda; Afonso, Susana Graciela; Meiss, Roberto; Buzaleh, Ana Maria; Batlle, Alcira

    2015-01-01

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

  11. 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.

  12. Impact of Gut Microbiota-Mediated Bile Acid Metabolism on the Solubilization Capacity of Bile Salt Micelles and Drug Solubility.

    Science.gov (United States)

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

    2017-04-03

    In recent years, the gut microbiome has gained increasing appreciation as a determinant of the health status of the human host. Bile salts that are secreted into the intestine may be biotransformed by enzymes produced by the gut bacteria. To date, bile acid research at the host-microbe interface has primarily been directed toward effects on host metabolism. The aim of this work was to investigate the effect of changes in gut microbial bile acid metabolism on the solubilization capacity of bile salt micelles and consequently intraluminal drug solubility. First, the impact of bile acid metabolism, mediated in vivo by the microbial enzymes bile salt hydrolase (BSH) and 7α-dehydroxylase, on drug solubility was assessed by comparing the solubilization capacity of (a) conjugated vs deconjugated and (b) primary vs secondary bile salts. A series of poorly water-soluble drugs (PWSDs) were selected as model solutes on the basis of an increased tendency to associate with bile micelles. Subsequently, PWSD solubility and dissolution was evaluated in conventional biorelevant simulated intestinal fluid containing host-derived bile acids, as well as in media modified to contain microbial bile acid metabolites. The findings suggest that deconjugation of the bile acid steroidal core, as dictated by BSH activity, influences micellar solubilization capacity for some PWSDs; however, these differences appear to be relatively minor. In contrast, the extent of bile acid hydroxylation, regulated by microbial 7α-dehydroxylase, was found to significantly affect the solubilization capacity of bile salt micelles for all nine drugs studied (p solubility and dissolution. Observed differences in biorelevant media appeared to be both drug- and amphiphile (bile salt/lecithin) concentration-dependent. Our studies herein indicate that bile acid modifications occurring at the host-microbe interface could lead to alterations in the capacity of intestinal bile salt micelles to solubilize drugs

  13. Biophysical investigations into the interactions of endotoxins with bile acids.

    Science.gov (United States)

    Fukuoka, Satoshi; Richter, Walter; Howe, Jörg; Andrä, Jörg; Rössle, Manfred; Alexander, Christian; Gutsmann, Thomas; Brandenburg, Klaus

    2012-04-01

    The interaction of selected endotoxin preparations (lipid A from Erwinia carotovora and LPS Re and Ra from Salmonella enterica sv. Minnesota strains R595 and R60, respectively) with selected bile acids was investigated biophysically. Endotoxin aggregates were analyzed for their gel-to-liquid crystalline phase behavior, the type of their aggregates, the conformation of particular functional groups, and their Zeta potential in the absence and presence of the bile acids by applying Fourier-transform infrared spectroscopy, differential scanning calorimetry, measurements of the electrophoretic mobility, and synchrotron radiation X-ray scattering. In addition, the ability of the endotoxins to induce cytokines in human mononuclear cells was tested in the absence and presence of varying concentrations of bile acids. The data show that the endotoxin:bile acid interaction is not governed by Coulomb forces, rather a hydrophobic interaction takes place. This leads to an enhanced formation of the inherent cubic aggregate structures of the endotoxins, concomitant with a slight disaggregation, as evidenced by freeze-fracture electron microscopy. Parallel to this, the addition of bile acids increased the bioactivity of lipid A and, to a lower degree, also that of the tested rough mutant LPS at lower concentrations of the endotoxin preparation, a finding similar as reported for the interaction of other agents such as hemoglobin. These data imply that there are general mechanisms that govern the expression of biological activities of endotoxins.

  14. Pyrene appended bile acid conjugates: Synthesis and a structure ...

    Indian Academy of Sciences (India)

    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 ...

  15. Bile acid malabsorption in chronic diarrhea: pathophysiology and treatment.

    Science.gov (United States)

    Barkun, Alan N; Love, Jonathan; Gould, Michael; Pluta, Henryk; Steinhart, Hillary

    2013-11-01

    Bile acid malabsorption (BAM) is a common but frequently under-recognized cause of chronic diarrhea, with an estimated prevalence of 4% to 5%. The published literature for the period 1965 to 2012 was examined for articles regarding the pathophysiology and treatment of BAM to provide an overview of the management of BAM in gastroenterology practice. BAM is classified as type 1 (secondary to ileal dysfunction), type 2 (idiopathic) or type 3 (secondary to gastrointestinal disorders not associated with ileal dysfunction). The estimated prevalence of BAM is >90% in patients with resected Crohn disease (CD) and 11% to 52% of unresected CD patients (type 1); 33% in diarrhea-predominant irritable bowel syndrome (type 2); and is a frequent finding postcholecystectomy or postvagotomy (type 3). Investigations include BAM fecal bile acid assay, 23-seleno-25-homo-tauro-cholic acid (SeHCAT) testing and high-performance liquid chromatography of serum 7-α-OH-4-cholesten-3-one (C4), to determine the level of bile acid synthesis. A less time-consuming and expensive alternative in practice is an empirical trial of the bile acid sequestering agent cholestyramine. An estimated 70% to 96% of chronic diarrhea patients with BAM respond to short-course cholestyramine. Adverse effects include constipation, nausea, borborygmi, flatulence, bloating and abdominal pain. Other bile acid sequestering agents, such as colestipol and colesevelam, are currently being investigated for the treatment of BAM-associated diarrhea. BAM is a common cause of chronic diarrhea presenting in gastroenterology practice. In accordance with current guidelines, an empirical trial of a bile acid sequestering agent is warranted as part of the clinical workup to rule out BAM.

  16. Colon cancer metastasis mimicking intraductal papillary neoplasm of the extra-hepatic bile duct.

    Science.gov (United States)

    Yamao, Takanobu; Hayashi, Hiromitsu; Higashi, Takaaki; Takeyama, Hideyuki; Kaida, Takayoshi; Nitta, Hidetoshi; Hashimoto, Daisuke; Chikamoto, Akira; Beppu, Toru; Baba, Hideo

    2015-01-01

    An accurate diagnosis of the primary cancer in cases with metastatic lesions is quite important because misdiagnosis may lead to the selection of incorrect adjuvant therapy and worse long-term outcomes after surgery. The metastatic sites associated with the dissemination of colon cancer are well known and normally predictable, which includes the lymphatic, haematogenous, or peritoneal regions, while other locations are quite rare. In this report, we present a case of colon cancer with an unusual metastatic pattern mimicking an intraductal papillary neoplasm of the bile duct (IPNB) present in the extra-hepatic bile duct with a cytokeratin (CK)-7-negative and CK-20-positive profile (intestinal type). In the case of this patient who had a history of colon cancer, immunohistochemical staining for the CKs was useful for distinguishing between primary IPNB and colon cancer metastases. We suspect that the metastatic pattern of this case of colon cancer that mimicked IPNB at the extra-hepatic bile duct developed incidentally via the bile stream. This is a rare case of colon cancer metastasis mimicking IPNB at the extra-hepatic bile duct. Our findings also suggest that there may be an incidental 4th metastatic route via the bile stream. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  17. 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.

  18. Bile acid nuclear receptor FXR and digestive system diseases.

    Science.gov (United States)

    Ding, Lili; Yang, Li; Wang, Zhengtao; Huang, Wendong

    2015-03-01

    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.

  19. Bilirubin and bile acids removal by haemoperfusion through synthetic resin "Persorb".

    Science.gov (United States)

    Filip, K; Malý, J; Horký, J; Tlustáková, M; Kálal, J; Vrána, M

    1990-01-01

    A new type of styrene-divinylbenzene copolymer coated with polyhema was tested for biocompatibility and ability to remove bile acid, bilirubin, phenols and cholesterol in dogs with surgically induced biliary obstruction. After 4-hr hemoperfusion through a polypropylene column containing 325 g of resin, performed 7-10 days after the ligature of the cystic and common bile duct, the serum levels of bile acids, bilirubin, phenols and cholesterol decreased by 60.9 +/- 30.3% (p less than 0.001), 34.8 +/- 12.2% (p less than 0.001), 19.4 +/- 15.6% (p less than 0.001) and 15.3 +/- 4.2% (p less than 0.05), respectively. The procedure was well tolerated, no bleeding or other adverse reactions occurred. The average platelet count decreased by 19.4 +/- 15.6% (p less than 0.05). Hemoperfusion through the Czechoslovak resin coated with polyhema is safe and efficient for removal of bile acids and other protein-bound and lipid-soluble substances which accumulate in cholestatic syndromes and hepatic failure. Thus, it may play an important role in the treatment of such events as a method of artificial liver support.

  20. Routine extra-hepatic bile duct resection in gallbladder cancer patients without bile duct infiltration: A systematic review.

    Science.gov (United States)

    Nigri, Giuseppe; Berardi, Giammauro; Mattana, Chiara; Mangogna, Livia; Petrucciani, Niccolò; Sagnotta, Andrea; Aurello, Paolo; D'Angelo, Francesco; Ramacciato, Giovanni

    2016-12-01

    The optimal treatment for advanced gallbladder cancer, in particular T2 stage cancer, is unclear. The use of "radical cholecystectomy" or more extended procedures with extra-hepatic bile duct resection are matter of debate. Due to the lack of consensus regarding the oncological significance of routine extra-hepatic bile duct (EBD) resection for gallbladder carcinoma, we decided to perform a systematic review investigating the real benefit of this procedure focusing on the primary outcomes of overall survival and disease-free survival. A systematic literature search was performed using PubMed, EMBASE, Scopus and the Cochrane Library Central according to the PRISMA statement guidelines for conducting and reporting systematic reviews. Multiple primary and secondary outcomes were analyzed. The selected articles included 424 patients who underwent routine EBD resection without bile duct infiltration. Only two papers discussed the number of dissected lymph nodes during EBD resection for gallbladder carcinoma. Four of the seven included papers reported on tumor involvement in lymph nodes at rates ranging between 39% and 83%. All of the studies included in this systematic review reported on results of overall survival. In general, 5-years OS rate of the EBD-resected patients was not significantly different than that of the EBD-preservation group, while the mobility was significantly higher in the EBD resection group. Routine EBD resection in gallbladder cancer patients without bile duct infiltration is not associated with improved overall survival, improved lymph-node harvesting or with minor recurrence rate, but it is associated with higher morbidity rates. Copyright © 2016 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Bon Jeong Ku

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

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

    Science.gov (United States)

    Brighton, Cheryl A; Rievaj, Juraj; Kuhre, Rune E; Glass, Leslie L; Schoonjans, Kristina; Holst, Jens J; Gribble, Fiona M; Reimann, Frank

    2015-11-01

    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-cells, we observed that taurodeoxycholate (TDCA) and taurolithocholate (TLCA) increased intracellular cAMP and Ca(2+). In primary intestinal cultures, TDCA was a more potent GLP-1 secretagogue than taurocholate (TCA) and TLCA, correlating with a stronger Ca(2+) response to TDCA. Using small-volume Ussing chambers optimized for measuring GLP-1 secretion, we found that both a GPBAR1 agonist and TDCA stimulated GLP-1 release better when applied from the basolateral than from the luminal direction and that luminal TDCA was ineffective when intestinal tissue was pretreated with an ASBT inhibitor. ASBT inhibition had no significant effect in nonpolarized primary cultures. Studies in the perfused rat gut confirmed that vascularly administered TDCA was more effective than luminal TDCA. Intestinal primary cultures and Ussing chamber-mounted tissues from GPBAR1-knockout mice did not secrete GLP-1 in response 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.

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

    Science.gov (United States)

    Brighton, Cheryl A.; Rievaj, Juraj; Kuhre, Rune E.; Glass, Leslie L.; Schoonjans, Kristina; Holst, Jens J.

    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-cells, we observed that taurodeoxycholate (TDCA) and taurolithocholate (TLCA) increased intracellular cAMP and Ca2+. In primary intestinal cultures, TDCA was a more potent GLP-1 secretagogue than taurocholate (TCA) and TLCA, correlating with a stronger Ca2+ response to TDCA. Using small-volume Ussing chambers optimized for measuring GLP-1 secretion, we found that both a GPBAR1 agonist and TDCA stimulated GLP-1 release better when applied from the basolateral than from the luminal direction and that luminal TDCA was ineffective when intestinal tissue was pretreated with an ASBT inhibitor. ASBT inhibition had no significant effect in nonpolarized primary cultures. Studies in the perfused rat gut confirmed that vascularly administered TDCA was more effective than luminal TDCA. Intestinal primary cultures and Ussing chamber–mounted tissues from GPBAR1-knockout mice did not secrete GLP-1 in response 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. PMID:26280129

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

    Science.gov (United States)

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

    2017-12-29

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

  5. 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

    2016-12-15

    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 liver, the expression of induction of the rate-limiting enzyme in bile salt synthesis, cytochrome P450 7a1 (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.

  6. Genetic Variation in Bile Acid Metabolism: Implications for Lipoprotein Homeostasis

    NARCIS (Netherlands)

    Hofman, M.K.

    2005-01-01

    Genetic factors play an important role in the homeostasis of cholesterol in the human body. An important pathway for eliminating cholesterol from the body is to convert it into bile acids in the liver. The rate-limiting enzyme in this catabolism of cholesterol is CYP7A1. In the gene of CYP7A1, a

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

    African Journals Online (AJOL)

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

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

    African Journals Online (AJOL)

    Background: Unclear pathogenesis existed for nasopharyngeal carcinoma. Aims: to analyze the role of bile acids in the pathogenesis of nasopharyngeal carcinoma. Methods: 20 healthy volunteers and 20 patients with nasopharyngeal carcinoma were enrolled between January 1st, 2013 and December 31st, 2014.

  9. Determinants of postprandial plasma bile acid kinetics in human volunteers

    NARCIS (Netherlands)

    Fiamoncini, J.; Yiorkas, A.M.; Gedrich, K.; Rundle, M.; Alsters, S.I.; Roeselers, G.; Broek, T.J. van den; Clavel, T.; Lagkouvardos, I.; Wopereis, S.; Frost, G.; Ommen, B. van; Blakemore, A.I.; Daniel, H.

    2017-01-01

    Bile acids (BA) are signaling molecules with a wide range of biological effects, also identified among the most responsive plasma metabolites in the postprandial state. We here describe this response to different dietary challenges and report on key determinants linked to its interindividual

  10. Effect of taurine and bile acid supplementation and their interaction ...

    African Journals Online (AJOL)

    Effect of taurine and bile acid supplementation and their interaction on performance, serum components, ileal viscosity and carcass characteristics of broiler chickens. ... feed conversion ratio (FCR), fat digestibility, serum cholesterol (Chol), triglyceride (TG), high-density lipoprotein (HDL), and low-density lipoprotein (HDL).

  11. Bile acid malabsorption in patients with chronic diarrhoea

    DEFF Research Database (Denmark)

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

    2003-01-01

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

  12. Target profiling analyses of bile acids in the evaluation of hepatoprotective effect of gentiopicroside on ANIT-induced cholestatic liver injury in mice.

    Science.gov (United States)

    Tang, Xiaowen; Yang, Qiaoling; Yang, Fan; Gong, Junting; Han, Han; Yang, Li; Wang, Zhengtao

    2016-12-24

    Gentiopicroside (GPS), one of iridoid glucoside representatives, is the most potential active component in Gentiana rigescens Franch. ex Hemsl and Gentiana macrophylla Pall. These two herbs have been used to treat jaundice and other hepatic and billiary diseases in traditional Chinese medicine for thousands of years. This study aimed to investigate the protective effects and mechanisms of GPS on α-naphthylisothiocyanate (ANIT) induced cholestatic liver injury in mice. Mice were treated with GPS (130mg/kg, ig) for 5 consecutive days. On the third day, mice were given a single dose of Alpha-naphthylisothiocyanate (75mg/kg, ig). Serum biochemical markers and individual bile acids in serum, liver, urine and feces were measured at different time points after ANIT administration. The expression of hepatic bile acid synthesis, uptake and transporter genes as well as ileum bile acid transporter genes were assayed. In this study, ANIT exposure resulted in serious cholestasis with liver injury, which was demonstrated by dramatically increased serum levels of ALT, ALP, TBA and TBIL along with TCA CA, MCAs and TMCAs accumulation in both liver and serum. Furthermore, ANIT significantly decreased bile acid synthesis related gene expressions, and increased expression of bile acid transporters in liver. Continuous treatment with GPS attenuated ANIT-induced acute cholestasis as well as liver injury and correct the dyshomeostasis of bile acids induced by ANIT. Our data showed that GPS significantly upregulated the hepatic mRNA levels of synthesis enzymes (Cyp8b1 and Cyp27a1) and transporters (Mrp4 Mdr1 and Ost-β) as well as ileal bile acid circulation mediators (Asbt and Fgf15), accompanied by serum and hepatic bile acid levels decrease and further urinary and fecal bile acid levels increase. GPS can change bile acids metabolism which highlights its importance in mitigating cholestasis, resulting in the marked decrease of intracellular bile acid pool back toward basal levels. And

  13. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-elicited effects on bile acid homeostasis: Alterations in biosynthesis, enterohepatic circulation, and microbial metabolism.

    Science.gov (United States)

    Fader, Kelly A; Nault, Rance; Zhang, Chen; Kumagai, Kazuyoshi; Harkema, Jack R; Zacharewski, Timothy R

    2017-07-19

    2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant which elicits hepatotoxicity through activation of the aryl hydrocarbon receptor (AhR). Male C57BL/6 mice orally gavaged with TCDD (0.01-30 µg/kg) every 4 days for 28 days exhibited bile duct proliferation and pericholangitis. Mass spectrometry analysis detected a 4.6-fold increase in total hepatic bile acid levels, despite the coordinated repression of genes involved in cholesterol and primary bile acid biosynthesis including Cyp7a1. Specifically, TCDD elicited a >200-fold increase in taurolithocholic acid (TLCA), a potent G protein-coupled bile acid receptor 1 (GPBAR1) agonist associated with bile duct proliferation. Increased levels of microbial bile acid metabolism loci (bsh, baiCD) are consistent with accumulation of TLCA and other secondary bile acids. Fecal bile acids decreased 2.8-fold, suggesting enhanced intestinal reabsorption due to induction of ileal transporters (Slc10a2, Slc51a) and increases in whole gut transit time and intestinal permeability. Moreover, serum bile acids were increased 45.4-fold, consistent with blood-to-hepatocyte transporter repression (Slco1a1, Slc10a1, Slco2b1, Slco1b2, Slco1a4) and hepatocyte-to-blood transporter induction (Abcc4, Abcc3). These results suggest that systemic alterations in enterohepatic circulation, as well as host and microbiota bile acid metabolism, favor bile acid accumulation that contributes to AhR-mediated hepatotoxicity.

  14. Structural studies of five novel bile acid-4-aminopyridine conjugates.

    Science.gov (United States)

    Ahonen, Kari V; Lahtinen, Manu K; Löfman, Miika S; Kiesilä, Anniina M; Valkonen, Arto M; Sievänen, Elina I; Nonappa; Kolehmainen, Erkki T

    2012-09-01

    Synthesis and solid-state structural characterization of five bile acid amides of 4-aminopyridine (4-AP) are reported. Systematic crystallization experiments revealed a number of structural modifications and/or solvate/hydrate systems for these conjugates. Particularly, cholic acid conjugate exhibited five distinct structure modifications, including one anhydrous form, mono- and dihydrates, as well as ethanol and 2-butanol solvates. The obtained crystal forms were examined extensively with various analytical methods, including solid-state NMR, Raman, and IR spectroscopies, powder and single crystal X-ray diffraction methods, thermogravimetry, and differential scanning calorimetry. After releasing their crystal solvent molecules, the resulted non-solvated structure forms showed 50-75°C higher melting points than corresponding bile acids, and thermal degradation occurred for all conjugates at about 300-330°C. Moreover, the single crystal X-ray structure of the ursodeoxycholic acid-4-aminopyridine conjugate is reported. Copyright © 2012 Elsevier Inc. All rights reserved.

  15. Ostα depletion protects liver from oral bile acid load.

    Science.gov (United States)

    Soroka, Carol J; Velazquez, Heino; Mennone, Albert; Ballatori, Nazzareno; Boyer, James L

    2011-09-01

    Bile acid homeostasis is tightly maintained through interactions between the liver, intestine, and kidney. During cholestasis, the liver is incapable of properly clearing bile acids from the circulation, and alternative excretory pathways are utilized. In obstructive cholestasis, urinary elimination is often increased, and this pathway is further enhanced after bile duct ligation in mice that are genetically deficient in the heteromeric, basolateral organic solute transporter alpha-beta (Ostα-Ostβ). In this study, we examined renal and intestinal function in Ostα-deficient and wild-type mice in a model of bile acid overload. After 1% cholic acid feeding, Ostα-deficient mice had significantly lower serum ALT levels compared with wild-type controls, indicating partial protection from liver injury. Urinary clearance of bile acids, but not clearance of [(3)H]inulin, was significantly higher in cholic acid-fed Ostα-deficient mice compared with wild-type mice but was not sufficient to account for the protection. Fecal excretion of bile acids over the 5 days of cholic acid feeding was responsible for almost all of the bile acid loss in Ostα-deficient mice, suggesting that intestinal losses of bile acids accounted for the protection from liver injury. Thus fecal loss of bile acids after bile acid overload reduced the need for the kidney to filter and excrete the excess bile acids. In conclusion, Ostα-deficient mice efficiently eliminate excess bile acids via the feces. Inhibition of intestinal bile acid absorption might be an effective therapeutic target in early stages of cholestasis when bile acids are still excreted into bile.

  16. 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

  17. Bile duct complications of hepatic arterial infusion chemotherapy evaluated by helical CT

    Energy Technology Data Exchange (ETDEWEB)

    Phongkitkarun, S. [Department of Diagnostic Radiology, University of Texas M. D. Anderson Cancer Center, Houston, TX (United States)]. E-mail: rasih@mahidol.ac.th; Kobayashi, S. [Department of Diagnostic Radiology, University of Texas M. D. Anderson Cancer Center, Houston, TX (United States); Varavithya, V. [Department of Diagnostic Radiology, University of Texas M. D. Anderson Cancer Center, Houston, TX (United States); Huang, X. [Department of Biostatistics, University of Texas M. D. Anderson Cancer Center, Houston, TX (United States); Curley, S.A. [Department of Surgical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX (United States); Charnsangavej, C. [Department of Diagnostic Radiology, University of Texas M. D. Anderson Cancer Center, Houston, TX (United States)

    2005-06-01

    AIM: To describe the imaging findings of bile duct complications of hepatic arterial infusion chemotherapy (HAIC) using helical CT, to set diagnostic criteria, to develop a CT grading system, and to correlate these with clinical findings and laboratory data. METHODS: Follow-up helical CT of the abdomen was performed every 3 months for 60 patients receiving HAIC. Three radiologists reviewed all CT studies before and after treatment, using either the picture archiving and communication system or hard copies. The findings of bile duct abnormalities were correlated with findings from other imaging techniques, clinical symptoms and laboratory data. RESULTS: Bile duct abnormalities developed in 34 (57%) of cases either during HAIC or 1 to 12 months after treatment. In 14 (41%) of these 34 patients, enhancement of the hepatic parenchyma along the dilated bile duct or in the segmental or lobar distribution was observed. In 43 cases (72%), normal or abnormal alkaline phosphatase levels were consistent with normal or abnormal CT findings, respectively. Increasing alkaline phosphatase and bilirubin levels were related to CT grade. CONCLUSION: Imaging findings of bile duct complications of HAIC are similar to those of primary sclerosing cholangitis, and correlate well with abnormal clinical and laboratory data. In the presence of such clinical abnormalities, thin-section helical CT with careful review of the imaging studies helps to determine the correct diagnosis, monitor the changes and guide appropriate treatment.

  18. [Study on effect of artificial CsB and its components on bile acid metabolism in rats with liver fibrosis and its mechanism].

    Science.gov (United States)

    Zhang, Xing; Li, Feng-Hua; Liu, Ping; Liu, Jia; Wang, Shuang

    2013-11-01

    Bile acid is a type of metabolite degraded from cholesterol in liver. Its accumulation in liver could cause liver diseases, liver damage and liver fibrosis. In this experiment, dimethyl nitrosamine (DMN) liver fibrosis was established in rats. The rats were delivered into the normal group, the model group and four treated groups. After the four-week modeling, the treated groups were orally administered with drugs for 2 weeks, whereas the model and normal groups were given equal amount of sterile water at the same time. In the experiment, serum bile acid was taken the as marker, and liver function indexes and changes in bile acid metabolism were detected and observed to identify liver damage-related bile acid targets. It was the first time to evaluate the reverse effect of artificial CsB and its components on liver fibrosis in rats with bile acid metabolic level, and discuss its potential mechanism. The main study contents and results are as follows: a quantitative analysis was made on totally 17 endogenous bile acids, including taurocholic acid conjugated bile acid, glycine conjugated bile acid and free bile acid, and a liver damage evaluation was made for the model according to the detection of serum biochemical indexes and the pathological biopsy. After modeling, ALT, AST activity and TBil content significantly increased, whereas Alb significantly decreased. According to the pathological biopsy HE staining, the model group showed damage in normal hepatic lobule structure, liver cell edema and connective tissue proliferation in portal area; The treated groups showed mitigation in pathological changes to varying degrees. Cordyceps sinensis and its components may impact the bile acid metabolism in rats by activating HDCA, TCA, TCDCA, TLCA, TUDCA, UDCA, THDCA metabolim-related receptors or blocking relevant signaling pathway.

  19. Human and rat bile acid-CoA : Amino acid N-acyltransferase are liver-specific peroxisomal enzymes: Implications for intracellular bile salt transport

    NARCIS (Netherlands)

    Pellicoro, Antonella; van den Heuvel, Fiona A. J.; Geuken, Mariska; Moshage, Han; Jansen, Peter L. M.; Faber, Klaas Nico

    Bile acid-coenzyme A:amino acid N-acyltransferase (BAAT) is the sole enzyme responsible for conjugation of primary and secondary bile acids to taurine and glycine. Previous studies indicate a peroxisomal location of BAAT in peroxisomes with variable amounts up to 95% detected in cytosolic fractions.

  20. Hypocholesterolemic effect of capsaicinoids by increased bile acids excretion in ovariectomized rats.

    Science.gov (United States)

    Zhang, Lei; Zhou, Min; Fang, Guoshan; Tang, Yan; Chen, Zongdao; Liu, Xiong

    2013-06-01

    This study investigated the interaction of dietary capsaicinoids with the mRNA and protein expressions of key receptors and enzymes involved in cholesterol metabolism in ovariectomized (OVX) rats. Female Sprague-Dawley rats were subjected to sham operation or ovariectomy. The sham group and OVX control group were fed with high-cholesterol diets, whereas the treatment group (control diet containing 0.01% capsaicinoids) was fed with high-cholesterol plus 0.01% capsaicinoids diet for 21 days. Capsaicinoids significantly decreased the body weight gain, plasma total cholesterol, LDL cholesterol, and triacylglycerol without affecting the high-density lipoprotein cholesterol in the OVX rats. The change in plasma lipoprotein profile was accompanied by a greater excretion of total bile acid in feces and small intestinal contents. Western blot and real-time PCR analyses revealed that capsaicinoids significantly enhanced the expressions of hepatic cholesterol 7α-hydroxylase and transient receptor potential vanilloid type-1 but did not affect the expression of 3-hydroxy-3-methylglutaryl-CoA reductase in the OVX rats. Capsaicinoids have cholesterol-lowering effects in OVX rats. The hypocholesterolemic activity of capsaicinoids is caused by the stimulating conversion of cholesterol to bile acids by upregulation of cholesterol 7α-hydroxylase expression and the increase in fecal total bile acid excretion. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. 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.

  2. Bile acid nuclear receptor FXR and digestive system diseases

    Institute of Scientific and Technical Information of China (English)

    Lili Ding; Li Yang; Zhengtao Wang; Wendong Huang

    2015-01-01

    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 bileacid-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 ofFXR in digestive system will accelerate the development of FXR ligands/modulators for the treatment of digestive system diseases.

  3. Effect of type and amount of dietary fat and 1,2-dimethylhydrazine on biliary bile acids, fecal bile acids, and neutral sterols in rats.

    Science.gov (United States)

    Reddy, B S; Mangat, S; Sheinfil, A; Weisburger, J H; Wynder, E L

    1977-07-01

    The effect of type (corn oil or lard) and quantity (5 or 20%) of dietary fat and 1,2-dimethylhydrazine (DMH) on the composition of biliary bile acids, fecal bile acids, and neutral sterols was studied in rats exposed to a given regimen for two generations prior to s.c. treatment with DMH for 20 weeks. Biliary excretion of total bile acids as well as cholic acid, beta-muricholic acid, ursodeoxycholic acid, and deoxycholic acid was higher in rats fed a diet containing 20% corn oil or lard than it was in rats fed diets containing 5% corn oil or lard. Treatment of animals with DMH produced an increase in biliary total bile acids, cholic acid, hyodeoxycholic acid, and deoxycholic acid irrespective of diets. High-fat (corn oil or lard at 20% level) intake was associated with an increased excretion of fecal neutral sterols and bile acids. The excretion of deoxycholic acid, lithocholic acid, and 12-ketolithocholic acid was increased in rats fed high-fat diets. The source of fat had no major influence on the excretory pattern of cholesterol metabolites and bile acids. DMH-treated animals excreted higher levels of fecal coprostanol, coprostanone, deoxycholic acid, lithocholic acid, and 12-ketolithocholic acid than did controls.

  4. Identity of hepatic membrane transport systems for bile salts, phalloidin, and antamanide by photoaffinity labeling.

    OpenAIRE

    Wieland, T.; Nassal, M.; Kramer, W.; Fricker, G; Bickel, U; Kurz, G.

    1984-01-01

    Phalloidin, a bicyclic heptapeptide, and antamanide, a monocyclic decapeptide from the poisonous mushroom Amanita phalloides, interact with bile-salt-binding polypeptides of the hepatocyte membrane, as demonstrated by photoaffinity labeling using the photolabile bile salt derivative 7,7,-azo-3 alpha, 12 alpha-dihydroxy-5 beta-cholan-24-oic acid, either unconjugated or taurine conjugated. With the photolabile derivatives of phalloidin, N-delta-(4-[(1-azi-2,2,2-trifluoroethyl) benzoyl]-beta-ala...

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

    DEFF Research Database (Denmark)

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

    2017-01-01

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

  6. Hepatitis E virus in liver and bile samples from slaughtered pigs of Brazil

    Directory of Open Access Journals (Sweden)

    Noemi Rovaris Gardinali

    2012-11-01

    Full Text Available The objective of this study was to detect and identify hepatitis E virus (HEV strains in liver and bile samples from slaughtered pigs in the state of Paraná, Brazil. Liver and bile samples were collected from 118 asymptomatic adult pigs at a slaughterhouse in a major Brazilian pork production area. The samples were assayed using a nested reverse transcription-polymerase chain reaction protocol with primer sets targeting open reading frames (ORF1 and 2 of the HEV genome. HEV RNA was detected in two (1.7% liver samples and one (0.84% bile sample using both primers sets. The HEV strains were classified as genotype 3b on the basis of their nucleotide sequences. These data suggest that healthy pigs may be a source of HEV infection for consumers of pig liver and slaughterhouse workers in Brazil.

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

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    Magdalena Panek-Jeziorna

    2017-08-01

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

  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 bile acids in carcinogenesis of pancreatic cancer: An old topic with new perspective.

    Science.gov (United States)

    Feng, Hui-Yi; Chen, Yang-Chao

    2016-09-07

    The role of bile acids in colorectal cancer has been well documented, but their role in pancreatic cancer remains unclear. In this review, we examined the risk factors of pancreatic cancer. We found that bile acids are associated with most of these factors. Alcohol intake, smoking, and a high-fat diet all lead to high secretion of bile acids, and bile acid metabolic dysfunction is a causal factor of gallstones. An increase in secretion of bile acids, in addition to a long common channel, may result in bile acid reflux into the pancreatic duct and to the epithelial cells or acinar cells, from which pancreatic adenocarcinoma is derived. The final pathophysiological process is pancreatitis, which promotes dedifferentiation of acinar cells into progenitor duct-like cells. Interestingly, bile acids act as regulatory molecules in metabolism, affecting adipose tissue distribution, insulin sensitivity and triglyceride metabolism. As a result, bile acids are associated with three risk factors of pancreatic cancer: obesity, diabetes and hypertriglyceridemia. In the second part of this review, we summarize several studies showing that bile acids act as cancer promoters in gastrointestinal cancer. However, more question are raised than have been solved, and further oncological and physiological experiments are needed to confirm the role of bile acids in pancreatic cancer carcinogenesis.

  10. Mutational Characterization of the Bile Acid Receptor TGR5 in Primary Sclerosing Cholangitis

    NARCIS (Netherlands)

    Hov, Johannes R.; Keitel, Verena; Laerdahl, Jon K.; Spomer, Lina; Ellinghaus, Eva; ElSharawy, Abdou; Melum, Espen; Boberg, Kirsten M.; Manke, Thomas; Balschun, Tobias; Schramm, Christoph; Bergquist, Annika; Weismueller, Tobias; Gotthardt, Daniel; Rust, Christian; Henckaerts, Liesbet; Onnie, Clive M.; Weersma, Rinse K.; Sterneck, Martina; Teufel, Andreas; Runz, Heiko; Stiehl, Adolf; Ponsioen, Cyriel Y.; Wijmenga, Cisca; Vatn, Morten H.; Stokkers, Pieter C. F.; Vermeire, Severine; Mathew, Christopher G.; Lie, Benedicte A.; Beuers, Ulrich; Manns, Michael P.; Schreiber, Stefan; Schrumpf, Erik; Haeussinger, Dieter; Franke, Andre; Karlsen, Tom H.

    2010-01-01

    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

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

    Directory of Open Access Journals (Sweden)

    CRISTINA DINU

    2009-05-01

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

  12. 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

    2015-09-01

    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. 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. 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. 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. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  13. 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.

  14. Bile acid-binding activity of young persimmon (Diospyros kaki) fruit and its hypolipidemic effect in mice.

    Science.gov (United States)

    Matsumoto, Kenji; Yokoyama, Shin-ichiro; Gato, Nobuki

    2010-02-01

    The hypolipidemic effects and bile acid-binding properties of young persimmon (Diospyros kaki) fruit were examined. In an animal experiment, male C57BL/6.Cr mice (n = 5) were fed an AIN-76-modified high fat diet supplemented with 2% or 5% (w/w) dried young persimmon fruit (YP) for 10 weeks. The intake of YP significantly enhanced fecal bile acid excretion and lowered the concentration of hepatic lipids and plasma cholesterol. Analysis of gene expression in liver tissue showed that 2% or 5% YP up-regulated the expression of the sterol regulatory element-binding protein-2 gene. In the 5% group, there were increased expressions of the genes for cholesterol 7alpha-hydroxylase and the low-density lipoprotein receptor. Next, the bile acid-binding ability of YP was analysed in vitro using cholic acid (CA). In 100-2000 microM CA solutions, 1% (w/v) YP adsorbed approximately 60% of CA, while dried mature persimmon fruit adsorbed approximately 20% of CA. The positive control, cholestyramine, adsorbed approximately 80% of CA in the 100-2000 microM CA solutions. A crude tannin extract from YP, which contained 54.7% condensed tannins, adsorbed approximately 78% of CA in the 2000 microM CA solutions. These results suggest that the ability of YP to bind bile acid contributes to its hypolipidemic effect in mice. (c) 2009 John Wiley & Sons, Ltd.

  15. 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...

  16. Secondary bile acid-induced dysbiosis promotes intestinal carcinogenesis.

    Science.gov (United States)

    Cao, Hailong; Xu, Mengque; Dong, Wenxiao; Deng, Baoru; Wang, Sinan; Zhang, Yujie; Wang, Shan; Luo, Shenhui; Wang, Weiqiang; Qi, Yanrong; Gao, Jianxin; Cao, Xiaocang; Yan, Fang; Wang, Bangmao

    2017-06-01

    The gut microbiota plays an important role in maintaining intestinal homeostasis. Dysbiosis is associated with intestinal tumorigenesis. Deoxycholic acid (DCA), a secondary bile acid increased by a western diet, correlates with intestinal carcinogenesis. However, evidence relating bile acids, intestinal microbiota and tumorigenesis are limited. In our study, we investigated the effect of DCA on induction of intestinal dysbiosis and its roles in intestinal carcinogenesis. Alteration of the composition of the intestinal microbiota was induced in DCA-treated APCmin/+ mice, which was accompanied by impaired intestinal barrier, gut low grade inflammation and tumor progression. The transfer of fecal microbiota from DCA-treated mice to another group of Apcmin/+ mice increased tumor multiplicity, induced inflammation and recruited M2 phenotype tumor-associated macrophages. Importantly, the fecal microbiota transplantation activated the tumor-associated Wnt/β-catenin signaling pathway. Moreover, microbiota depletion by a cocktail of antibiotics was sufficient to block DCA-induced intestinal carcinogenesis, further suggesting the role of dysbiosis in tumor development. Our study demonstrated that alteration of the microbial community induced by DCA promoted intestinal carcinogenesis. © 2017 UICC.

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

    Directory of Open Access Journals (Sweden)

    Titia E Woudenberg-Vrenken

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

  18. Metformin Protects Rat Hepatocytes against Bile Acid-Induced Apoptosis

    Science.gov (United States)

    Woudenberg-Vrenken, Titia E.; Conde de la Rosa, Laura; Buist-Homan, Manon; Faber, Klaas Nico; Moshage, Han

    2013-01-01

    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. PMID:23951244

  19. Metabolomic profiling of 17 bile acids in serum from patients with primary biliary cirrhosis and primary sclerosing cholangitis: a pilot study.

    Science.gov (United States)

    Trottier, Jocelyn; Białek, Andrzej; Caron, Patrick; Straka, Robert J; Heathcote, Jenny; Milkiewicz, Piotr; Barbier, Olivier

    2012-04-01

    Primary biliary cirrhosis and primary sclerosing cholangitis are two cholestatic diseases characterised by hepatic accumulation of bile acids. This study compares serum bile acid levels in patients with primary biliary cirrhosis and primary sclerosing cholangitis and from age and sex-matched non cholestatic donors. Seventeen bile acids were quantified using liquid chromatography coupled to tandem mass spectrometry. Serum samples from cholestatic patients were compared with those of non-cholestatic donors. The concentration of total bile acids, taurine and glycine conjugates of primary bile acids was elevated in both patients with primary biliary cirrhosis and primary sclerosing cholangitis when compared to non-cholestatic donors. Samples from primary sclerosing cholangitis patients displayed reduced levels of secondary acids, when compared to non cholestatic and primary biliary cirrhosis sera. The ratio of total glycine versus total taurine conjugates was reduced in patients with primary biliary cirrhosis, but not in primary sclerosing cholangitis. The present study suggests that circulating bile acids are altered differentially in primary biliary cirrhosis and primary sclerosing cholangitis patients. Copyright © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  20. Analysis of the Serum Bile Acid Composition for Differential Diagnosis in Patients with Liver Disease

    Directory of Open Access Journals (Sweden)

    Tomonori Sugita

    2015-01-01

    Full Text Available Objectives. We determined the serum bile acid (BA composition in patients with liver diseases and healthy volunteers to investigate the relationship between the etiologies of liver disease and BA metabolism. Material and Methods. Sera from 150 patients with liver diseases and 46 healthy volunteers were obtained. The serum concentrations of the 16 different BAs were determined according to the LC-MS/MS method and were compared between the different liver diseases. Results. A total of 150 subjects, including patients with hepatitis C virus (HCV (n=44, hepatitis B virus (HBV (n=23, alcoholic liver disease (ALD (n=21, biliary tract disease (n=20, nonalcoholic fatty liver disease (NAFLD (n=13, and other liver diseases (n=29, were recruited. The levels of UDCA and GUDCA were significantly higher in the ALD group, and the levels of DCA and UDCA were significantly lower in the biliary tract diseases group than in viral hepatitis group. In the UDCA therapy (− subgroup, a significantly lower level of TLCA was observed in the ALD group, with lower levels of CDCA, DCA, and GLCA noted in biliary tract diseases group compared to viral hepatitis group. Conclusions. Analysis of the BA composition may be useful for differential diagnosis in liver disease.

  1. Analysis of the serum bile Acid composition for differential diagnosis in patients with liver disease.

    Science.gov (United States)

    Sugita, Tomonori; Amano, Katsushi; Nakano, Masanori; Masubuchi, Noriko; Sugihara, Masahiro; Matsuura, Tomokazu

    2015-01-01

    Objectives. We determined the serum bile acid (BA) composition in patients with liver diseases and healthy volunteers to investigate the relationship between the etiologies of liver disease and BA metabolism. Material and Methods. Sera from 150 patients with liver diseases and 46 healthy volunteers were obtained. The serum concentrations of the 16 different BAs were determined according to the LC-MS/MS method and were compared between the different liver diseases. Results. A total of 150 subjects, including patients with hepatitis C virus (HCV) (n = 44), hepatitis B virus (HBV) (n = 23), alcoholic liver disease (ALD) (n = 21), biliary tract disease (n = 20), nonalcoholic fatty liver disease (NAFLD) (n = 13), and other liver diseases (n = 29), were recruited. The levels of UDCA and GUDCA were significantly higher in the ALD group, and the levels of DCA and UDCA were significantly lower in the biliary tract diseases group than in viral hepatitis group. In the UDCA therapy (-) subgroup, a significantly lower level of TLCA was observed in the ALD group, with lower levels of CDCA, DCA, and GLCA noted in biliary tract diseases group compared to viral hepatitis group. Conclusions. Analysis of the BA composition may be useful for differential diagnosis in liver disease.

  2. Unusual binding of ursodeoxycholic acid to ileal bile acid binding protein: role in activation of FXRα.

    Science.gov (United States)

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

    2012-04-01

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

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

    Science.gov (United States)

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

    2014-01-01

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

  4. Longitudinal profiles of 15 serum bile acids in patients with intrahepatic cholestasis of pregnancy.

    Science.gov (United States)

    Tribe, Rachel M; Dann, Anthony T; Kenyon, Anna P; Seed, Paul; Shennan, Andrew H; Mallet, Anthony

    2010-03-01

    Increased maternal serum bile acids are implicated in intrahepatic cholestasis of pregnancy. Individual bile acid profiles and their relationship with disease progression, however, remain unknown. The purpose of this prospective study was to determine the temporal changes in bile acids in normal pregnancy and in pregnancies complicated with intrahepatic cholestasis of pregnancy and pruritus gravidarum. A validated method for the evaluation of 15 bile acids (conjugated and unconjugated) in a single serum sample was developed using high-performance liquid chromatography/mass spectrometry (HPLC-MS) with an electrospray interface. Bile acid concentrations were assessed in samples (16 weeks of gestation to 4 weeks postpartum) from women with, or who later developed, intrahepatic cholestasis of pregnancy (n=63) and were compared with those from normal pregnant women (n=26) and from women with pruritus gravidarum (n=43). Intrahepatic cholestasis of pregnancy was associated with a predominant increase in cholic acid conjugated with taurine and glycine, from 24 weeks of pregnancy. Ursodeoxycholic acid (UDCA) treatment (> or =21 days, n=15) significantly reduced serum taurocholic and taurodeoxycholic acid concentrations (Pacid profiles were similar in normal pregnancy and pregnancy associated with pruritus gravidarum. The bile acid profiles and effects of treatment by UDCA implicate a role for taurine-conjugated bile acids in the syndrome of intrahepatic cholestasis of pregnancy. [corrected] With regard to individual bile acid profiles, pruritus gravidarum is a disorder quite distinct from intrahepatic cholestasis of pregnancy.

  5. [The effect of desmopressin on changes of bile acids specter in rats].

    Science.gov (United States)

    Horenko, Z A; Karbovs'ka, L S; Mehdi, S P H; Luk'ianenko, I A; Vesel's'kyĭ, S P

    2009-01-01

    We studied the effect of the synthetic analogue of antidiuretic hormone-desmopressin on the level of choleresis and the bile acids spectrum in acute experiments in bile duct-cannulated rats. It is shown that desmopressin increases bile flow and concentration of taurin-conjugated bile acids. In this situation, the concentration ofglycocholates practically is not changed, and concentration of free bile acids is diminished, which results in increase in the conjugation coefficient. Blockade of V(1a) vasopressin receptors decreases the efficiency of desmopressin regulatory effect on certain aspects of bile secretion. Indexes of choleresis volume velocity were less than those obtained following peptide introduction. The changes in concentration of conjugated and free bile acids had opposite dynamics. Concentration of tauro- and glycocholates was diminished, while concentration of free bile acids was increased, which resulted in a decrease in conjugation coefficient. The data obtained indicate that desmopressin affects both the synthesis and in a higher degree the conjugation process of bile acids with amino acids through V(1a) vasopressin receptors.

  6. Fifty years with bile acids and steroids in health and disease.

    Science.gov (United States)

    Sjövall, Jan

    2004-08-01

    Cholesterol and its metabolites, e.g., steroid hormones and bile acids, constitute a class of compounds of great biological importance. Their chemistry, biochemistry, and regulation in the body have been intensely studied for more than two centuries. The author has studied aspects of the biochemistry and clinical chemistry of steroids and bile acids for more than 50 years, and this paper, which is an extended version of the Schroepfer Medal Award lecture, reviews and discusses part of this work. Development and application of analytical methods based on chromatography and mass spectrometry (MS) have been a central part of many projects, aiming at detailed characterization and quantification of metabolic profiles of steroids and bile acids under different conditions. In present terminology, much of the work may be termed steroidomics and cholanoidomics. Topics discussed are bile acids in human bile and feces, bile acid production, bacterial dehydroxylation of bile acids and steroids during the enterohepatic circulation, profiles of steroid sulfates in plasma of humans and other primates, development of neutral and ion-exchanging lipophilic derivatives of Sephadex for sample preparation and group separation of steroid and bile acid conjugates, profiles of steroids and bile acids in human urine under different conditions, hydroxylation of bile acids in liver disease, effects of alcohol-induced redox changes on steroid synthesis and metabolism, alcohol-induced changes of bile acid biosynthesis, compartmentation of bile acid synthesis studied with 3H-labeled ethanol, formation and metabolism of sulfated metabolites of progesterone in human pregnancy, abnormal patterns of these in patients with intrahepatic cholestasis of pregnancy corrected by ursodeoxycholic acid, inherited and acquired defects of bile acid biosynthesis and their treatment, conjugation of bile acids and steroids with N-acetylglucosamine, sulfate-glucuronide double conjugates of hydroxycholesterols

  7. Shock releases bile acid inducing platelet inhibition and fibrinolysis.

    Science.gov (United States)

    Wiener, Gregory; Moore, Hunter B; Moore, Ernest E; Gonzalez, Eduardo; Diamond, Scott; Zhu, Shu; D'Alessandro, Angelo; Banerjee, Anirban

    2015-05-15

    Metabolites are underappreciated for their effect on coagulation. Taurocholic acid (TUCA), a bile acid, has been shown to regulate cellular activity and promote fibrin sealant degradation. We hypothesize that TUCA impairs whole blood clot formation and promotes fibrinolysis. TUCA was exogenously added to whole blood obtained from volunteers. A titration from 250 μM-750 μM was used due to biologic relevance. Whole blood mixtures were assayed using thrombelastography for clot strength (maximum amplitude [MA]) and fibrinolysis (LY30) quantification. Tranexamic acid was used to block plasmin-mediated fibrinolysis. Platelet microfluidics were performed. A proteomic analysis was completed on citrated plasma obtained from a shock and resuscitation rat model. Fibrinolysis increased when 750-μM TUCA was added to whole blood (median LY30 0.08-5.7, P = 0.010) and clot strength decreased (median MA of 53.3-43.8, P = 0.010). The addition of tranexamic acid, to a 750-μM TUCA titration, partially reversed the induced fibrinolysis (LY30: without 7.7 versus with 2.7) and the decrease in clot strength (MA: without 48.2 versus with 53.2), but did not reverse the effects to whole blood levels. Platelet function reduced by 50% in the presence of 100-μM TUCA. Rats had a median 52-fold increase in TUCA, after a shock state that stayed elevated after resuscitation. TUCA reduces clot strength and promotes fibrinolysis. The clot strength reduction is attributable to platelet inhibition. This metabolic effect on coagulation warrants further investigation, as localized areas of the body, with high levels of bile acid, may be at risk for postoperative bleeding. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. [Effect of bile acids on surface tension of bronchoalveolar lavage fluid in rabbits].

    Science.gov (United States)

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

    2014-10-01

    To observe changes in surface tension of bronchoalveolar lavage fluids (BALF) in rabbits with hyperbilirubinemia and the influence of bile diluents and 5 different bile acids on BALF surface tension to provide better insight into the regulatory role of bile acids on respiratory function. Bronchoalveolar lavage with 0.9% normal saline was carried out in 30 male New Zealand rabbits and the surface tensions of BALF were measured. The changes in BALF surface tension was measured in rabbits with hyperbilirubinemia. Different concentrations of bile diluents, normal saline, or water solutions of 5 bile acids were added into the collected BALF to test their influence on the surface tension of BALF. The BALF from rabbits with hyperbilirubinemia showed a significantly increased surface tension (Psurface tension of the BALF by 21.15%, 26.09%, and 19.64%, respectively. Among the water solutions of the 5 bile acids, UDCA produced no significant influence on the surface tension of BALF while CDCA, CA, LCA, and DCA increased the surface tension by 16.10%, 21.66%, 14.21%, and 13.05%, respectively. The surface tension of BALF increases significantly during hyperbilirubinemia. Bile diluents as well as the free bile acids CDCA, CA, LCA and DCA, but not UDCA, can increase the surface tension of BALF, suggesting that these bile acids may emulsify pulmonary alveolar surfactants to increase the alveolar surface tension.

  9. Tauroursodeoxycholic acid reduces bile acid-induced apoptosis by modulation of AP-1

    NARCIS (Netherlands)

    Pusl, Thomas; Vennegeerts, Timo; Wimmer, Ralf; Denk, Gerald U.; Beuers, Ulrich; Rust, Christian

    2008-01-01

    Ursodeoxycholic acid (UDCA) is used in the therapy of cholestatic liver diseases. Apoptosis induced by toxic bile acids plays an important role in the pathogenesis of liver injury during cholestasis and appears to be mediated by the human transcription factor AP-1. We aimed to study if TUDCA can

  10. Lactoferrin interacts with bile acids and increases fecal cholesterol excretion in rats.

    Science.gov (United States)

    Nakamura, Kanae; Morishita, Satoru; Ono, Tomoji; Murakoshi, Michiaki; Sugiyama, Keikichi; Kato, Hisanori; Ikeda, Ikuo; Nishino, Hoyoku

    2017-02-01

    Lactoferrin (LF) is a multifunctional cationic protein (pI 8.2-8.9) in mammalian milk. We previously reported that enteric-LF prevented hypercholesterolemia and atherosclerosis in a diet-induced atherosclerosis model using Microminipig, although the underlying mechanisms remain unclear. Because LF is assumed to electrostatically interact with bile acids to inhibit intestinal cholesterol absorption, LF could promote cholesterol excretion. In this study, we assessed the interaction between LF and taurocholate in vitro, and the effect of LF on cholesterol excretion in rats. The binding rate of taurocholate to LF was significantly higher than that to transferrin (pI 5.2-6.3). When rats were administered a high-cholesterol diet (HCD) containing 5% LF, LF was detected using ELISA in the upper small intestine from 7.5 to 60 min after the administration. Rats were fed one of the following diets: control, HCD, or HCD + 5% LF for 21 days. Fecal neutral steroids and hepatic cholesterol levels in the HCD group were significantly higher than those in the control group. The addition of LF to a HCD significantly increased fecal neutral steroids levels (22% increase, p cholesterol levels (17% decrease, p cholesterol excretion via interactions with bile acids.

  11. Fish oil increases bile acid synthesis in male patients with hypertriglyceridemia

    NARCIS (Netherlands)

    Jonkers, Iris J. A. M.; Smelt, Augustinus H. M.; Princen, Hans M. G.; Kuipers, Folkert; Romijn, Johannes A.; Boverhof, Renze; Masclee, Ad A. M.; Stellaard, Frans

    2006-01-01

    Fibrates are drugs of choice in patients with hypertriglyceridemia (HTG), but may increase the risk for gallstones by decreasing bile acid synthesis. Fish oil might be a therapeutic alternative, but its effect on bile acid metabolism in humans is unknown. We compared the effects of

  12. Fish oil increases bile acid synthesis in male patients with hypertriglyceridemia

    NARCIS (Netherlands)

    Jonkers, IJAM; Princen, HMG; Kuipers, F; Romijn, JA; Boverhof, R; Masclee, AAM; Stellaard, F

    Fibrates are drugs of choice in patients with hypertriglyceridemia (HTG), but may increase the risk for gallstones by decreasing bile acid synthesis. Fish oil might be a therapeutic alternative, but its effect on bile acid metabolism in humans is unknown. We compared the effects of

  13. Bile Acid-induced Apoptosis in Hepatocytes Is Caspase-6-dependent

    NARCIS (Netherlands)

    Rust, Christian; Wild, Nadine; Bernt, Carina; Vennegeerts, Timo; Wimmer, Ralf; Beuers, Ulrich

    2009-01-01

    Apoptosis induced by hydrophobic bile acids is thought to contribute to liver injury during cholestasis. Caspase-6 is an executioner caspase that also appears to have regulatory functions in hematopoetic cell lines. We aimed to elucidate the role of caspase-6 in bile acid-induced apoptosis. The

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

    DEFF Research Database (Denmark)

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

    2010-01-01

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

  15. 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,

  16. 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.

  17. 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.

  18. Development of a micro-planar amperometric bile acid biosensor for urinalysis.

    Science.gov (United States)

    Koide, S; Ito, N; Karube, I

    2007-04-15

    The determination of bile acid concentration in urine is useful for the screening and diagnosis of various hepatobiliary diseases. Currently, there is no concise method to determine bile acid concentration in urine. This study describes a bile acid biosensor fabricated by electrochemical technique for urinalysis. The micro-planar electrodes employed for the study consisted of a working electrode (platinum), a counter electrode (platinum) and a reference electrode (silver/silver chloride (Ag/AgCl)). The sensor chip was coated with Nafion using a spin-coater in order to both eliminate many interference species in urine and achieve long-term stability of the reference electrode. Nafion coating allowed the sensor chip to prevent the electrode reaction from interference species in urine, because it is charged negative strongly (Nafion contains sulfonic acid group). Three enzymes (bile acid sulfate sulfatase: BSS, beta-hydroxysteroid dehydrogenase: beta-HSD, and NADH oxidase: NHO) were immobilized by glutaraldehyde (GA: cross-linker) onto the sensor chip, because the immobilization of enzymes by GA is simple and commonly carried out. The sensor chip was able to detect bile acid in buffer solution. The optimum enzyme ratio immobilized onto the sensor chip was BSS:beta-HSD:NHO=4:4:20 U/1 chip. There was a relationship between the concentration of bile acid and the response current value. The dynamic range of the sensor chip was 2-100 microM for bile acid. Additionally, bile acid in the urine specimen could be detected using this bile acid biosensor. We present a simple and rapid bile acid biosensor with high sensitivity and high reproducibility.

  19. Protective effects of nonionic tri-block copolymers on bile acid-mediated epithelial barrier disruption.

    Energy Technology Data Exchange (ETDEWEB)

    Edelstein, A.; Fink, D.; Musch, M.; Valuckaite, V.; Zabornia, O.; Grubjesic, S.; Firestone, M. A.; Matthews, J. B.; Alverdy, J. C. (Materials Science Division); (Univ. of Chicago)

    2011-11-01

    Translocation of bacteria and other luminal factors from the intestine following surgical injury can be a major driver of critical illness. Bile acids have been shown to play a key role in the loss of intestinal epithelial barrier function during states of host stress. Experiments to study the ability of nonionic block copolymers to abrogate barrier failure in response to bile acid exposure are described. In vitro experiments were performed with the bile salt sodium deoxycholate on Caco-2 enterocyte monolayers using transepithelial electrical resistance to assay barrier function. A bisphenol A coupled triblock polyethylene glycol (PEG), PEG 15-20, was shown to prevent sodium deoxycholate-induced barrier failure. Enzyme-linked immunosorbent assay, lactate dehydrogenase, and caspase 3-based cell death detection assays demonstrated that bile acid-induced apoptosis and necrosis were prevented with PEG 15-20. Immunofluorescence microscopic visualization of the tight junctional protein zonula occludens 1 (ZO-1) demonstrated that PEG 15-20 prevented significant changes in tight junction organization induced by bile acid exposure. Preliminary transepithelial electrical resistance-based studies examining structure-function correlates of polymer protection against bile acid damage were performed with a small library of PEG-based copolymers. Polymer properties associated with optimal protection against bile acid-induced barrier disruption were PEG-based compounds with a molecular weight greater than 10 kd and amphiphilicity. The data demonstrate that PEG-based copolymer architecture is an important determinant that confers protection against bile acid injury of intestinal epithelia.

  20. 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

    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...

  1. In vivo studies of biliary ceftriaxone excretion and solubility in guinea pig hepatic bile.

    Science.gov (United States)

    Purdum, P P; Shiffman, M L; Moore, E W

    1992-10-01

    Ceftriaxone (CFTX), a third-generation cephalosporin, has occasionally been reported to produce biliary sludge composed of its calcium salt. We performed studies in guinea pigs to (1) investigate the hepatic route of CFTX excretion, (2) determine ceftriaione's effects on bile flow and composition, and (3) quantify the solubility and metastability of the calcium salt as a function of administered dose. Our results show that even at high doses ceftriaxone has only minimal effects on bile flow and biliary electrolyte secretion, either alone or in combination with bile salt (taurocholate) infusion. A significant increase in total calcium concentration was observed without change in free Ca2+ concentration, this is compatible with formation of a soluble calcium salt of ceftriaxone, as previously demonstrated in vitro. Ion products of Ca2+ and ceftriaxone as high as 3.5 times the solubility product constant without crystal formation were observed, confirming the presence of a metastable state for the calcium salt of ceftriaxone in the living animal. Biliary excretion of ceftriaxone inhibited excretion of indocyanine green, suggesting that ceftriaxone and indocyanine green share a common anionic excretory pathway in this species.

  2. Bile acid malabsorption in patients with chronic diarrhoea

    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...... with idiopathic BAM presented with steatorrhoea as opposed to 11 patients with type 1 and 3 BAM. Patients with idiopathic BAM and/or SeHCAT retention values chronic diarrhoea...

  3. 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.

  4. 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.

  5. Removal of bile acids by two different extracorporeal liver support systems in acute-on-chronic liver failure

    NARCIS (Netherlands)

    Stadlbauer, Vanessa; Krisper, Peter; Beuers, Ulrich; Haditsch, Bernd; Schneditz, Daniel; Jung, Aleksandra; Putz-Bankuti, Csilla; Holzer, Herwig; Trauner, Michael; Stauber, Rudolf E.

    2007-01-01

    Acute-on-chronic liver failure (ACLF) is accompanied by marked intrahepatic cholestasis leading to accumulation of cytotoxic bile acids. Extracorporeal liver support systems efficiently remove bile acids, but their effect on bile acid composition in ACLF is unknown. The aim of the present study was

  6. Bile acids initiate cholestatic liver injury by triggering a hepatocyte-specific inflammatory response.

    Science.gov (United States)

    Cai, Shi-Ying; Ouyang, Xinshou; Chen, Yonglin; Soroka, Carol J; Wang, Juxian; Mennone, Albert; Wang, Yucheng; Mehal, Wajahat Z; Jain, Dhanpat; Boyer, James L

    2017-03-09

    Mechanisms of bile acid-induced (BA-induced) liver injury in cholestasis are controversial, limiting development of new therapies. We examined how BAs initiate liver injury using isolated liver cells from humans and mice and in-vivo mouse models. At pathophysiologic concentrations, BAs induced proinflammatory cytokine expression in mouse and human hepatocytes, but not in nonparenchymal cells or cholangiocytes. These hepatocyte-specific cytokines stimulated neutrophil chemotaxis. Inflammatory injury was mitigated in Ccl2(-/-) mice treated with BA or after bile duct ligation, where less hepatic infiltration of neutrophils was detected. Neutrophils in periportal areas of livers from cholestatic patients also correlated with elevations in their serum aminotransferases. This liver-specific inflammatory response required BA entry into hepatocytes via basolateral transporter Ntcp. Pathophysiologic levels of BAs induced markers of ER stress and mitochondrial damage in mouse hepatocytes. Chemokine induction by BAs was reduced in hepatocytes from Tlr9(-/-) mice, while liver injury was diminished both in conventional and hepatocyte-specific Tlr9(-/-) mice, confirming a role for Tlr9 in BA-induced liver injury. These findings reveal potentially novel mechanisms whereby BAs elicit a hepatocyte-specific cytokine-induced inflammatory liver injury that involves innate immunity and point to likely novel pathways for treating cholestatic liver disease.

  7. Regulation of bile acid synthesis in man. Presence of a diurnal rhythm.

    OpenAIRE

    Duane, W C; Levitt, D G; Mueller, S M; Behrens, J C

    1983-01-01

    Regulation of bile acid synthesis in man is incompletely understood, in part because of difficulty in making measurements over short time periods when the enterohepatic circulation is intact. We investigated the possibility of a diurnal rhythm of bile acid synthesis in three human subjects given [26-14C]cholesterol. When this isotope of cholesterol, which is randomly labeled in the 26 and 27 positions, is converted to bile acid, the 14C is released as propionic acid randomly labeled in the 1 ...

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

    DEFF Research Database (Denmark)

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

    2015-01-01

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

  9. [Chemico-physical property and bile acid binding capacity of several antacids].

    Science.gov (United States)

    Salvioli, G; Tambara, E; Gaetti, E; Lugli, R

    1989-01-01

    Liquid alginate (Gaviscon) binds small amount of bile acids. At pH 7 its viscosity (at low shear rate) is higher than that of other antiacids. High viscosity reduces the diffusion rate of bile salts and glucose and this property can play a role in the treatment of gastro-esophageal and duodeno-gastric refluxes.

  10. 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...

  11. Bile Acid Metabolome after an Oral Lipid Tolerance Test by Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS.

    Directory of Open Access Journals (Sweden)

    Andreas Schmid

    Full Text Available Besides their role in intestinal resorption of lipids, bile acids are regarded as endocrine and metabolic signaling molecules. The detailed profile of bile acid species in peripheral blood after an oral lipid tolerance test (OLTT is unknown.We quantified the regulation of 18 bile acids after OLTT in healthy individuals.100 volunteers were characterized by anthropometric and laboratory parameters and underwent OLTT. Venous blood was drawn in the fasted state (0 h and at 2h, 4h, and 6 h after OLTT. Serum concentrations of 18 bile acids were measured by LC-MS/MS.All of the 6 taurine-conjugated bile acids (TUDCA, THDCA, TCA, TCDCA, TDCA, TLCA and all of the 6 glycine-conjugated bile acids (GUDCA, GHDCA, GCA, GCDCA, GDCA, GLCA rose significantly at 2h and remained elevated during OLTT. Of the primary bile acids, CA remained unchanged, whereas CDCA significantly decreased at 4h. Of the secondary bile acids, DCA, UDCA and HDCA were not altered, whereas LCA decreased. There was a significant positive correlation between the intestinal feed-back regulator of bile acid synthesis FGF-19 and bile acids. This correlation seems to depend on all of the six taurine-conjugated bile acids and on GCA, GDCA, and GCDCA. Females and users of hormonal contraception displayed higher levels of taurine-conjugated bile acids.The novelty of the study is based on the identification of single bile acids during OLTT. LC-MS/MS-based quantification of bile acids in serum provides a reliable tool for future investigation of endocrine and metabolic effects of bile acids.

  12. Bile Acid Metabolome after an Oral Lipid Tolerance Test by Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS).

    Science.gov (United States)

    Schmid, Andreas; Neumann, Hannah; Karrasch, Thomas; Liebisch, Gerhard; Schäffler, Andreas

    2016-01-01

    Besides their role in intestinal resorption of lipids, bile acids are regarded as endocrine and metabolic signaling molecules. The detailed profile of bile acid species in peripheral blood after an oral lipid tolerance test (OLTT) is unknown. We quantified the regulation of 18 bile acids after OLTT in healthy individuals. 100 volunteers were characterized by anthropometric and laboratory parameters and underwent OLTT. Venous blood was drawn in the fasted state (0 h) and at 2h, 4h, and 6 h after OLTT. Serum concentrations of 18 bile acids were measured by LC-MS/MS. All of the 6 taurine-conjugated bile acids (TUDCA, THDCA, TCA, TCDCA, TDCA, TLCA) and all of the 6 glycine-conjugated bile acids (GUDCA, GHDCA, GCA, GCDCA, GDCA, GLCA) rose significantly at 2h and remained elevated during OLTT. Of the primary bile acids, CA remained unchanged, whereas CDCA significantly decreased at 4h. Of the secondary bile acids, DCA, UDCA and HDCA were not altered, whereas LCA decreased. There was a significant positive correlation between the intestinal feed-back regulator of bile acid synthesis FGF-19 and bile acids. This correlation seems to depend on all of the six taurine-conjugated bile acids and on GCA, GDCA, and GCDCA. Females and users of hormonal contraception displayed higher levels of taurine-conjugated bile acids. The novelty of the study is based on the identification of single bile acids during OLTT. LC-MS/MS-based quantification of bile acids in serum provides a reliable tool for future investigation of endocrine and metabolic effects of bile acids.

  13. Farnesoid X Receptor Agonist Treatment Alters Bile Acid Metabolism but Exacerbates Liver Damage in a Piglet Model of Short-Bowel SyndromeSummary

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    Prue M. Pereira-Fantini

    2017-07-01

    Full Text Available Background & Aims: Options for the prevention of short-bowel syndrome–associated liver disease (SBS-ALDs are limited and often ineffective. The farnesoid X receptor (FXR is a newly emerging pharmaceutical target and FXR agonists have been shown to ameliorate cholestasis and metabolic disorders. The aim of this study was to assess the efficacy of obeticholic acid (OCA treatment in preventing SBS-ALDs. Methods: Piglets underwent 75% small-bowel resection (SBS or sham surgery (sham and were assigned to either a daily dose of OCA (2.4 mg/kg/day or were untreated. Clinical measures included weight gain and stool studies. Histologic features were assessed. Ultraperformance liquid chromatography tandem mass spectrometry was used to determine bile acid composition in end point bile and portal serum samples. Gene expression of key FXR targets was assessed in intestinal and hepatic tissues via quantitative polymerase chain reaction. Results: OCA-treated SBS piglets showed decreased stool fat and altered liver histology when compared with nontreated SBS piglets. OCA prevented SBS-associated taurine depletion, however, further analysis of bile and portal serum samples indicated that OCA did not prevent SBS-associated alterations in bile acid composition. The expression of FXR target genes involved in bile acid transport and synthesis increased within the liver of SBS piglets after OCA administration whereas, paradoxically, intestinal expression of FXR target genes were decreased by OCA administration. Conclusions: Administration of OCA in SBS reduced fat malabsorption and altered bile acid composition, but did not prevent the development of SBS-ALDs. We postulate that extensive small resection impacts the ability of the remnant intestine to respond to FXR activation. Keywords: Short-Bowel Syndrome, Liver Disease, Intestinal Failure–Associated Liver Disease, Obeticholic Acid, Bile Acids, Farnesoid X Receptor

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

    Science.gov (United States)

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

    2015-03-01

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

  15. 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 ...

  16. 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.

  17. Design of novel synthetic MTS conjugates of bile acids for site-directed sulfhydryl labeling of cysteine residues in bile acid binding and transporting proteins.

    Science.gov (United States)

    Ray, Abhijit; Banerjee, Antara; Chang, Cheng; Khantwal, Chandra M; Swaan, Peter W

    2006-03-15

    The purpose of this study was to design bile acid-containing methanethiosulfonate (MTS) agents with appropriate physical attributes to effectively modify the cysteine residues present in the human apical sodium-dependent bile acid transporter. Four physical properties including surface area, molecular volume, ClogP, and dipole moment were calculated for each semiempirically optimized structure of MTS compounds. The specificity of the synthesized bile acid-MTS conjugate toward native cysteines and putative bile acid interacting domains of hASBT was supported by the effect of 1mM cholyl-MTS, cholylglycyl-MTS, and 3-amino-cholyl-MTS on uptake activity, that displayed a significant decrease in TCA affinity (K(T)=69.9+/-4.5, 69.01+/-6.2, and 63.24+/-0.26 microM and J(max)=35.8+/-0.3, 24.03+/-1.22, 46.49+/-5.01 pmol mg protein min(-1), respectively). These compounds prove to be effective tools in probing the structural and functional effects of cysteine residues in bile acid binding and transporting proteins.

  18. Bile acids stimulate ATP hydrolysis in the purified cholesterol transporter ABCG5/G8.

    Science.gov (United States)

    Johnson, Brandy J Harvey; Lee, Jyh-Yeuan; Pickert, Amanda; Urbatsch, Ina L

    2010-04-27

    ABCG5 and ABCG8 are half-size ABC transporters that function as heterodimers (ABCG5/G8) to reduce sterol absorption in the intestines and increase sterol excretion from the liver. Previous studies demonstrated that bile acids increased ABCG5/G8 specific cholesterol efflux in cell models. In this study we tested the effects of bile acids on ATP hydrolysis in Pichia pastoris purified ABCG5/G8 and found that they stimulated hydrolysis approximately 20-fold in wild-type ABCG5/G8 but not in a hydrolysis-deficient mutant. Nonconjugated cholate supported the highest ATPase activity in ABCG5/G8 (256 +/- 9 nmol min(-1) mg(-1)). ATP hydrolysis was also stimulated by other conjugated bile acids and a mixture of bile acids resembling human bile with activities ranging from 129 +/- 4 to 147 +/- 14 nmol min(-1) mg(-1). The kinetic parameters, inhibitor profiles, and lipid requirements of bile acid stimulated ATP hydrolysis were characterized. Cholate-stimulated ATP hydrolysis was maximal at concentrations of >or=10 mM MgATP and had a relatively high K(M) (MgATP) of approximately 1 mM. Orthovanadate, BeFx, and AlFx effectively inhibited ABCG5/G8 at concentrations of 1 mM. Various lipid mixtures supported bile acid-stimulated ATP hydrolysis, which increased when cholesterol was present. The data demonstrate that bile acids together with lipids and cholesterol increase ATP hydrolysis in purified ABCG5/G8. Bile acids may promote an active conformation of purified ABCG5/G8 either by global stabilization of the transporter or by binding to a specific site on ABCG5/G8.

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

    National Research Council Canada - National Science Library

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

    2014-01-01

    .... ICP is commonly treated with ursodeoxycholic acid (UDCA). This study aimed to determine the fetal and maternal bile acid profiles in normal and ICP pregnancies, and to examine the effect of UDCA treatment...

  20. A model of in vitro UDP-glucuronosyltransferase inhibition by bile acids predicts possible metabolic disorders.

    Science.gov (United States)

    Fang, Zhong-Ze; He, Rong-Rong; Cao, Yun-Feng; Tanaka, Naoki; Jiang, Changtao; Krausz, Kristopher W; Qi, Yunpeng; Dong, Pei-Pei; Ai, Chun-Zhi; Sun, Xiao-Yu; Hong, Mo; Ge, Guang-Bo; Gonzalez, Frank J; Ma, Xiao-Chi; Sun, Hong-Zhi

    2013-12-01

    Increased levels of bile acids (BAs) due to the various hepatic diseases could interfere with the metabolism of xenobiotics, such as drugs, and endobiotics including steroid hormones. UDP-glucuronosyltransferases (UGTs) are involved in the conjugation and elimination of many xenobiotics and endogenous compounds. The present study sought to investigate the potential for inhibition of UGT enzymes by BAs. The results showed that taurolithocholic acid (TLCA) exhibited the strongest inhibition toward UGTs, followed by lithocholic acid. Structure-UGT inhibition relationships of BAs were examined and in vitro-in vivo extrapolation performed by using in vitro inhibition kinetic parameters (Ki) in combination with calculated in vivo levels of TLCA. Substitution of a hydrogen with a hydroxyl group in the R1, R3, R4, R5 sites of BAs significantly weakens their inhibition ability toward most UGTs. The in vivo inhibition by TLCA toward UGT forms was determined with following orders of potency: UGT1A4 > UGT2B7 > UGT1A3 > UGT1A1 ∼ UGT1A7 ∼ UGT1A10 ∼ UGT2B15. In conclusion, these studies suggest that disrupted homeostasis of BAs, notably taurolithocholic acid, found in various diseases such as cholestasis, could lead to altered metabolism of xenobiotics and endobiotics through inhibition of UGT enzymes.

  1. The role of bile acids in morphological changes оf gastric mucosa in rats

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    A.I. Rudenko

    2014-12-01

    Full Text Available The present study was conducted on 60 white male laboratory rats in order to investigate the role of bile acids in morphofunctional changes of gastric mucosa in rats with due regard to exposure of bile and its concentration. It was found that in the early stages of duodenogastric reflux in experiment bile in low concentrations carries protective adaptive-trophic function and promotes cell renewal of the surface epithelium. At the same time long-term exposure to the bile acids regardless of its concentration can lead to the significant dystrophic changes in gastric mucosa, pilorization and atrophy of the gastric glands. In the case of the oral administration of bile followed by «immobilization and cold stress» for one hour (I group experiment’s results can confirm that the combined effects of several aggressive factors lead to the more severe pathological changes in the gastric mucosa: first erosive and later ulcerative lesions.

  2. 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.

  3. Intrahepatic cholestasis of pregnancy: changes in maternal-fetal bile acid balance and improvement by ursodeoxycholic acid.

    Science.gov (United States)

    Brites, Dora

    2002-01-01

    Intrahepatic cholestasis of pregnancy (ICP) is a disease characterized by generalized pruritus and biochemical cholestasis that appears typically during the last trimester of gestation. The most predictive and accurate markers for diagnosis and follow-up of ICP are increased total bile acid levels (above 11,0 micromol/L), enhanced cholic acid percentage (above 42%) and decreased glycine/taurine bile acid ratio (below 1.0). Although essentially benign for the mother, evidence associates ICP with fetal poor prognosis resulting from increased transfer of bile acids from mother to fetus, who showed reduced ability to eliminate bile acids across the placenta. Those conditions lead to an accumulation of bile acids in the cord blood serum, meconium and amniotic fluid that may account for a diminished fetal well-being and sudden intra-uterine death by ICP. Ursodeoxycholic acid (UDCA) treatment was shown to reduce the bile acid content in the fetal compartment, while restoring the ability of the placenta to carry out vectorial transfer of these compounds towards the mother, decreasing bile acid levels in maternal serum and its passage to the fetus. In addition, UDCA administered to the mother also lowers the amount of bile acids present in colostrum without either increasing the UDCA concentration or causing major changes in lithocholic acid levels, further supporting the safety of UDCA in late pregnancy. Therefore, it is tempting to indicate UDCA as a first choice therapy for ICP as much as relevant aspects of fetal outcome may also be improved. This review focuses on the altered bile acid profiles in maternal and fetal compartments during ICP and its recovery by UDCA administration. Further elucidation of the precise mechanisms of action of UDCA and its therapeutic potential in improving fetal prognosis could result in the approval of UDCA for ICP treatment.

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

    Directory of Open Access Journals (Sweden)

    Victoria Geenes

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

  5. 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.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1989-11-01

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

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

    Science.gov (United States)

    Hofmann, Alan F; Hagey, Lee R

    2014-08-01

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

  8. Atorvastatin alters the expression of genes related to bile acid metabolism and circadian clock in livers of mice

    Directory of Open Access Journals (Sweden)

    Wen-Kai Li

    2017-05-01

    Full Text Available Aim Atorvastatin is a HMG-CoA reductase inhibitor used for hyperlipidemia. Atorvastatin is generally safe but may induce cholestasis. The present study aimed to examine the effects of atorvastatin on hepatic gene expression related to bile acid metabolism and homeostasis, as well as the expression of circadian clock genes in livers of mice. Methods Adult male mice were given atorvastatin (10, 30, and 100 mg/kg, po daily for 30 days, and blood biochemistry, histopathology, and gene expression were examined. Results Repeated administration of atorvastatin did not affect animal body weight gain or liver weights. Serum enzyme activities were in the normal range. Histologically, the high dose of atorvastatin produced scattered swollen hepatocytes, foci of feathery-like degeneration, together with increased expression of Egr-1 and metallothionein-1. Atorvastatin increased the expression of Cyp7a1 in the liver, along with FXR and SHP. In contract, atorvastatin decreased the expression of bile acid transporters Ntcp, Bsep, Ostα, and Ostβ. The most dramatic change was the 30-fold induction of Cyp7a1. Because Cyp7a1 is a circadian clock-controlled gene, we further examined the effect of atorvastatin on clock gene expression. Atorvastatin increased the expression of clock core master genes Bmal1 and Npas2, decreased the expression of clock feedback genes Per2, Per3, and the clock targeted genes Dbp and Tef, whereas it had no effect on Cry1 and Nr1d1 expression. Conclusion Repeated administration of atorvastatin affects bile acid metabolism and markedly increases the expression of the bile acid synthesis rate-limiting enzyme gene Cyp7a1, together with alterations in the expression of circadian clock genes.

  9. [Analysis of clinical prognosis and the correlation between bile duct injury after transcatheter arterial chemoembolization and the level of hepatic arterial embolization in patients with hepatocellular carcinoma].

    Science.gov (United States)

    Xu, H Y; Yu, X P; Feng, R; Hu, H J; Xiao, W W

    2017-05-23

    Objective: To evaluate the correlation between bile duct injury after transcatheter arterial chemoembolization and the level of hepatic arterial embolization, and to analyze the clinical prognosis of hepatocellular carcinoma patients. Methods: From January18, 2012 to December18, 2014, 21 patients underwent TACE for HCC were retrospectively reviewed, including patients' clinical and pathological data. The clinical outcome and relevant factors for bile duct injury were analyzed. Results: A total of 21 patients were identified with bile duct injury at our single institution. All patients received 48 TACE treatments, including proper hepatic artery (14), left hepatic artery (3), the right hepatic artery (10), left and right hepatic artery (9) and tumor artery branches (12). Thirty-five bile duct injury occurred in 21 patients: 7 cases was close to the tumor, 2 distant to the tumor, 7 at right liver, 2 left liver, 11 both lobes of liver and 6 hepatic hilar. After medical conservative treatment and biliary tract inside and outside drainage, liver function of 10 cases were improved. In four patients with hepatic bile duct stricture and biloma, the effect of drainage was not obvious, which subsequently caused biliary complications such as infection, gallbladder and common bile duct stones. Three patients with liver cirrhosis at decompensation stage developed complications, and one of them died of hepatic encephalopathy. Four patients experienced tumor recurrence during the follow-up period. Conclusions: The location of bile duct injury after transcatheter arterial chemoembolization is quite consistent with the level of hepatic arterial embolization. There may be some blood vessels mainly involved in blood supply of biliary duct. Complete embolism of these vessels may lead to bile duct injuries. Biliary drainage is ineffective in patients with hilar bile duct stricture, and can lead to complications of biliary tract later on.

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

    Directory of Open Access Journals (Sweden)

    Julie B. Hjerpsted

    2016-03-01

    Conclusion: We were not able to confirm the hypothesis that calcium from cheese increases the excretion of fecal bile acids. Therefore, the mechanisms responsible for the lowering of cholesterol concentrations with cheese compared to butter intake remains unresolved.

  11. Bile acid patterns in meconium are influenced by cholestasis of pregnancy and not altered by ursodeoxycholic acid treatment

    Science.gov (United States)

    Rodrigues, C; Marin, J; Brites, D

    1999-01-01

    BACKGROUND—Data on meconium bile acid composition in newborn babies of patients with intrahepatic cholestasis of pregnancy (ICP) are relatively scant, and changes that occur on ursodeoxycholic acid (UDCA) administration have not been evaluated.
AIMS—To investigate bile acid profiles in meconium of neonates from untreated and UDCA treated patients with ICP. Maternal serum bile acid composition was also analysed both at diagnosis and delivery to determine whether this influences the concentration and proportion of bile acids in the meconium.
PATIENTS/METHODS—The population included eight healthy pregnant women and 16 patients with ICP, nine of which received UDCA (12.5-15.0 mg/kg body weight/day) for 15±4 days until parturition. Bile acids were assessed in the meconium by gas chromatography-mass spectrometry and in maternal serum by high performance liquid chromatography.
RESULTS—Total bile acid and cholic acid concentrations in the meconium were increased (pacid and cholic acid levels in the maternal serum (r = 0.85 and r = 0.84, pacid concentrations decreased in the mother (~3-fold, pacid concentration in the meconium was not increased by UDCA treatment.
CONCLUSIONS—UDCA administration does not influence the concentration and proportion of bile acids in the meconium, which in turn are altered by ICP. Moreover, this beneficial treatment for the mother does not increase meconium levels of potentially toxic metabolites of UDCA such as lithocholic acid.


Keywords: bile acids; cholestasis; pregnancy; cholic acid; meconium; ursodeoxycholic acid therapy PMID:10446117

  12. 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. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

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

    DEFF Research Database (Denmark)

    Brønden, Andreas; Albér, Anders; Rohde, Ulrich

    2017-01-01

    -controlled, and double-blinded cross-over study including 15 metformin-treated patients with type 2 diabetes. Four experimental study days in randomized order with administration of either sevelamer 3,200 mg or placebo in combination with intravenous infusion of cholecystokinin (CCK) (0.4 pmol sulfated CCK-8/kg......AIMS: The discovery of the specific bile acid receptors farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) in enteroendocrine L cells has prompted research focusing on the impact of bile acids on glucagon-like peptide-1 (GLP-1) secretion and glucose metabolism. The aim...

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

    Science.gov (United States)

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

    2017-02-01

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

  15. Hepatocyte MyD88 affects bile acids, gut microbiota and metabolome contributing to regulate glucose and lipid metabolism

    Science.gov (United States)

    Duparc, Thibaut; Plovier, Hubert; Marrachelli, Vannina G; Van Hul, Matthias; Essaghir, Ahmed; Ståhlman, Marcus; Matamoros, Sébastien; Geurts, Lucie; Pardo-Tendero, Mercedes M; Druart, Céline; Delzenne, Nathalie M; Demoulin, Jean-Baptiste; van der Merwe, Schalk W; van Pelt, Jos; Bäckhed, Fredrik; Monleon, Daniel; Everard, Amandine; Cani, Patrice D

    2017-01-01

    Objective To examine the role of hepatocyte myeloid differentiation primary-response gene 88 (MyD88) on glucose and lipid metabolism. Design To study the impact of the innate immune system at the level of the hepatocyte and metabolism, we generated mice harbouring hepatocyte-specific deletion of MyD88. We investigated the impact of the deletion on metabolism by feeding mice with a normal control diet or a high-fat diet for 8 weeks. We evaluated body weight, fat mass gain (using time-domain nuclear magnetic resonance), glucose metabolism and energy homeostasis (using metabolic chambers). We 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 Hepatocyte-specific deletion of MyD88 predisposes to glucose intolerance, inflammation and hepatic insulin resistance independently of body weight and adiposity. These phenotypic differences were partially attributed to differences in gene expression, transcriptional factor activity (ie, peroxisome proliferator activator receptor-α, farnesoid X receptor (FXR), liver X receptors and STAT3) and bile acid profiles involved in glucose, lipid metabolism and inflammation. In addition to these alterations, the genetic deletion of MyD88 in hepatocytes changes the gut microbiota composition and their metabolomes, resembling those observed during diet-induced obesity. Finally, obese humans with NASH displayed a decreased expression of different cytochromes P450 involved in bioactive lipid synthesis. Conclusions Our study identifies a new link between innate immunity and hepatic synthesis of bile acids and bioactive lipids. This dialogue appears to be involved in the susceptibility to alterations associated with obesity such as type 2 diabetes and NASH, both in mice and humans. PMID

  16. Probiotics--interactions with bile acids and impact on cholesterol metabolism.

    Science.gov (United States)

    Pavlović, Nebojša; Stankov, Karmen; Mikov, Momir

    2012-12-01

    The use of probiotics, alone or in interaction with bile acids, is a modern strategy in the prevention and treatment of hypercholesterolemia. Numerous mechanisms for hypocholesterolemic effect of probiotics have been hypothesized, based mostly on in vitro evidence. Interaction with bile acids through reaction of deconjugation catalyzed by bile salt hydrolase enzymes (BSH) is considered as the main mechanism of cholesterol-lowering effects of probiotic bacteria, but it has been reported that microbial BSH activity could be potentially detrimental to the human host. There are several approaches for prevention of possible side effects associated with BSH activity, which at the same time increase the viability of probiotics in the intestines and also in food matrices. The aim of our study was to summarize present knowledge of probiotics-bile acids interactions, with special reference to cholesterol-lowering mechanisms of probiotics, and to report novel biotechnological approaches for increasing the pharmacological benefits of probiotics.

  17. Pectin penta-oligogalacturonide reduces cholesterol accumulation by promoting bile acid biosynthesis and excretion in high-cholesterol-fed mice.

    Science.gov (United States)

    Zhu, Ru-Gang; Sun, Yan-Di; Hou, Yu-Ting; Fan, Jun-Gang; Chen, Gang; Li, Tuo-Ping

    2017-06-25

    Haw pectin penta-oligogalacturonide (HPPS) has important role in improving cholesterol metabolism and promoting the conversion of cholesterol to bile acids (BA) in mice fed high-cholesterol diet (HCD). However, the mechanism is not clear. This study aims to investigate the effects of HPPS on cholesterol accumulation and the regulation of hepatic BA synthesis and transport in HCD-fed mice. Results showed that HPPS significantly decreased plasma and hepatic TC levels but increased plasma high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (apoA-I) levels, compared to HCD. BA analysis showed that HPPS markedly decreased hepatic and small intestine BA levels but increased the gallbladder BA levels, and finally decreased the total BA pool size, compared to HCD. Studies of molecular mechanism revealed that HPPS promoted hepatic ATP-binding cassette transporter A1 (ABCA1), ATP-binding cassette transporter G1 (ABCG1), and scavenger receptor BI (SR-BI) expression but did not affect ATB binding cassette transporter G5/G8 (ABCG5/8) expression. HPPS inactivated hepatic farnesoid X receptor (FXR) and target genes expression, which resulted in significant increase of cholesterol 7α-hydroxylase 1 (CYP7A1) and sterol 12α-hydroxylase (CYP8B1) expression, with up-regulations of 204.2% and 33.5% for mRNA levels, respectively, compared with HCD. In addition, HPPS markedly enhanced bile salt export pump (BSEP) expression but didn't affect the sodium/taurocholate co-transporting polypeptide (NTCP) expression. In conclusion, the study revealed that HPPS reduced cholesterol accumulation by promoting BA synthesis in the liver and excretion in the feces, and might promote macrophage-to-liver reverse cholesterol transport (RCT) but did not liver-to-fecal RCT. Copyright © 2017 Elsevier B.V. All rights reserved.

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

    DEFF Research Database (Denmark)

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

    2016-01-01

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

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

    Science.gov (United States)

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

    2011-01-01

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

  20. 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, C. O.; Milkiewicz, P.; Müller, M.; Roma, M. G.; Havinga, R.; Coleman, R.; Kuipers, F.; Jansen, P. L.; Elias, E.

    1999-01-01

    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. We analyzed biliary excretion kinetics of cholyl lysyl fluorescein (CLF),

  1. 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

  2. Bile acid dysregulation, gut dysbiosis, and gastrointestinal cancer.

    Science.gov (United States)

    Tsuei, Jessica; Chau, Thinh; Mills, David; Wan, Yu-Jui Yvonne

    2014-11-01

    Because of increasingly widespread sedentary lifestyles and diets high in fat and sugar, the global diabetes and obesity epidemic continues to grow unabated. A substantial body of evidence has been accumulated which associates diabetes and obesity to dramatically higher risk of cancer development, particularly in the liver and gastrointestinal tract. Additionally, diabetic and obese individuals have been shown to suffer from dysregulation of bile acid (BA) homeostasis and dysbiosis of the intestinal microbiome. Abnormally elevated levels of cytotoxic secondary BAs and a pro-inflammatory shift in gut microbial profile have individually been linked to numerous enterohepatic diseases including cancer. However, recent findings have implicated a detrimental interplay between BA dysregulation and intestinal dysbiosis that promotes carcinogenesis along the gut-liver axis. This review seeks to examine the currently investigated interactions between the regulation of BA metabolism and activity of the intestinal microbiota and how these interactions can drive cancer formation in the context of diabesity. The precarcinogenic effects of BA dysregulation and gut dysbiosis including excessive inflammation, heightened oxidative DNA damage, and increased cell proliferation are discussed. Furthermore, by focusing on the mediatory roles of BA nuclear receptor farnesoid x receptor, ileal transporter apical sodium dependent BA transporter, and G-coupled protein receptor TGR5, this review attempts to connect BA dysregulation, gut dysbiosis, and enterohepatic carcinogenesis at a mechanistic level. A better understanding of the intricate interplay between BA homeostasis and gut microbiome can yield novel avenues to combat the impending rise in diabesity-related cancers. © 2014 by the Society for Experimental Biology and Medicine.

  3. Nutritional factors (nutritional aspects) in biliary disorders: bile acid and lipid metabolism in gallstone diseases and pancreaticobiliary maljunction.

    Science.gov (United States)

    Tazuma, Susumu; Kanno, Keishi; Sugiyama, Akiko; Kishikawa, Nobusuke

    2013-12-01

    Nutritional factors play a key role in the pathogenesis of biliary diseases such as gallstones and pancreaticobiliary maljunction. Gallstones are primarily classified into cholesterol stone and pigment stone according to the major composition. Cholesterol gallstone formation is very likely based upon supersaturated bile formation, and pigment stones are formed in bile rich in bilirubin. Thus, defects of hepatic metabolism of lipids and organic anions lead to biliary stones. Here, the recent understanding of cholesterol gallstone pathogenesis is elaborated. On the other hand, there is another important link of biliary lipid degradation to serious biliary disease, namely pancreaticobiliary maljunction. Lysophosphatidylcholine (lysoPC), a derivative of phosphatidylcholine hydrolysis by phospholipase A2, is a highly abundant bioactive lipid mediator present in circulation as well as in bile. Increases in bile of lysoPC and phospholipase A2 have been reported in pancreaticobiliary maljunction and considered to be the major risk factor for biliary tract cancers. Further, oxidized fatty acids have been established as a potent ligand for G2A, a member of G protein-coupled receptor family that mediates a diverse array of biological processes including cell growth and apoptosis. Thus, both of lysoPC and free fatty acids are supposed to play an important role through G2A in biliary inflammation and carcinogenesis of pancreaticobiliary maljunction. Taken together, nutritional factors, especially lipid compounds, are seemingly crucial in the pathogenesis of biliary diseases, and such a causal relationship is reviewed by mainly authors' previous publications. © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

  4. Bile acid signaling in lipid metabolism: metabolomic and lipidomic analysis of lipid and bile acid markers linked to anti-obesity and anti-diabetes in mice.

    Science.gov (United States)

    Qi, Yunpeng; Jiang, Changtao; Cheng, Jie; Krausz, Kristopher W; Li, Tiangang; Ferrell, Jessica M; Gonzalez, Frank J; Chiang, John Y L

    2015-01-01

    Bile acid synthesis is the major pathway for catabolism of cholesterol. Cholesterol 7α-hydroxylase (CYP7A1) is the rate-limiting enzyme in the bile acid biosynthetic pathway in the liver and plays an important role in regulating lipid, glucose and energy metabolism. Transgenic mice overexpressing CYP7A1 (CYP7A1-tg mice) were resistant to high-fat diet (HFD)-induced obesity, fatty liver, and diabetes. However the mechanism of resistance to HFD-induced obesity of CYP7A1-tg mice has not been determined. In this study, metabolomic and lipidomic profiles of CYP7A1-tg mice were analyzed to explore the metabolic alterations in CYP7A1-tg mice that govern the protection against obesity and insulin resistance by using ultra-performance liquid chromatography-coupled with electrospray ionization quadrupole time-of-flight mass spectrometry combined with multivariate analyses. Lipidomics analysis identified seven lipid markers including lysophosphatidylcholines, phosphatidylcholines, sphingomyelins and ceramides that were significantly decreased in serum of HFD-fed CYP7A1-tg mice. Metabolomics analysis identified 13 metabolites in bile acid synthesis including taurochenodeoxycholic acid, taurodeoxycholic acid, tauroursodeoxycholic acid, taurocholic acid, and tauro-β-muricholic acid (T-β-MCA) that differed between CYP7A1-tg and wild-type mice. Notably, T-β-MCA, an antagonist of the farnesoid X receptor (FXR) was significantly increased in intestine of CYP7A1-tg mice. This study suggests that reducing 12α-hydroxylated bile acids and increasing intestinal T-β-MCA may reduce high fat diet-induced increase of phospholipids, sphingomyelins and ceramides, and ameliorate diabetes and obesity. This article is part of a Special Issue entitled Linking transcription to physiology in lipodomics. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. Hepatic synthesis and urinary elimination of acetaminophen glucuronide are exacerbated in bile duct-ligated rats.

    Science.gov (United States)

    Villanueva, Silvina S M; Ruiz, María L; Ghanem, Carolina I; Luquita, Marcelo G; Catania, Viviana A; Mottino, Aldo D

    2008-03-01

    Renal and intestinal disposition of acetaminophen glucuronide (APAP-GLU), a common substrate for multidrug resistance-associated proteins 2 and 3 (Mrp2 and Mrp3), was assessed in bile duct-ligated rats (BDL) 7 days after surgery using an in vivo perfused jejunum model with simultaneous urine collection. Doses of 150 mg/kg b.w. (i.v.) or 1 g/kg b.w. (i.p.) of acetaminophen (APAP) were administered, and its glucuronide was determined in bile (only Shams), urine, and intestinal perfusate throughout a 150-min period. Intestinal excretion of APAP-GLU was unchanged or decreased (-58%) by BDL for the 150 mg and 1 g/kg b.w. doses of APAP, respectively. In contrast, renal excretion was increased by 200 and 320%, respectively. Western studies revealed decreased levels of apical Mrp2 in liver and jejunum but increased levels in renal cortex from BDL animals, whereas Mrp3 was substantially increased in liver and not affected in kidney or intestine. The global synthesis of APAP-GLU, determined as the sum of cumulative excretions, was higher in BDL rats (+51 and +110%) for these same doses of APAP as a consequence of a significant increase in functional liver mass, with no changes in specific glucuronidating activity. Expression of apical breast cancer resistance protein, which also transports nontoxic metabolites of APAP, was decreased by BDL in liver and renal cortex, suggesting a minor participation of this route. We demonstrate a more efficient hepatic synthesis and basolateral excretion of APAP-GLU followed by its urinary elimination in BDL group, the latter two processes consistent with up-regulation of liver Mrp3 and renal Mrp2.

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

    African Journals Online (AJOL)

    Yomi

    2012-01-16

    Jan 16, 2012 ... fermentation of baobab seeds can be useful as starter cultures for improving maari quality and safety with respect to protection against food spoilage and pathogenic microorganisms. ..... growth of lactobacilli in MRS broth without bile was used as a positive control (Table 3). All the tested strains showed full ...

  7. 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

  8. Analysis of the Ileal Bile Acid Transporter Gene, SLC10A2, in Subjects With Familial Hypertriglyceridemia

    National Research Council Canada - National Science Library

    Love, Martha W; Craddock, Ann L; Angelin, Bo; Brunzell, John D; Duane, William C; Dawson, Paul A

    2001-01-01

    Familial hypertriglyceridemia (FHTG), a disease characterized by elevated plasma very low density lipoprotein triglyceride levels, has been associated with impaired intestinal absorption of bile acids...

  9. 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.

  10. Aminoterminal propeptide of type III procollagen: a marker of hepatic fibrosis after bile duct obstruction in the monkey.

    Science.gov (United States)

    Ruf, G; Mappes, H J; Koch, H; Baumgartner, U; Hagmann, W; Farthmann, E H

    1996-01-01

    In an experimental study in monkeys, liver fibrosis development after segmental bile duct obstruction was investigated and correlated with the aminoterminal propeptide of type III procollagen (PIIINP). Segmental bile duct obstruction was produced by ligation and section of the left hepatic bile duct in all monkeys. Fibrosis induction was examined by intravenous leukotriene C4 (LTC4, 5 nmol/kg) application, endogenous LT-production stimulated by endotoxin (LPS,salmonella abortus equi, 50 ng/kg), fibrosis inhibition by dexamethasone (1 mg/kg) intramuscularly and subsequent endogenous LT-production stimulation by LPS (50 ng/kg). Ligated and unligated liver lobe biopsies were taken 3, 7 and 12 weeks after ligation. All portal areas were measured morphometrically. PIIINP was measured by a specific radioimmunoassay each week and correlated with the morphometric results. Bile duct obstruction leads to secondary sclerosing cholangitis with bile duct vanishing and subsequent biliary cirrhosis combined with perivenous sclerosis and cavernous transformation of the terminal vein. The collagen concentration increased in the nonligated lobe from mean +/-SEM 1.05 +/- 0.03% to 1.53 +/- 0.19% only after LTC4 and with no difference in the other groups. In the ligated lobe collagen concentration increased significantly in all groups continuously from 1.05 +/- 0.03% up to: controls 6.1 +/- 0.9%, dexamethasone 5.9 +/- 0.8%, LPS 8.2 +/- 0.8%, LTC4 9.075 +/- 1.4%. PIIINP concentration rose within 6 weeks in the controls with hepatic bile duct obstruction from 34.43 +/- 15 ng/ml up to 57 +/- 13.27 ng/ml, after dexamethasone to 48.5 +/- 18.23 ng/ml, after LPS to 57 +/- 13.27 ng/ml, after LTC4 to 80.25 +/- 16.04 ng/ml. After 12 weeks, PIIINP decreased in the controls resp. after dexamethasone to 41.25 +/- 6.94 ng/ml resp. 33.5 +/- 7.72 ng/ml and increased after LPS resp. LTC4 up to 64.25 +/- 17.07 ng/ml resp.104 +/- 22.46 ng/ ml. The correlation of collagen deposition and PIIINP was in the

  11. Tauroursodeoxycholic acid reduces bile acid-induced apoptosis by modulation of AP-1.

    Science.gov (United States)

    Pusl, Thomas; Vennegeerts, Timo; Wimmer, Ralf; Denk, Gerald U; Beuers, Ulrich; Rust, Christian

    2008-02-29

    Ursodeoxycholic acid (UDCA) is used in the therapy of cholestatic liver diseases. Apoptosis induced by toxic bile acids plays an important role in the pathogenesis of liver injury during cholestasis and appears to be mediated by the human transcription factor AP-1. We aimed to study if TUDCA can decrease taurolitholic acid (TLCA)-induced apoptosis by modulating AP-1. TLCA (20 microM) upregulated AP-1 proteins cFos (26-fold) and JunB (11-fold) as determined by quantitative real-time PCR in HepG2-Ntcp hepatoma cells. AP-1 transcriptional activity increased by 300% after exposure to TLCA. cFos and JunB expression as well as AP-1 transcriptional activity were unaffected by TUDCA (75 microM). However, TUDCA significantly decreased TLCA-induced upregulation of cFos and JunB. Furthermore, TUDCA inhibited TLCA-induced AP-1 transcriptional activity and reduced TLCA-induced apoptosis. These data suggest that reversal of bile acid-induced AP-1 activation may be relevant for the antiapoptotic effect of TUDCA in liver cells.

  12. Perinatal Hypercholesterolemia Exacerbates Atherosclerosis Lesions in Offspring by Altering Metabolism of Trimethylamine-N-Oxide and Bile Acids.

    Science.gov (United States)

    Trenteseaux, Charlotte; Gaston, Anh-Thu; Aguesse, Audrey; Poupeau, Guillaume; de Coppet, Pierre; Andriantsitohaina, Ramaroson; Laschet, Jamila; Amarger, Valérie; Krempf, Michel; Nobecourt-Dupuy, Estelle; Ouguerram, Khadija

    2017-11-01

    Experimental studies suggest that maternal hypercholesterolemia may be relevant for the early onset of cardiovascular disease in offspring. We investigated the effect of perinatal hypercholesterolemia on the atherosclerosis development in the offspring of apolipoprotein E-deficient mice and the underlying mechanism. Atherosclerosis and related parameters were studied in adult male or female apolipoprotein E-deficient mice offspring from either normocholesterolemic or hypercholesterolemic mothers and normocholesterolemic fathers. Female born to hypercholesterolemic mothers had more aortic root lesions than female born to normocholesterolemic mothers. Lesions in whole aorta did not differ between groups. Higher trimethylamine-N-oxide levels and Fmo3 hepatic gene expression were higher in female born to hypercholesterolemic mothers offspring compared with female born to normocholesterolemic mothers and male. Trimethylamine-N-oxide levels were correlated with the size of atherosclerotic root lesions. Levels of hepatic cholesterol and gallbladder bile acid were greater in male born to hypercholesterolemic mothers compared with male born to normocholesterolemic mothers. At 18 weeks of age, female born to hypercholesterolemic mothers showed lower hepatic Scarb1 and Cyp7a1 but higher Nr1h4 gene expression compared with female born to normocholesterolemic mothers. Male born to hypercholesterolemic mothers showed an increase in Scarb1 and Ldlr gene expression compared with male born to normocholesterolemic mothers. At 25 weeks of age, female born to hypercholesterolemic mothers had lower Cyp7a1 gene expression compared with female born to normocholesterolemic mothers. DNA methylation of Fmo3, Scarb1, and Ldlr promoter regions was slightly modified and may explain the mRNA expression modulation. Our findings suggest that maternal hypercholesterolemia may exacerbate the development of atherosclerosis in female offspring by affecting metabolism of trimethylamine-N-oxide and

  13. Mouse ghrelin-O-acyltransferase (GOAT) plays a critical role in bile acid reabsorption.

    Science.gov (United States)

    Kang, Kihwa; Schmahl, Jennifer; Lee, Jong-Min; Garcia, Karen; Patil, Ketan; Chen, Amelia; Keene, Michelle; Murphy, Andrew; Sleeman, Mark W

    2012-01-01

    Ghrelin is a unique peptide gut hormone that requires post-translational modification to stimulate both feeding and growth hormone release. Ghrelin O-acyltransferase (GOAT) was identified as a specific acyl-transferase for ghrelin, and recent genetic deletion studies of the Goat gene (Goat(-/-)) uncovered the role of ghrelin in the regulation of glucose homeostasis. To further understand the physiological functions of the GOAT/ghrelin system, we have conducted a metabolomic and microarray profile of Goat-null mice, as well as determined Goat expression in different tissues using the lacZ reporter gene. Serum metabolite profile analysis revealed that Goat(-/-) mice exhibited increased secondary bile acids >2.5-fold. This was attributed to increased mRNA and protein expression of the ileal sodium-dependent bile acid transporter (ISBT) in the intestinal and biliary tract. Increased expression of additional solute carrier proteins, including Slc5a12 (>10-fold) were also detected in the small intestine and bile duct. Goat staining was consistently observed in the pituitary glands, stomach, and intestines, and to a lesser extent in the gallbladder and pancreatic duct. This is the first report that the GOAT/ghrelin system regulates bile acid metabolism, and these findings suggest a novel function of GOAT in the regulation of intestinal bile acid reabsorption..

  14. Elevated levels of bile acids in colostrum of patients with cholestasis of pregnancy are decreased following ursodeoxycholic acid therapy [see comemnts].

    Science.gov (United States)

    Brites, D; Rodrigues, C M

    1998-11-01

    Intrahepatic cholestasis of pregnancy is characterised by increased levels of serum bile acids. Ursodeoxycholic acid therapy corrects the serum bile acid profile. The aims of this study were: (i) to investigate bile acid excretion into colostrum of women with intrahepatic cholestasis of pregnancy; (ii) to compare concentrations of bile acids in serum and colostrum of non-treated and ursodeoxycholic acid-treated patients; and (iii) to clarify whether ursodeoxycholic acid is eliminated into colostrum following treatment. Bile acids were assessed by gas chromatography and high-performance liquid chromatography in serum collected at delivery, and in colostrum obtained at 2+/-1 days after labour, from patients with intrahepatic cholestasis of pregnancy, non-treated (n=9) and treated (n=7) with ursodeoxycholic acid (14 mg/kg bw per day, for 14+/-7 days) until parturition. The concentration of total bile acids in colostrum from patients with intrahepatic cholestasis of pregnancy was higher than in normals (23.3+/-14.8 micromol/l vs. 0.7+/-0.2 micromol/l, pacid was a major species (19.0+/-13.1 micromol/l), reflecting the elevated concentrations in maternal serum (48.9+/-21.0 micromol/l, total bile acids; 33.9+/-16.7 micromol/l, cholic acid. Following ursodeoxycholic acid administration, total bile acids and cholic acid levels in colostrum diminished to 5.7+/-2.5 micromol/l and 3.6+/-1.5 micromol/l, respectively; the proportion of cholic acid decreased (60.6+/-8.0% vs. 76.8+/-5.0%, pursodeoxycholic acid concentration in colostrum was maintained following treatment; its increased percentage (9.4+/-3.2% vs. 1.0+/-0.2%, pacid was found in colostrum following therapy. Bile acid concentrations are elevated and cholic acid is the major species accumulating in colostrum, reflecting serum bile acid profiles in intrahepatic cholestasis of pregnancy. Ursodeoxycholic acid therapy decreases endogenous bile acid levels in colostrum.

  15. Hepatic extraction of chenodeoxycholic acid in dogs chronically intoxicated with dimethylnitrosamine.

    Science.gov (United States)

    Kawasaki, S; Umekita, N; Beppu, T; Wada, T; Sugiyama, Y; Iga, T; Hanano, M

    1984-10-15

    The pharmacokinetics of chenodeoxycholic acid (CDCA) in hepatic dysfunction were evaluated by analyzing the plasma disappearance curves after simultaneous administration of [3H]- and [14C]-CDCA through the femoral and portal veins, respectively, in dogs chronically intoxicated with dimethylnitrosamine (DMN). The plasma concentration-time curve of intravenously administered [3H]-CDCA was best fitted to a three-exponential equation, while that of intraportally administered [14C]-CDCA was fitted to either a two- or a three-exponential equation. In the DMN-intoxicated dogs, significant decreases were observed in total body plasma clearance (CLp), hepatic extraction ratio (EH) and apparent intrinsic clearance (CLint) compared to those of the untreated (control) dogs. The hepatic blood flow (QH), calculated from CLp, CLint and blood-to-plasma concentration ratio (RB) according to the equation reported by Wilkinson and Shand [Clin. Pharmac. Ther. 18, 377 (1975)], was reduced to approximately 70% in the DMN-intoxicated dogs compared to the control dogs. The bindings of CDCA to plasma and liver cytosol fraction were determined by equilibrium dialysis; no significant difference was observed in the unbound fraction between the DMN-treated and control dogs. By comparing both pharmacokinetic parameters obtained from intravenous and intraportal administration, the usefulness of the oral bile acid tolerance test was examined. From these findings, it was suggested that the decrease in the CLp of the DMN-intoxicated dogs was due to both the decrease in QH and that in CLint, and that the decrease in CLint may be due not to an alteration of plasma or cytosol binding but to that of a carrier-mediated transport system. It is also suggested that the measurement of fasting plasma bile acid concentration or the oral bile acid tolerance test is more sensitive for the detection of hepatic dysfunction than the intravenous bile acid tolerance test.

  16. Effects of structural modifications on physicochemical and bile acid-binding properties of psyllium.

    Science.gov (United States)

    Niu, Yuge; Xie, Zhuohong; Zhang, Hua; Sheng, Yi; Yu, Liangli Lucy

    2013-01-23

    The effects of sulfation, hydroxypropylation, and succinylation on gelling, water uptake, swelling, and bile acid-binding capacities of psyllium were examined and compared at the same molar substitution degree. Sulfated, hydroxypropylated, and succinylated psyllium were prepared with substitution levels of 1.02, 0.88, and 0.79, respectively, and their structures were characterized using FT-IR, SEM, and ζ-potential determination. All three derivatization methods reduced the gelling and swelling capacities of psyllium and increased the water uptake and bile acid-binding capacities compared to the original psyllium. Interestingly, it was observed for the first time that introduction of a stronger negatively charged group into the molecule might more effectively enhance the bile acid-binding capacity of psyllium. On the other hand, the steric effect of the substitution groups seemed to be more critical in altering the gelling and swelling properties of psyllium.

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

    DEFF Research Database (Denmark)

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

    2016-01-01

    The gut microbiota is considered a metabolic "organ" that not only facilitates harvesting of nutrients and energy from the ingested food but also produces numerous metabolites that signal through their cognate receptors to regulate host metabolism. One such class of metabolites, bile acids, is pr...... by altered microbiota composition.......The gut microbiota is considered a metabolic "organ" that not only facilitates harvesting of nutrients and energy from the ingested food but also produces numerous metabolites that signal through their cognate receptors to regulate host metabolism. One such class of metabolites, bile acids......, is produced in the liver from cholesterol and metabolized in the intestine by the gut microbiota. These bioconversions modulate the signaling properties of bile acids via the nuclear farnesoid X receptor and the G protein-coupled membrane receptor 5, which regulate numerous metabolic pathways in the host...

  18. 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

    BACKGROUND & AIMS: Obesity has been associated with changes in the composition and function of the intestinal microbiota. Modulation of the microbiota by antibiotics also alters bile acid and glucose metabolism in mice. Hence, we hypothesized that short term administration of oral antibiotics...... 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...

  19. 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...

  20. Characterization of AQPs in Mouse, Rat, and Human Colon and Their Selective Regulation by Bile Acids

    DEFF Research Database (Denmark)

    Yde, Jonathan; Keely, Stephen; Wu, Qi

    2016-01-01

    In normal individuals, the epithelium of the colon absorbs 1.5-2 l of water a day to generate dehydrated feces. However, in the condition of bile acid malabsorption (BAM), an excess of bile acids in the colon results in diarrhea. Several studies have attempted to address the mechanisms contributing...... to BAM induced by various bile acids. However, none have addressed a potential dysregulation of aquaporin (AQP) water channels, which are responsible for the majority of transcellular water transport in epithelial cells, as a contributing factor to the onset of diarrhea and the pathogenesis of BAM....... In this study, we aimed to systematically analyze the expression of AQPs in colonic epithelia from rat, mouse, and human and determine whether their expression is altered in a rat model of BAM. Mass spectrometry-based proteomics, RT-PCR, and western blotting identified various AQPs in isolated colonic...

  1. Medical treatment of primary sclerosing cholangitis: a role for novel bile acids and other (post-)transcriptional modulators?

    Science.gov (United States)

    Beuers, Ulrich; Kullak-Ublick, Gerd A; Pusl, Thomas; Rauws, Erik R; Rust, Christian

    2009-02-01

    Primary sclerosing cholangitis (PSC) is a rare chronic cholestatic disease of the liver and bile ducts that is associated with inflammatory bowel disease, generally leads to end-stage liver disease, and is complicated by malignancies of the biliary tree and the large intestine. The pathogenesis of PSC remains enigmatic, making the development of targeted therapeutic strategies difficult. Immunosuppressive and antifibrotic therapeutic agents were ineffective or accompanied by major side effects. Ursodeoxycholic acid (UDCA) has consistently been shown to improve serum liver tests and might lower the risk of colon carcinoma and cholangiocarcinoma by yet unknown mechanisms. Whether "high dose" UDCA improves the long-term prognosis in PSC as suggested by small pilot trials remains to be demonstrated. The present overview discusses potential therapeutic options aside of targeted immunological therapies and UDCA. The C23 bile acid norUDCA has been shown to markedly improve biochemical and histological features in a mouse model of sclerosing cholangitis without any toxic effects. Studies in humans are eagerly being awaited. Nuclear receptors like the farnesoid-X receptor (FXR), pregnane-X receptor (PXR), vitamin D receptor (VDR), and peroxisome-proliferator-activator receptors (PPARs) have been shown to induce expression of diverse carriers and biotransformation enzymes of the intestinal and hepatic detoxification machinery and/or to modulate fibrogenesis. Pros and cons of respective receptor agonists for the future treatment of PSC are discussed in detail. In our view, the novel bile acid norUDCA and agonists of PPARs, VDR, and PXR appear particularly attractive for further studies in PSC.

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

    Science.gov (United States)

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

    2012-07-01

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

  3. Bile acid profiles over 5 years after gastric bypass and duodenal switch: results from a randomized clinical trial.

    Science.gov (United States)

    Risstad, Hilde; Kristinsson, Jon A; Fagerland, Morten W; le Roux, Carel W; Birkeland, Kåre I; Gulseth, Hanne L; Thorsby, Per M; Vincent, Royce P; Engström, My; Olbers, Torsten; Mala, Tom

    2017-09-01

    Bile acids have been proposed as key mediators of the metabolic effects after bariatric surgery. Currently no reports on bile acid profiles after duodenal switch exist, and long-term data after gastric bypass are lacking. To investigate bile acid profiles up to 5 years after Roux-en-Y gastric bypass and biliopancreatic diversion with duodenal switch and to explore the relationship among bile acids and weight loss, lipid profile, and glucose metabolism. Two Scandinavian University Hospitals. We present data from a randomized clinical trial of 60 patients with body mass index 50-60 kg/m2 operated with gastric bypass or duodenal switch. Repeated measurements of total and individual bile acids from fasting serum during 5 years after surgery were performed. Mean concentrations of total bile acids increased from 2.3 µmol/L (95% confidence interval [CI], -.1 to 4.7) at baseline to 5.9 µmol/L (3.5-8.3) 5 years after gastric bypass and from 1.0 µmol/L (95% CI, -1.4 to 3.5) to 9.5 µmol/L (95% CI, 7.1-11.9) after duodenal switch; mean between-group difference was -4.8 µmol/L (95% CI, -9.3 to -.3), P = .036. Mean concentrations of primary bile acids increased more after duodenal switch, whereas secondary bile acids increased proportionally across the groups. Higher levels of total bile acids at 5 years were associated with lower body mass index, greater weight loss, and lower total cholesterol. Total bile acid concentrations increased substantially over 5 years after both gastric bypass and duodenal switch, with greater increases in total and primary bile acids after duodenal switch. (Surg Obes Relat Dis 2017;0:000-000.) © 2017 American Society for Metabolic and Bariatric Surgery. All rights reserved. Copyright © 2017 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.

  4. Ultrasonographic Measurement of the Diameter of a Normal Bile Duct, Hepatic Artery and Portal Vein in Infants Younger Than 3 Months

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sang Yoon; Lee, Young Seok [Dankook University Hospital, Cheonan (Korea, Republic of)

    2009-09-15

    This study focused on measuring the diameter of the normal bile duct, hepatic artery and portal vein with high resolution US in infants younger than 3 months, and we wanted to determine the relative ratio of these diameters. Fifty US examinations were performed on infants younger than 3 months and who did not have any clinical or laboratory abnormality associated with the hepatobiliary system. We measured the diameter of the bile duct, hepatic artery and portal vein at the level of the portal vein bifurcation with using 17-5 MHz US and we determined the relative ratios of these diameters. To evaluate the statistical difference in the diameter of the bile duct, hepatic artery and portal vein, we performed one-way ANOVA and Scheffe's multiple comparison test. To determine the relative ratio of these diameters, the ratio of the bile duct to the hepatic artery was defined as the hepatic artery/bile duct, the ratio of the hepatic artery to the portal vein was defined as the portal vein/hepatic artery and the ratio of the bile duct to the portal vein was defined as the portal vein/bile duct. We calculated the averages {+-} standard deviations of this data (minimum {approx} maximum). In all fifty infants, the bile duct, hepatic artery and portal vein were detectable and measurable. The average diameter of a bile duct was 0.85 {+-} 0.19 mm (0.56 {approx} 1.47 mm), it was 1.33 {+-} 0.31 mm (0.90 {approx} 2.37 mm) for the hepatic artery and 3.32 {+-} 0.68 mm (2.06 {approx} 5.08 mm) for the portal vein. The diameter of these structures was significantly different from each other according to one-way ANOVA (p < 0.001). The average diameter of the hepatic artery was significantly larger than that of the bile duct and the average diameter of the portal vein was significantly larger than that of bile duct and hepatic artery on Scheffe's multiple comparison test. The relative ratio of the bile duct to the hepatic artery was 1.60 {+-} 0.41 (0.77 {approx} 2.66), that of

  5. Prevention of taurolithocholate-induced hepatic bile canalicular distortions by HPLC-characterized extracts of artichoke (Cynara scolymus) leaves.

    Science.gov (United States)

    Gebhardt, R

    2002-09-01

    The effects of water-soluble extracts of artichoke (Cynara scolymus L.) leaves on taurolithocholate-induced cholestatic bile canalicular membrane distortions were studied in primary cultured rat hepatocytes using electron microscopy. Artichoke extracts at concentrations between 0.08 and 0.5 mg/ml were able to prevent the formation of bizarre canalicular membrane transformations in a dose-dependent manner when added simultaneously with the bile acid. However, prevention also occurred when the hepatocytes were preincubated with the extracts, indicating that absorption of the bile acid to components of the extracts was not involved. These results demonstrate that artichoke leaf extracts exert a potent anticholestatic action at least in the case of taurolithocholate. This effect may contribute to the overall hepatoprotective influence of this herbal formulation.

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

    Science.gov (United States)

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

    2012-01-01

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

  7. A case of the hepatic hilar bile duct cancer with external radiation. Efficacy and severe side effect of external radiation therapy

    Energy Technology Data Exchange (ETDEWEB)

    Andoh, Hideaki; Yasui, Ouki; Ise, Norihito [Akita Univ. (Japan). School of Medicine

    2003-04-01

    Hepatic hilar bile duct cancer was difficult to cure by surgical treatment and its prognosis was very poor. We present the case of non-curative resection of hepatic hilar bile duct cancer, controlled with external radiation. 72 years-old-female, she complained jaundice and diagnosed hepatic hilar bile duct cancer with abdominal ultrasonography. Hepatic hilar resection was performed but curative resection could not be done, because cancer was diffusely spreaded to the hepatic and duodenal ends of the bile duct. After surgery, external radiation (1.8 Gy/day; total 50.4 Gy) was performed. Three months after operation, sometimes, cholangitis was occurred but we could not detect the intrahepatic bile duct dilatation and improved with antibiotics. After seven months, she was dead for sepsis, liver abscess and biliary cirrhosis. From autopsy findings, severe hepatic hilar fibrosis around the irradiation area, stenosis of the hepatico-jejunostomy and portal vein were existed but could not detect the remnant cancer cells. External radiation was sometimes effective, especially for this case. But we should consider the side effect of fibrosis and preventive treatments such as biliary stenting or early biliary drainage. (author)

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

    DEFF Research Database (Denmark)

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

    2017-01-01

    The bile acid receptor TGR5 (also known as GPBAR1) is a promising target for the development of pharmacological interventions in metabolic diseases, including type 2 diabetes, obesity, and non-alcoholic steatohepatitis. TGR5 is expressed in many metabolically active tissues, but complex...... such as weight loss, glucose metabolism, energy expenditure, and suppression of inflammation. However, clinical studies are scarce. We give a summary of key concepts in bile acid metabolism; outline different downstream effects of TGR5 activation; and review available data on TGR5 activation, with a focus...

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

    DEFF Research Database (Denmark)

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

    2016-01-01

    Vertical transmission of the maternal microbiota is assumed to be crucial for the offspring’s development. A disrupted microbiota composition leading to an altered metabolic activity of the microbiota can affect bile acid profiles, which are known to influence host metabolism. Here, we examined...... whether perturbation of the maternal gut microbiota during pregnancy, induced by administration of either amoxicillin or vancomycin to pregnant rats, influenced bile acid profiles in the offspring. The dams were treated with antibiotics from 8 days before the dams gave birth and continued until weaning (4...

  10. 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...

  11. 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'

  12. Oxidative stress markers, secondary bile acids and sulfated bile acids classify the clinical liver injury type: Promising diagnostic biomarkers for cholestasis.

    Science.gov (United States)

    Masubuchi, Noriko; Sugihara, Masahiro; Sugita, Tomonori; Amano, Katsushi; Nakano, Masanori; Matsuura, Tomokazu

    2016-08-05

    Clinicians sometimes encounter difficulty in choosing a therapeutic strategy due to the uncertainty regarding the type of liver injury. In particular, cholestasis is difficult to diagnose by conventional markers at an early stage of disease. The aim of this study was to identify promising biomarkers for distinguishing the symptom-based types of liver injury (e.g. hepatocellular injury, cholestasis), which was derived from a rigorously statistical perspective. The associations between diagnostic biomarkers (e.g. bile acid components, oxidative stress markers and liver fibrosis markers) and the liver injury types were assessed by a multiple logistic regression analysis using 304 blood samples from patients with liver disease. As a result, reductions in the lithocholic acid (LCA) and deoxycholic acid (DCA) levels, and elevation of the serum sulfated bile acid (SSBA), liver fibrosis marker IV collagen (type IV collagen), hyaluronic acid (HA) and reactive oxygen species (ROS) levels were all significantly associated with cholestasis. On the other hand, elevations in the LCA and type IV collagen levels, and a reduction in the ursodeoxy cholic acid (UDCA) level, were significantly associated with hepatocellular injury. The receiver operating characteristic (ROC) analyses showed that the largest area under the ROC curve (AUC) was found for ROS, followed by DCA, HA, LCA, SSBA and type IV collagen in the cholestatic-type cases. These results indicated that ROS, the secondary bile acid levels such as DCA and LCA, and SSBA are promising biomarkers for cholestasis and for classifying the type of liver injuries. This comprehensive approach will allow for an accurate diagnosis, which will facilitate the selection of an appropriate therapy at the onset of disease. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  13. Bile acid-induced apoptosis in hepatocytes is caspase-6-dependent.

    Science.gov (United States)

    Rust, Christian; Wild, Nadine; Bernt, Carina; Vennegeerts, Timo; Wimmer, Ralf; Beuers, Ulrich

    2009-01-30

    Apoptosis induced by hydrophobic bile acids is thought to contribute to liver injury during cholestasis. Caspase-6 is an executioner caspase that also appears to have regulatory functions in hematopoetic cell lines. We aimed to elucidate the role of caspase-6 in bile acid-induced apoptosis. The major human hydrophobic bile acid, glycochenodeoxycholic acid (GCDCA, 75 micromol/liter), rapidly induced caspase-6 cleavage in HepG2-Ntcp human hepatoma cells. GCDCA-induced, but not tumor necrosis factor alpha- or etoposide-induced activation of effector caspases-3 and -7 was significantly reduced by 50% in caspase-6-deficient HepG2-Ntcp cells as well as in primary rat hepatocytes pretreated with a caspase-6 inhibitor. Inhibition of caspase-9 reduced GCDCA-induced activation of caspase-6, whereas inhibition of caspase-6 reduced activation of caspase-8 placing caspase-6 between caspase-9 and caspase-8. GCDCA also induced apoptosis in Fas-deficient Hep3B-Ntcp and HuH7-Ntcp hepatoma cells. In addition, GCDCA-induced apoptosis was reduced by 50% in FADD-deficient HepG2-Ntcp cells, whereas apoptosis induced by tumor necrosis factor alpha was reduced by 90%. Collectively, these observations suggest that GCDCA can induce hepatocyte apoptosis in the absence of death receptor signaling, presumably by a compensatory mitochondrial pathway. In conclusion, caspase-6 appears to play an important regulatory role in the promotion of bile acid-induced apoptosis as part of a feedback loop.

  14. 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.

  15. Postoperative radiotherapy dose correlates with locoregional control in patients with extra-hepatic bile duct cancer

    Energy Technology Data Exchange (ETDEWEB)

    Im, Jung Ho; Seong, Jinsil; Lee, Jeong Shim; Kim, Yong Bae; Kim, Kyung Sik; Lee, Woo Jung [Severance Hospital, Yonsei University College of Medicine, Seoul (Korea, Republic of); Lee, Ik Jae; Park, Jun Sung; Yoon, Dong Sup [Sangnam Severance Hospital, Yonsei University College of Medicine, Seoul (Korea, Republic of)

    2013-12-15

    To evaluate the results of postoperative radiotherapy in patients with extra-hepatic bile duct cancer (EHBDC) and identify the prognostic factors for local control and survival. Between January 2001 and December 2010, we retrospectively reviewed the cases of 70 patients with EHBDC who had undergone curative resection and received postoperative radiotherapy. The median radiation dose was 50.4 Gy (range, 41.4 to 54 Gy). The resection margin status was R0 in 30 patients (42.9%), R1 in 25 patients (35.7%), and R2 in 15 patients (21.4%). The 5-year rates of overall survival (OS), event-free survival (EFS), and locoregional control (LRC) for all patients were 42.9%, 38.3%, and 61.2%, respectively. The major pattern of failure was distant relapses (33 patients, 47.1%). A multivariate analysis showed that the postradiotherapy CA19-9 level, radiation dose (≥50 Gy), R2 resection margins, perineural invasion, and T stage were the significant prognostic factors for OS, EFS, and LRC. OS was not significantly different between the patients receiving R0 and R1 resections, but was significantly lower among those receiving R2 resection (54.6%, 56.1%, and 7.1% for R0, R1, and R2 resections, respectively). In patients with EHBDC who had undergone curative resection, a postoperative radiotherapy dose less than 50 Gy was suboptimal for OS and LRC. Higher radiation doses may be needed to obtain better LRC. Further investigation of novel therapy or palliative treatment should be considered for patients receiving R2 resection.

  16. ABCA1-dependent but apoA-I-independent cholesterol efflux mediated by fatty acid-bile acid conjugates (FABACs)

    NARCIS (Netherlands)

    Goldiner, Ilana; van der Velde, Astrid E.; Vandenberghe, Kristin E.; van Wijland, Michel A.; Halpern, Zamir; Gilat, Tuvia; Konikoff, Fred M.; Veldman, Robert Jan; Groen, Albert K.

    2006-01-01

    FABACs (fatty acid-bile acid conjugates) are synthetic molecules that are designed to treat a range of lipid disorders. The compounds prevent cholesterol gallstone formation and diet-induced fatty liver, and increase reverse cholesterol transport in rodents. The aim of the present study was to

  17. 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

  18. 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.

  19. (75)SeHCAT scan in bile acid malabsorption in chronic diarrhoea.

    Science.gov (United States)

    Mena Bares, L M; Carmona Asenjo, E; García Sánchez, M V; Moreno Ortega, E; Maza Muret, F R; Guiote Moreno, M V; Santos Bueno, A M; Iglesias Flores, E; Benítez Cantero, J M; Vallejo Casas, J A

    Chronic diarrhoea is a common entity in daily clinical practice and it leads to a loss in these patients quality of life. It may be the main symptom of multiple ethiologies including bile acid malabsorption (BAM) which has a comparable prevalence to celiac disease. The BAM results from imbalances in the homeostasis of bile acids in the enterohepatic circulation. It can be a consequence of ileal disease or ileal dysfunction (BAM type i), it can be considered idiopathic or primary (BAM type ii) or associated with other gastrointestinal entities (BAM type iii). Among the different diagnostic methods available, (75)SeHCAT study is the primary current method due to its sensitivity, specificity, safety and low cost. The main disadvantage is that it's not available in all countries, so other diagnostic methods have appeared, such as serum measurement of FGF19 and C4, however they are significantly more complex and costly. The first-line treatment of bile acid diarrhoea is bile acid sequestrant, such as cholestyramine, which can be difficult to administer due to its poor tolerability and gastrointestinal side effects. These are less prominent with newer agents such as colesevelam. In summary, the BAM is a common entity underdiagnosed and undertreated, so it is essential to establish a diagnosis algorithm of chronic diarrhoea in which the (75)SeHCAT study would be first or second line in the differential diagnosis of these patients. Copyright © 2016 Elsevier España, S.L.U. y SEMNIM. All rights reserved.

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

    NARCIS (Netherlands)

    Vrieze, A.; Out, C.; Fuentes Enriquez de Salamanca, S.; Jonker, L.; Reuling, I.; Kootte, R.S.; Nood, van E.; Holleman, F.; Knaapen, M.; Romijn, J.A.; Soeters, M.R.; Blaak, E.E.; Dallinga-Thie, G.M.; Reijnders, D.; Ackermans, M.T.; Serlie, M.J.; Knop, F.K.; Holst, J.J.; Ley, C.V.; Kema, I.P.; Zoetendal, E.G.; Vos, de W.M.; Hoekstra, J.B.; Stroes, E.S.; Groen, A.K.; Nieuwdorp, M.

    2014-01-01

    BACKGROUND: Obesity has been associated with changes in the composition and function of the intestinal microbiota. Modulation of the microbiota by antibiotics also alters bile acid and glucose metabolism in mice. Hence, we hypothesized that short term administration of oral antibiotics in humans

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

    NARCIS (Netherlands)

    Vrieze, Anne; Out, Carolien; Fuentes, Susana; Jonker, Lisanne; Reuling, Isaie; Kootte, Ruud S.; van Nood, Els; Holleman, Frits; Knaapen, Max; Romijn, Johannes A.; Soeters, Maarten R.; Blaak, Ellen E.; Dallinga-Thie, Geesje M.; Reijnders, Dorien; Ackermans, Mariette T.; Serlie, Mireille J.; Knop, Filip K.; Holst, Jenst J.; van der Ley, Claude; Kema, Ido P.; Zoetendal, Erwin G.; de Vos, Willem M.; Hoekstra, Joost B. L.; Stroes, Erik S.; Groen, Albert K.; Nieuwdorp, Max

    2014-01-01

    Obesity has been associated with changes in the composition and function of the intestinal microbiota. Modulation of the microbiota by antibiotics also alters bile acid and glucose metabolism in mice. Hence, we hypothesized that short term administration of oral antibiotics in humans would affect

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

    NARCIS (Netherlands)

    Vrieze, Anne; Out, Carolien; Fuentes, Susana; Jonker, Lisanne; Reuling, Isaie; Kootte, Ruud S.; van Nood, Els; Holleman, Frits; Knaapen, Max; Romijn, Johannes A.; Soeters, Maarten R.; Blaak, Ellen E.; Dallinga-Thie, Geesje M.; Reijnders, Dorien; Ackermans, Mariette T.; Serlie, Mireille J.; Knop, Filip K.; Holst, Jenst J.; van der Ley, Claude; Kema, Ido P.; Zoetendal, Erwin G.; de Vos, Willem M.; Hoekstra, Joost B. L.; Stroes, Erik S.; Groen, Albert K.; Nieuwdorp, Max

    Background & Aims: Obesity has been associated with changes in the composition and function of the intestinal microbiota. Modulation of the microbiota by antibiotics also alters bile acid and glucose metabolism in mice. Hence, we hypothesized that short term administration of oral antibiotics in

  3. 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 th...

  4. 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

  5. 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

    be evaluated. RESULTS: In 44% of patients, bile acid absorption was normal with SeHCAT retention > or = 15%. Impaired SeHCAT retention was found in 56%. All patients with ileocaecal resections had retention values microscopic colitis presented with BAM in 39%. Only one patient...

  6. Anti-oxidants do not prevent bile acid-induced cell death in rat hepatocytes.

    NARCIS (Netherlands)

    Woudenberg-Vrenken, T.E.; Buist-Homan, M.; Conde de la Rosa, L.; Faber, K.N.; Moshage, H.

    2010-01-01

    BACKGROUND: Bile acids, reactive oxygen species (ROS) and inflammatory cytokines are crucial regulators of cell death in acute and chronic liver diseases. The contribution of each factor to hepatocyte death, either apoptosis or necrosis, has not been clarified as yet. It has been suggested that the

  7. Anti-oxidants do not prevent bile acid-induced cell death in rat hepatocytes

    NARCIS (Netherlands)

    Woudenberg-Vrenken, Titia E.; Buist-Homan, Manon; Conde de la Rosa, Laura; Faber, Klaas Nico; Moshage, Han

    2010-01-01

    Background Bile acids, reactive oxygen species (ROS) and inflammatory cytokines are crucial regulators of cell death in acute and chronic liver diseases. The contribution of each factor to hepatocyte death, either apoptosis or necrosis, has not been clarified as yet. It has been suggested that the

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

    NARCIS (Netherlands)

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

    1992-01-01

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

  9. Hepatocyte MyD88 affects bile acids, gut microbiota and metabolome contributing to regulate glucose and lipid metabolism.

    Science.gov (United States)

    Duparc, Thibaut; Plovier, Hubert; Marrachelli, Vannina G; Van Hul, Matthias; Essaghir, Ahmed; Ståhlman, Marcus; Matamoros, Sébastien; Geurts, Lucie; Pardo-Tendero, Mercedes M; Druart, Céline; Delzenne, Nathalie M; Demoulin, Jean-Baptiste; van der Merwe, Schalk W; van Pelt, Jos; Bäckhed, Fredrik; Monleon, Daniel; Everard, Amandine; Cani, Patrice D

    2017-04-01

    To examine the role of hepatocyte myeloid differentiation primary-response gene 88 (MyD88) on glucose and lipid metabolism. To study the impact of the innate immune system at the level of the hepatocyte and metabolism, we generated mice harbouring hepatocyte-specific deletion of MyD88 . We investigated the impact of the deletion on metabolism by feeding mice with a normal control diet or a high-fat diet for 8 weeks. We evaluated body weight, fat mass gain (using time-domain nuclear magnetic resonance), glucose metabolism and energy homeostasis (using metabolic chambers). We 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). Hepatocyte-specific deletion of MyD88 predisposes to glucose intolerance, inflammation and hepatic insulin resistance independently of body weight and adiposity. These phenotypic differences were partially attributed to differences in gene expression, transcriptional factor activity (ie, peroxisome proliferator activator receptor-α, farnesoid X receptor (FXR), liver X receptors and STAT3) and bile acid profiles involved in glucose, lipid metabolism and inflammation. In addition to these alterations, the genetic deletion of MyD88 in hepatocytes changes the gut microbiota composition and their metabolomes, resembling those observed during diet-induced obesity. Finally, obese humans with NASH displayed a decreased expression of different cytochromes P450 involved in bioactive lipid synthesis. Our study identifies a new link between innate immunity and hepatic synthesis of bile acids and bioactive lipids. This dialogue appears to be involved in the susceptibility to alterations associated with obesity such as type 2 diabetes and NASH, both in mice and humans. Published by the BMJ Publishing Group Limited

  10. 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

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

    NARCIS (Netherlands)

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

    1993-01-01

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

  12. Quantitative targeted bile acid profiling as new markers for DILI in a model of methapyrilene-induced liver injury in rats.

    Science.gov (United States)

    Slopianka, Markus; Herrmann, Anne; Pavkovic, Mira; Ellinger-Ziegelbauer, Heidrun; Ernst, Rainer; Mally, Angela; Keck, Matthias; Riefke, Bjoern

    2017-07-01

    Recently, bile acids (BAs) were reported as promising markers for drug-induced liver injury (DILI). BAs have been suggested to correlate with hepatocellular and hepatobiliary damage; however a clear connection of BA patterns with different types of DILI remains to be established. To investigate if BAs can improve the assessment of liver injury, 20 specific BAs were quantitatively profiled via LC-MS/MS in plasma and liver tissue in a model of methapyrilene-induced liver injury in rats. Methapyrilene, a known hepatotoxin was dosed daily over 14-days at doses of 30 and 80mg/kg, followed by a recovery phase of 10days. Conventional preclinical safety endpoints were related to BA perturbations and to hepatic gene expression profiling for a mechanistic interpretation of effects. Histopathological signs of hepatocellular and hepatobiliary damage with significant changes of clinical chemistry markers were accompanied by significantly increased levels of indivdual BAs in plasma and liver tissue. BA perturbations were already evident at the earliest time point after 30mg/kg treatment, and thereby indicating better sensitivity than clinical chemistry parameters. Furthermore, the latter markers suggested recovery of liver injury, whereas BA levels in plasma and liver remained significantly elevated during the recovery phase, in line with persistent histopathological findings of bile duct hyperplasia (BDH) and bile pigment deposition. Gene expression profiling revealed downregulation of genes involved in BA synthesis (AMACR, BAAT, ACOX2) and hepatocellular uptake (NTCP, OATs), and upregulation for efflux transporters (MRP2, MRP4), suggesting an adaptive hepatocellular protection mechanism against cytotoxic bile acid accumulation. In summary, our data suggests that specific BAs with high reliability such as cholic acid (CA) and chenodeoxycholic acid (CDCA) followed by glycocholic acid (GCA), taurocholic acid (TCA) and deoxycholic acid (DCA) can serve as additional biomarkers for

  13. 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

    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....../retroperitoneal adipose tissues of rats fed saithe FPH. Our results provide the first evidence that dietary protein sources with different amino acid compositions can modulate the level of plasma bile acids and our data suggest potential novel mechanisms by which dietary protein sources can affect energy metabolism....... 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...

  14. The bile acid chenodeoxycholic acid directly modulates metabolic pathways in white adipose tissue in vitro: insight into how bile acids decrease obesity.

    Science.gov (United States)

    Teodoro, João Soeiro; Rolo, Anabela Pinto; Jarak, Ivana; Palmeira, Carlos Marques; Carvalho, Rui Albuquerque

    2016-10-01

    Obesity is a worldwide epidemic, and associated pathologies, including type 2 diabetes and cardiovascular alterations, are increasingly escalating morbidity and mortality. Despite intensive study, no effective simple treatment for these conditions exists. As such, the need for go-to drugs is serious. Bile acids (BAs) present the possibility of reversing these problems, as various in vivo studies and clinical trials have shown significant effects with regard to weight and obesity reduction, insulin sensitivity restoration and cardiovascular improvements. However, the mechanism of action of BA-induced metabolic improvement has yet to be fully established. The currently most accepted model involves non-shivering thermogenesis for energy waste, but this is disputed. As such, we propose to determine whether the BA chenodeoxycholic acid (CDCA) can exert anti-obesogenic effects in vitro, independent of thermogenic brown adipose tissue activation. By exposing differentiated 3 T3-L1 adipocytes to high glucose and CDCA, we demonstrate that this BA has anti-obesity effects in vitro. Nuclear magnetic resonance spectroscopic analysis of metabolic pathways clearly indicates an improvement in metabolic status, as these cells become more oxidative rather than glycolytic, which may be associated with an increase in fatty acid oxidation. Our work demonstrates that CDCA-induced metabolic alterations occur in white and brown adipocytes and are not totally dependent on endocrine/nervous system signaling, as thought until now. Furthermore, future exploration of the mechanisms behind these effects will undoubtedly reveal interesting targets for clinical modulation. Copyright © 2016 John Wiley & Sons, Ltd.

  15. Changes in Colonic Bile Acid Composition following Fecal Microbiota Transplantation Are Sufficient to Control Clostridium difficile Germination and Growth.

    Directory of Open Access Journals (Sweden)

    Alexa R Weingarden

    Full Text Available Fecal microbiota transplantation (FMT is a highly effective therapy for recurrent Clostridium difficile infection (R-CDI, but its mechanisms remain poorly understood. Emerging evidence suggests that gut bile acids have significant influence on the physiology of C. difficile, and therefore on patient susceptibility to recurrent infection. We analyzed spore germination of 10 clinical C. difficile isolates exposed to combinations of bile acids present in patient feces before and after FMT. Bile acids at concentrations found in patients' feces prior to FMT induced germination of C. difficile, although with variable potency across different strains. However, bile acids at concentrations found in patients after FMT did not induce germination and inhibited vegetative growth of all C. difficile strains. Sequencing of the newly identified germinant receptor in C. difficile, CspC, revealed a possible correspondence of variation in germination responses across isolates with mutations in this receptor. This may be related to interstrain variability in spore germination and vegetative growth in response to bile acids seen in this and other studies. These results support the idea that intra-colonic bile acids play a key mechanistic role in the success of FMT, and suggests that novel therapeutic alternatives for treatment of R-CDI may be developed by targeted manipulation of bile acid composition in the colon.

  16. Bile composition, plasma lipids and oxidative hepatic damage induced by calcium supplementation; effects of goat or cow milk consumption.

    Science.gov (United States)

    Díaz-Castro, Javier; Alférez, María J M; López-Aliaga, Inmaculada; Nestares, Teresa; Sánchez-Alcover, Ana; Campos, Margarita S

    2013-05-01

    Calcium-fortified foods, especially milk and dairy products are recommended to be consumed daily for groups in risk of nutritional deficiency, including children, young adults, menopausal women, pregnant women and the elderly, however Ca-supplementation promotes gallstone formation because Ca is a nucleating factor. The objective of the current study was to assess the influence of cow or goat milk-based diets, either normal or Ca-supplemented, on bile composition, biochemical parameters and hepatic antioxidant status. Weanling male rats were randomly divided into six groups, fed standard, goat or cow milk-based diets, either with normal Ca content (5.0 g/kg), or Ca-supplemented (10.0 g/kg), for 2 weeks. Bile cholesterol concentration and output was higher in rats fed goat milk in comparison with those fed with standard and cow-milk-based diet. Ca-supplementation increased lithogenic index with the standard and cow-milk based diets, this change was not observed with the goat milk diet. Activities of plasma transaminases were also lower in the animals fed Ca-supplemented goat milk, in comparison with the other diets assayed. In general, Ca-supplement in the diet led to an increase in the hepatic oxidative damage, with an increase in the activities of all the antioxidant enzymes studied in the standard and cow milk diet, but not with goat milk. The habitual consumption of goat milk has positive effects on the plasma lipid profile, biliary composition and hepatic antioxidant defence. In addition, under our experimental conditions, Ca-supplementation of this type of milk does not increase the lithogenic index, or hepatic oxidative damage.

  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. Matrix proteins of basement membrane of intrahepatic bile ducts are degraded in congenital hepatic fibrosis and Caroli's disease.

    Science.gov (United States)

    Yasoshima, Mitsue; Sato, Yasunori; Furubo, Shinichi; Kizawa, Kazuo; Sanzen, Takahiro; Ozaki, Satoru; Harada, Kenichi; Nakanuma, Yasuni

    2009-02-01

    Congenital hepatic fibrosis (CHF) and Caroli's disease are though to result from ductal plate malformation, and the basal laminar components play important roles in biliary differentiation during development. To clarify the involvement of basal laminar components in the ductal plate malformation, this study examined the immunohistochemical expression of laminin and type IV collagen in the livers of CHF and Caroli's disease. Using the polycystic kidney (PCK) rat, an animal model of Caroli's disease with CHF, in vivo and in vitro experiments were also performed. Immunostaining showed that basement membrane expression of laminin and type IV collagen around intrahepatic bile ducts was degraded in CHF, Caroli's disease, and the PCK rats. The degradation of laminin and type IV collagen around bile ducts was also observed in foci of cholangiocarcinoma in situ of Caroli's disease. In vitro, PCK cholangiocytes were found to overexpress plasminogen and a serine proteinase, the tissue-type plasminogen activator (tPA). When PCK cholangiocytes were cultured in Matrigel, the amounts of laminin and collagen in the gel were significantly reduced, and addition of alpha2-antiplasmin in the culture medium inhibited the degradation of laminin and collagen in Matrigel. These results suggest that biliary overexpression of plasminogen and tPA leads to the generation of excessive amounts of plasmin, and subsequent plasmin-dependent lysis of the extracellular matrix molecules may contribute to the biliary dysgenesis in CHF and Caroli's disease, including progressive cystic dilatation of the intrahepatic bile ducts in Caroli's disease. In addition, it is suggested that once cholangiocarcinoma in situ develops in the biliary epithelium of CHF and Caroli's disease, it tends to transform into invasive carcinoma, due to instability of the basement membrane of the bile ducts.

  19. 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

  20. 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

  1. A model of in vitro UDP-glucuronosyltransferase inhibition by bile acids predicts possible metabolic disorders[S

    Science.gov (United States)

    Fang, Zhong-Ze; He, Rong-Rong; Cao, Yun-Feng; Tanaka, Naoki; Jiang, Changtao; Krausz, Kristopher W.; Qi, Yunpeng; Dong, Pei-Pei; Ai, Chun-Zhi; Sun, Xiao-Yu; Hong, Mo; Ge, Guang-Bo; Gonzalez, Frank J.; Ma, Xiao-Chi; Sun, Hong-Zhi

    2013-01-01

    Increased levels of bile acids (BAs) due to the various hepatic diseases could interfere with the metabolism of xenobiotics, such as drugs, and endobiotics including steroid hormones. UDP-glucuronosyltransferases (UGTs) are involved in the conjugation and elimination of many xenobiotics and endogenous compounds. The present study sought to investigate the potential for inhibition of UGT enzymes by BAs. The results showed that taurolithocholic acid (TLCA) exhibited the strongest inhibition toward UGTs, followed by lithocholic acid. Structure-UGT inhibition relationships of BAs were examined and in vitro-in vivo extrapolation performed by using in vitro inhibition kinetic parameters (Ki) in combination with calculated in vivo levels of TLCA. Substitution of a hydrogen with a hydroxyl group in the R1, R3, R4, R5 sites of BAs significantly weakens their inhibition ability toward most UGTs. The in vivo inhibition by TLCA toward UGT forms was determined with following orders of potency: UGT1A4 > UGT2B7 > UGT1A3 > UGT1A1 ∼ UGT1A7 ∼ UGT1A10 ∼ UGT2B15. In conclusion, these studies suggest that disrupted homeostasis of BAs, notably taurolithocholic acid, found in various diseases such as cholestasis, could lead to altered metabolism of xenobiotics and endobiotics through inhibition of UGT enzymes. PMID:24115227

  2. Protective role of biliverdin against bile acid-induced oxidative stress in liver cells.

    Science.gov (United States)

    Gonzalez-Sanchez, Ester; Perez, Maria J; Nytofte, Nikolaj S; Briz, Oscar; Monte, Maria J; Lozano, Elisa; Serrano, Maria A; Marin, Jose J G

    2016-08-01

    The accumulation of bile acids affects mitochondria causing oxidative stress. Antioxidant defense is accepted to include biotransformation of biliverdin (BV) into bilirubin (BR) through BV reductase α (BVRα). The mutation (c.214C>A) in BLVRA results in a non-functional enzyme (mutBVRα). Consequently, homozygous carriers suffering from cholestasis develop green jaundice. Whether BVRα deficiency reduces BV-dependent protection against bile acids is a relevant question because a screening of the mut-BLVRA allele (a) in 311 individuals in Greenland revealed that this SNP was relatively frequent in the Inuit population studied (1% a/a and 4.5% A/a). In three human liver cell lines an inverse correlation between BVRα expression (HepG2>Alexander>HuH-7) and basal reactive oxygen species (ROS) levels was found, however the ability of BV to reduce oxidative stress and cell death induced by deoxycholic acid (DCA) or potassium dichromate (PDC) was similar in these cells. The transduction of BVRα or mutBVRα in human placenta JAr cells with negligible BVRα expression or the silencing of endogenous BVRα expression in liver cells had no effect on DCA-induced oxidative stress and cell death or BV-mediated cytoprotection. DCA stimulated both superoxide anion and hydrogen peroxide production, whereas BV only inhibited the latter. DCA and other dihydroxy-bile acids, but not PDC, induced up-regulation of both BVRα and heme oxygenase-1 (HO-1) in liver cells through a FXR independent and BV insensitive mechanism. In conclusion, BV exerts direct and BVRα-independent antioxidant and cytoprotective effects, whereas bile acid accumulation in cholestasis stimulates the expression of enzymes favoring the heme biotransformation into BV and BR. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Intrahepatic cholestasis of pregnancy: correlation of preterm delivery with bile acids.

    Science.gov (United States)

    Pata, Ozlem; Vardarelı, Eser; Ozcan, Alihan; Serteser, Mustafa; Unsal, Ibrahim; Saruç, Murat; Unlü, Cihat; Tözün, Nurdan

    2011-12-01

    The aim of this study was to determine the incidence, obstetrical and fetal complication rates of intrahepatic cholestasis of pregnancy in patients managed actively around 38 weeks and evaluate the correlation of these results with liver function tests and bile acids. In this cohort study 3710 women were booked for delivery, of which 32 pregnant women were diagnosed as intrahepatic cholestasis of pregnancy. All data concerning obstetric- medical history, laboratory results, symptom onset time, pruritus degree, treatment response, and delivery time and infants information were recorded in the study protocol. Statistical analyses were conducted with SPSS 12.0 version and correlations were assessed by Spearman Rank correlation analysis. The incidence of intrahepatic cholestasis of pregnancy was 0.86%. The symptoms appeared around 32 weeks. 16.6% multiparas had a previously affected pregnancy and 21.8% of intrahepatic cholestasis of pregnancy patients had family history of intrahepatic cholestasis of pregnancy. Symptom onset varied according to season (pursodeoxycholic acid treatment. Total bile acids tended to be higher in patients with preterm delivery (r=0.409, p=0.038). Total bile acids are correlated with preterm delivery. An attempt to deliver at around 38 weeks may improve perinatal outcome.

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

    Science.gov (United States)

    Mooranian, Armin; Negrulj, Rebecca; Chen-Tan, Nigel; Watts, Gerald F; Arfuso, Frank; Al-Salami, Hani

    2014-01-01

    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 microcapsule stability. Hence, PB-DCA-SA microcapsules have good rheological and compatibility characteristics and may be suitable for the oral delivery of PB in type 2 diabetes. PMID:25302020

  5. Bile acid-binding ability of kaki-tannin from young fruits of persimmon (Diospyros kaki) in vitro and in vivo.

    Science.gov (United States)

    Matsumoto, Kenji; Kadowaki, Akio; Ozaki, Natsumi; Takenaka, Makiko; Ono, Hiroshi; Yokoyama, Shin-ichiro; Gato, Nobuki

    2011-04-01

    The bile acid-binding ability of a highly polymerized tannin (kaki-tannin) extracted from dried-young fruits of persimmon (Diospyros kaki) was examined. The kaki-tannin was composed mainly of epicatechin, epigallocatechin, epicatechin-3-O-gallate and epigallocatechin-3-O-gallate. Bile acid-binding ability of kaki-tannin was examined against cholic acid, glycocholic acid, taurocholic acid and deoxycholic acid in vitro, and its effect on fecal bile acid excretion in mice was also examined. Although the bile acid-binding ability of kaki-tannin was weaker than that of cholestyramine, kaki-tannin adsorbed all the bile acids tested and significantly promoted fecal bile acid excretion in mice when supplied at 1% (w/w) in the diet. Copyright © 2010 John Wiley & Sons, Ltd.

  6. 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...

  7. Role of mitogen-activated protein kinases in tauroursodeoxycholic acid-induced bile formation in cholestatic rat liver

    NARCIS (Netherlands)

    Denk, Gerald Ulrich; Hohenester, Simon; Wimmer, Ralf; Boehland, Claudia; Rust, Christian; Beuers, Ulrich

    2008-01-01

    Aim: Ursodeoxycholic acid exerts anticholestatic effects in various cholestatic disorders and experimental models of cholestasis. Its taurine conjugate (TUDCA) stimulates bile salt secretion in isolated perfused rat livers (IPRL) under physiological, non-cholestatic conditions, in part by

  8. Forced expression of fibroblast growth factor 21 reverses the sustained impairment of liver regeneration in hPPARα(PAC) mice due to dysregulated bile acid synthesis.

    Science.gov (United States)

    Liu, Hui-Xin; Hu, Ying; French, Samuel W; Gonzalez, Frank J; Wan, Yu-Jui Yvonne

    2015-01-01

    Peroxisome proliferator activated receptor α (PPARα) stimulates hepatocellular proliferation is species-specific. Activation of mouse, but not human, PPARα induces hepatocellular proliferation, hepatomegaly, and liver cancer. Here we tested the hypothesis that human and mouse PPARα affects liver regeneration differentially. PPARα-humanized mice (hPPARα(PAC)) were similar to wild type mice in responding to fasting-induced PPARα signaling. However, these mouse livers failed to regenerate in response to partial hepatectomy (PH). The liver-to-body weight ratios did not recover even 3 months after PH in hPPARα(PAC). The mouse PPARα-mediated down-regulation of let-7c was absent in hPPARα(PAC), which might partially be responsible for impaired proliferation. After PH, hPPARα(PAC) displayed steatosis, necrosis, and inflammation mainly in periportal zone 1, which suggested bile-induced toxicity. Quantification of hepatic bile acids (BA) revealed BA overload with increased hydrophobic BA in hPPARα(PAC). Forced FGF21 expression in partial hepatectomized hPPARα(PAC) reduced hepatic steatosis, prevented focal necrosis, and restored liver mass. Compared to mouse PPARα, human PPARα has a reduced capacity to regulate metabolic pathways required for liver regeneration. In addition, FGF21 can compensate for the reduced ability of human PPARα in stimulating liver regeneration, which suggests the potential application of FGF21 in promoting hepatic growth in injured and steatotic livers in humans.

  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. Polymeric bile acid sequestrants: review of design, in vitro binding activities, and hypocholesterolemic effects

    Czech Academy of Sciences Publication Activity Database

    Heřmánková, Eva; Žák, A.; Poláková, Lenka; Hobzová, Radka; Hromádka, R.; Širc, Jakub

    2018-01-01

    Roč. 144, 20 January (2018), s. 300-317 ISSN 0223-5234 R&D Projects: GA MPO(CZ) FV10380; GA MŠk(CZ) LQ1604; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:61389013 Keywords : review * bile acid sequestrant * pleiotropic effect Subject RIV: EB - Genetics ; Molecular Biology OBOR OECD: Biochemical research methods Impact factor: 4.519, year: 2016

  11. Bile acids evoke placental inflammation by activating Gpbar1/NF-κB pathway in intrahepatic cholestasis of pregnancy.

    Science.gov (United States)

    Zhang, YouHua; Pan, YouDong; Lin, ChangDong; Zheng, YaJuan; Sun, Hao; Zhang, HaiLong; Wang, JunLei; Yuan, MengYa; Duan, Tao; Du, QiaoLing; Chen, JianFeng

    2016-12-01

    Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic disorder with potentially deleterious consequences for fetuses. Although a clear correlation between the elevated levels of maternal serum bile acids and deficient fetal outcome has been established in clinical practice, the underlying mechanisms remain elusive. Herein, we report that bile acids induce NF-κB pathway activation via G protein-coupled bile acid receptor 1 (Gpbar1), with consequent upregulation of inflammatory genes in trophoblasts, leading to aberrant leukocyte infiltration and inflammation in placenta. Ursodeoxycholic acid (UDCA), a drug used clinically to treat ICP, competes with other bile acids for binding with Gpbar1 and thus inhibits bile acid-induced inflammatory response in trophoblasts and improves fetal survival in pregnant rats with obstructive cholestasis. Notably, inhibition of NF-κB by andrographolide is more effective than UDCA in benefiting placentas and fetuses. Thus, anti-inflammation therapy targeting Gpbar1/NF-κB pathway could be effective in suppressing bile acid-induced inflammation and alleviating ICP-associated fetal disorders. © The Author (2016). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.

  12. Influence of various bile acids on the metabolism of glycyrrhizin and glycyrrhetic acid by Ruminococcus sp. PO1-3 of human intestinal bacteria.

    Science.gov (United States)

    Akao, T

    1999-08-01

    Ruminococcus sp. PO1-3, an intestinal bacterium isolated from human feces, metabolized glycyrrhizin (GL) to glycyrrhetic acid (GA) and GA to 3-oxo-glycyrrhetic acid (3-oxo-GA) and possessed GL beta-D-glucuronidase and 3beta-hydroxysteroid dehydrogenase (3beta-HSD) involved in the metabolism of GL. This bacterial growth was enhanced by GL at a concentration of 0.4 mm and was suppressed by GA at concentration of 1.0 mM. Chenodeoxycholic acid, deoxycholic acid and lithocholic acid among the bile acids added to this bacterium suppressed the growth and GL beta-D-glucuronidase activity and 3beta-HSD activity incident to it at a concentration of 1.0 mM, while cholic acid, hyodeoxycholic acid and glycine and taurin conjugates of cholic acid, chenodeoxycholic acid, deoxycholic acid and lithocholic acid had almost no effect on this bacterium at a concentration of 0.2 to 1.0 mm. However, these enzyme activities of this sonicated bacteria were inhibited by all of these bile acids. Although each bile acid and GL added to bacteria at the same time suppressed the growth and the amount of metabolite GA by all bile acids used except cholic acid, taurocholic acid and taurodeoxycholic acid with GL, a combination of each bile acid and GA eased the growth inhibition caused by GA at a concentration of 0.2 mM and enhanced the amount of metabolite 3-oxo-GA by the glycine conjugate of bile acids with GA. GL or GA added after 6 h culture with each of these bile acids and bacteria was metabolized to a relatively large amount of GA by chenodeoxycholic acid and lithocholic acid and their glycine and taurine conjugates, glycocholic acid and taurodeoxycholic acid, or had almost no effect on the amount of metabolite 3-oxo-GA, respectively. These results showed that although GL added after the exposure to bile acid and GA and bile acid added at the same time as bacteria had different bile acid action, these conditions enhanced the amount of metabolite GA from GL and metabolite 3-oxo-GA from GA.

  13. In vitro bile acid binding and short-chain fatty acid profile of flax fiber and ethanol co-products.

    Science.gov (United States)

    Fodje, Adele M L; Chang, Peter R; Leterme, Pascal

    2009-10-01

    Fibers from flaxseed and co-products from ethanol production could be potential sources of dietary fiber in human diet. In vitro fermentation and bile acid binding models were used to investigate the metabolic effects of lignaMax (Bioriginal Food and Science Corp., Saskatoon, SK, Canada) flax meal, spent flax meal, soluble flax gum, wheat insoluble fiber (WIF), and rye insoluble fiber (RIF). Wheat and rye bran were used as reference samples. Bile acid binding of substrates was analysed at taurocholate ([(14)C]taurocholate) concentration of 12.5 mM. Soluble flax gum showed the highest bile acid binding (0.57 micromol/mg of fiber) (P fiber) and WIF (0.26 micromol/mg of fiber). RIF had higher (P fiber) than rye bran (0.13 micromol/mg of fiber). Substrates were hydrolyzed and incubated with pig fecal samples. Short-chain fatty acid (SCFA) profile and gas accumulation (G(f)) were compared. Soluble flax gum generated the highest amount of acetic and propionic acids. SCFA profiles of wheat/rye brans and WIF/RIF were similar (except for butyric acid). G(f) for soluble flax gum was greater (P flax meal. G(f) values of the wheat samples were similar, whereas the G(f) of the rye bran was higher (P flax gum. Oil-depleted flaxseed fractions and WIF/RIF (co-products from ethanol production) could be potential sources of dietary fiber in human nutrition.

  14. Branched-chain amino acids for hepatic encephalopathy

    DEFF Research Database (Denmark)

    Als-Nielsen, B; Koretz, R L; Kjaergard, L L

    2003-01-01

    Hepatic encephalopathy may be caused by a decreased plasma ratio of branched-chain amino acids (BCAA) to aromatic amino acids. Treatment with BCAA may therefore have a beneficial effect on patients with hepatic encephalopathy.......Hepatic encephalopathy may be caused by a decreased plasma ratio of branched-chain amino acids (BCAA) to aromatic amino acids. Treatment with BCAA may therefore have a beneficial effect on patients with hepatic encephalopathy....

  15. [Post-cholecystectomy condition: duodeno-gastric reflux and bile acid concentration in the gastric juice].

    Science.gov (United States)

    Koelsch, K A; Kühne, C; Zemlin, C

    1979-07-01

    In cholecystectomized patients highly significantly more frequently a duodenogastric reflux was found than in a group of patients with a healthy abdomen and a group of patients with cholelithiasis. The average concentration of bile acid in the gastric juice was after the removal of the gall-bladder manifoldly higher than in the control groups. The number of patients with concentrated reflux was also highly significantly larger than in patients with cholelithiasis not operated on and in patients with a healthy abdomen. Despite the high reflux rate and the high concentration of the bile acids influencing on the mucous membrane of the stomach the number of patients with ulcera ventriculi was not significantly larger than in a group of not cholecystectomized persons. These observations plead for the fact that the bile acids in the duodenogastric reflux alone are not to be regarded as an ulcerogenic agent, but that perhaps other components of the duodenal juice have to be considered as causes of lesions of the gastric mucous membrane.

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

    Energy Technology Data Exchange (ETDEWEB)

    Cai, Huan; Zhao, Fang; Si, Hailin; Zhang, Shuaishuai; Wang, Chunchun; Qi, Peirong [Shihezi Univ., Shihezi (China)

    2012-12-15

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

  17. Role of dietary onion in modifying the faecal bile acid content in rats fed a high-cholesterol diet.

    Science.gov (United States)

    González-Peña, Diana; Giménez, Lucía; de Ancos, Begoña; Sánchez-Moreno, Concepción

    2017-06-01

    The determination of faecal bile patterns offers new opportunities in the search for non-invasive biomarkers of disease status. The objective of this study was to describe the shifts in faecal bile acid (BA) composition induced by feeding a high-cholesterol/cholic acid diet (HC) over 7 weeks of experimental feeding in Wistar rats, and to evaluate the effect of onion included as a functional ingredient (HCO). A HPLC-MS/MS method allowed the detection of 29 bile acids, 10 of which were tentatively identified and 12 confirmed and quantified by means of standards and calibration curves. The excretion of bile acids revealed a discriminating bile acid profile between the HC and HCO groups compared with the C group. HCO feeding indicated significant changes in specific primary and secondary BA in both the unconjugated and conjugated forms caused by the addition of the onion ingredient to the diet. The results suggest that the induction of microbiome modifications by the HC and HCO diets acts as a critical modifier of the faecal bile acid composition. These modifications might reflect and be linked to changes in the reabsorption of BA at an intestinal level and the process of BA deconjugation in the course of hypercholesterolemia.

  18. INTRACELLULAR SITES INVOLVED IN THE BIOGENESIS OF BILE CANALICULI IN HEPATIC CELLS

    NARCIS (Netherlands)

    ZAAL, KJM; KOK, JW; SORMUNEN, R; ESKELINEN, S; HOEKSTRA, D

    Studies in hepatoma cells and hepatocytes have revealed that the biogenesis of bile canalicular membrane involves microvilli-lined vesicles (MLV), which are formed in well diferentiated cells. The vesicles grow as a function of time and are presumably vectorially transported to cell surface contact

  19. Bile acids in a multicenter, population-based case-control study of stillbirth

    Science.gov (United States)

    Silver, Robert M.; Parker, Corette B.; Goldenberg, Robert; Reddy, Uma M.; Dudley, Donald J.; Saade, George R.; Hogue, Carol J. Rowland; Coustan, Donald; Varner, Michael W.; Koch, Matthew A.; Conway, Deborah; Bukowski, Radek; Pinar, Halit; Stoll, Barbara; Moore, Janet; Willinger, Marian

    2015-01-01

    OBJECTIVE We sought to compare bile acids in women with and without stillbirth in a population-based study. STUDY DESIGN The Stillbirth Collaborative Research Network conducted a multisite, population-based case-control study of stillbirth (fetal deaths ≥20 weeks). Maternal sera were obtained at the time of enrollment and frozen at −80° until assay for bile acids. RESULTS Assays were performed in 581 women with stillbirth and 1546 women with live births. Bile acid levels were slightly higher in women with stillbirth (geometric mean [95% confidence interval {CI}] = 3.2 [3.0–3.5]) compared to live births (2.9 [2.7–3.1], P = .0327). However, the difference was not significant after adjustment for baseline risk factors for stillbirth. The proportion of women with elevated levels (≥10 or ≥40 μmol/L) was similar in stillbirths and live births. Results were similar when the analysis was limited to subsets of stillbirths and live births. In women with stillbirths not associated with fetal anomalies or obstetric complications bile acid levels were higher than in women with term live births (geometric mean [95% CI] = 3.4 [3.0–3.8] vs 2.9 [2.7–3.0], P = .0152, unadjusted; P = .06, adjusted). However, a similar proportion of women in both groups had levels ≥10 mmol/L (10.7 vs 7.2%; odds ratio [OR], 1.54; 95% CI, 0.97–2.44; adjusted OR, 1.29; 95% CI, 0.78–2.15) and ≥40 μmol/L (1.7 vs 0.7%; OR, 2.58; 95% CI, 0.85–7.84; adjusted OR, 2.28; 95% CI, 0.79–6.56). CONCLUSION Our data do not support testing for bile acids in cases of stillbirth in the absence of clinical evidence of intrahepatic cholestasis of pregnancy. PMID:24215860

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

    Science.gov (United States)

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

    2017-11-01

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

  1. A simple and accurate HPLC method for fecal bile acid profile in healthy and cirrhotic subjects: validation by GC-MS and LC-MS[S

    Science.gov (United States)

    Kakiyama, Genta; Muto, Akina; Takei, Hajime; Nittono, Hiroshi; Murai, Tsuyoshi; Kurosawa, Takao; Hofmann, Alan F.; Pandak, William M.; Bajaj, Jasmohan S.

    2014-01-01

    We have developed a simple and accurate HPLC method for measurement of fecal bile acids using phenacyl derivatives of unconjugated bile acids, and applied it to the measurement of fecal bile acids in cirrhotic patients. The HPLC method has the following steps: 1) lyophilization of the stool sample; 2) reconstitution in buffer and enzymatic deconjugation using cholylglycine hydrolase/sulfatase; 3) incubation with 0.1 N NaOH in 50% isopropanol at 60°C to hydrolyze esterified bile acids; 4) extraction of bile acids from particulate material using 0.1 N NaOH; 5) isolation of deconjugated bile acids by solid phase extraction; 6) formation of phenacyl esters by derivatization using phenacyl bromide; and 7) HPLC separation measuring eluted peaks at 254 nm. The method was validated by showing that results obtained by HPLC agreed with those obtained by LC-MS/MS and GC-MS. We then applied the method to measuring total fecal bile acid (concentration) and bile acid profile in samples from 38 patients with cirrhosis (17 early, 21 advanced) and 10 healthy subjects. Bile acid concentrations were significantly lower in patients with advanced cirrhosis, suggesting impaired bile acid synthesis. PMID:24627129

  2. Bile acid TUDCA improves insulin clearance by increasing the expression of insulin-degrading enzyme in the liver of obese mice.

    Science.gov (United States)

    Vettorazzi, Jean Franciesco; Kurauti, Mirian Ayumi; Soares, Gabriela Moreira; Borck, Patricia Cristine; Ferreira, Sandra Mara; Branco, Renato Chaves Souto; Michelone, Luciana de Souza Lima; Boschero, Antonio Carlos; Junior, Jose Maria Costa; Carneiro, Everardo Magalhães

    2017-11-01

    Disruption of insulin secretion and clearance both contribute to obesity-induced hyperinsulinemia, though reduced insulin clearance seems to be the main factor. The liver is the major site for insulin degradation, a process mainly coordinated by the insulin-degrading enzyme (IDE). The beneficial effects of taurine conjugated bile acid (TUDCA) on insulin secretion as well as insulin sensitivity have been recently described. However, the possible role of TUDCA in insulin clearance had not yet been explored. Here, we demonstrated that 15 days treatment with TUDCA reestablished plasma insulin to physiological concentrations in high fat diet (HFD) mice, a phenomenon associated with increased insulin clearance and liver IDE expression. TUDCA also increased IDE expression in human hepatic cell line HepG2. This effect was not observed in the presence of an inhibitor of the hepatic membrane bile acid receptor, S1PR2, nor when its downstream proteins were inhibited, including IR, PI3K and Akt. These results indicate that treatment with TUDCA may be helpful to counteract obesity-induced hyperinsulinemia through increasing insulin clearance, likely through enhanced liver IDE expression in a mechanism dependent on S1PR2-Insulin pathway activation.

  3. Intrahepatic bile duct adenoma in a patient with chronic hepatitis B accompanied by elevation of alpha-fetoprotein

    Directory of Open Access Journals (Sweden)

    Jem Ma Ahn

    2015-12-01

    Full Text Available A 51-year-old male patient with chronic hepatitis B was referred to our hospital due to a 1-cm liver nodule on ultrasonography. Alpha-fetoprotein (AFP was slightly elevated. The nodule showed prolonged enhancement on dynamic liver magnetic resonance imaging and appeared as a hyperintensity on both diffusion-weighted and T2-weighted imaging. The nodule was followed up because it was small and typical findings of hepatocellular carcinoma (HCC were not observed in the dynamic imaging investigations. However, liver contrast-enhanced ultrasonography performed 1 month later showed enhancement during the arterial phase and definite washout during the delayed phase. Also, AFP had increased to over 200 ng/mL even though AST and ALT were decreased after administering an antiviral agent. He was presumptively diagnosed as HCC and underwent liver segmentectomy. Microscopy findings of the specimen indicated bile duct adenoma. After resection, the follow-up AFP had decreased to within the normal range. This patient represents a case of bile duct adenoma with AFP elevation mimicking HCC on contrast-enhanced ultrasonography.

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

    NARCIS (Netherlands)

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

    2013-01-01

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

  5. Septicemia with Streptococcus pseudopneumoniae: report of three cases with an apparent hepatic or bile duct association.

    Science.gov (United States)

    Fuursted, Kurt; Littauer, Pia Jeanette; Greve, Thomas; Scholz, Christian F P

    2016-08-01

    Streptococcus pseudopneumoniae was described in 2004 as a new human pathogen, acknowledged in a range of clinical infections typically associated to the respiratory tract. This report demonstrates that S. pseudopneumoniae has the potential to cause invasive infection. In blood cultures from three patients, growth of an atypical Streptococcus pneumoniae (non-capsular, non-serotypeable, optochin susceptible under ambient atmosphere and bile-intermediately soluble) was recovered. All three patients had a history of a haematological disease (myelodysplastic syndrome and multiple myeloma) and an apparent origin of infection related to the liver or bile duct. All isolates were genome sequenced and subsequently identified as S. pseudopneumoniae by multi-locus sequence analysis (MLSA). Multi-locus sequence typing (MLST) based on the S. pneumoniae scheme revealed unknown sequence types and the antibiogram and resistome revealed no antibiotic resistance.

  6. MicroRNA-29a Alleviates Bile Duct Ligation Exacerbation of Hepatic Fibrosis in Mice through Epigenetic Control of Methyltransferases

    Directory of Open Access Journals (Sweden)

    Ya-Ling Yang

    2017-01-01

    Full Text Available MicroRNA-29 (miR-29 is found to modulate hepatic stellate cells’ (HSCs activation and, thereby, reduces liver fibrosis pathogenesis. Histone methyltransferase regulation of epigenetic reactions reportedly participates in hepatic fibrosis. This study is undertaken to investigate the miR-29a regulation of the methyltransferase signaling and epigenetic program in hepatic fibrosis progression. miR-29a transgenic mice (miR-29aTg mice and wild-type littermates were subjected to bile duct-ligation (BDL to develop cholestatic liver fibrosis. Primary HSCs were transfected with a miR-29a mimic and antisense inhibitor. Profibrogenic gene expression, histone methyltransferases and global genetic methylation were probed with real-time quantitative RT-PCR, immunohistochemical stain, Western blot and ELISA. Hepatic tissue in miR-29aTg mice displayed weak fibrotic matrix as evidenced by Sirius Red staining concomitant with low fibrotic matrix collagen 1α1 expression within affected tissues compared to the wild-type mice. miR-29a overexpression reduced the BDL exaggeration of methyltransferases, DNMT1, DNMT3b and SET domain containing 1A (SET1A expression. It also elevated phosphatase and tensin homolog deleted on chromosome 10 (PTEN signaling within liver tissue. In vitro, miR-29a mimic transfection lowered collagen 1α1, DNMT1, DNMT3b and SET1A expression in HSCs. Gain of miR-29a signaling resulted in DNA hypomethylation and high PTEN expression. This study shines a new light on miR-29a inhibition of methyltransferase, a protective effect to maintain the DNA hypomethylation state that decreases fibrogenic activities in HSC. These robust analyses also highlight the miR-29a regulation of epigenetic actions to ameliorate excessive fibrosis during cholestatic liver fibrosis development.

  7. Review article: Small intestinal bacterial overgrowth, bile acid malabsorption and gluten intolerance as possible causes of chronic watery diarrhoea.

    Science.gov (United States)

    Fan, X; Sellin, J H

    2009-05-15

    Chronic watery diarrhoea is one of the most common symptoms prompting GI evaluation. Recently, new diagnostic considerations have emerged as possible factors in chronic diarrhoea. To review available data regarding diagnosis and treatment of chronic diarrhoea with an emphasis on bacterial overgrowth and bile acid malabsorption. A systematic search of the English language literature of chronic diarrhoea was performed focused on three possible aetiologies of diarrhoea: small intestinal bacterial overgrowth (SIBO), idiopathic bile salt malabsorption (IBAM), gluten responsive enteropathy. Recent studies suggest that SIBO and bile acid malabsorption may have been underestimated as possible causes of chronic watery diarrhoea. Gluten intolerance with negative coeliac serology is a contentious possible cause of watery diarrhoea, but requires further research before acceptance as an entity. In patients with otherwise unexplained chronic watery diarrhoea, small intestinal bacterial overgrowth and bile salt malabsorption should be considered and investigated.

  8. Enhanced dispersion of boron nitride nanosheets in aqueous media by using bile acid-based surfactants

    Science.gov (United States)

    Chae, Ari; Park, Soo-Jin; Min, Byunggak; In, Insik

    2018-01-01

    Facile noncovalent surface functionalization of hydroxylated boron nitride nanosheet (BNNS-OH) was attempted through the sonication-assisted exfoliation of h-BN in aqueous media in the presence of bile acid-based surfactants such as sodium cholic acid (SC) or sodium deoxycholic acid (SDC), resulting in SC- or SDC-BNNS-OH dispersion with high up to 2 mg ml‑1 and enhanced dispersion stability due to the increased negative zeta potential. While prepared SC-BNNS-OH revealed multi-layered BNNS structures, the large lateral sizes of hundreds nanometers and clear h-BN lattice structures are very promising for the preparation and application of water-processable BNNS-based nanomaterials. It is regarded that noncovalent functionalization of BNNS-OH based on σ-π interaction between with σ-rich bile acid-based amphiphiles and π-rich BNNS is very effective to formulate multi-functional BNNS-based nanomaterials or hybrids that can be utilized in various applications where both the pristine properties of BNNS and the extra functions are simultaneously required.

  9. [Combined treatment including ozonotherapy of patients with viral hepatitis ].

    Science.gov (United States)

    Chernyshev, A L; Filimonov, R M; Karasev, A V; Neronov, V A; Maksimov, V A

    2008-01-01

    Patients with viral hepatitis have disturbances of biliary tract motor function with the tendency to hypertonus of Oddi's sphincter, changes of physic-colloid properties of bile with increase in density of gall and hepatic bile, pH shift to acid side, microlites formation, disorders in biochemical composition of bile. More than 80% patients have biliar insufficiency. According to our data, with the purpose to correct of disturbances of hepatic exocrine function in patients with viral hepatitis and to prevent stone formation, it is reasonable to use together with antiviral therapy also intravenous injection of ozonated physiological solution and preparations of ursodeoxycholic acid.

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

    Science.gov (United States)

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

    2015-02-01

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

  11. Ferritin and bile acid levels during the intrauterine pre-treatment of gastroschisis by serial amnioexchange

    Science.gov (United States)

    Demir, Namık; Canda, Mehmet Tunç; Kuday, Şamil; Öztürk, Cengiz; Sezer, Orçun; Danaoğlu, Nihal

    2013-01-01

    We present a case of gastroschisis managed with serial amnioex-changes. Marked decreases were detected in both ferritin and bile acid levels following the procedure. The bowels were not severely affected, as expected. After delivery, single primary closure of the defect was performed. Early enteral feeding and shorter hospital stay were the main outcome measures. Intrauterine pre-treatment of gastroschisis by serial amnioexchange may provide benefits by decreasing the levels of inflammatory products in the amniotic fluid in order to lower the possible risk of bowel damage, and this may help to achieve better surgical and postnatal outcomes. PMID:24592073

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

    DEFF Research Database (Denmark)

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

    2013-01-01

    Early weaning is a stressful event characterized by a transient period of intestinal atrophy that may be mediated by reduced secretion of glucagon-like peptide (GLP) 2. We tested whether enterally fed bile acids or plant sterols could increase nutrient-dependent GLP-2 secretion and improve...... 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 ... administration of the bile acid CDC potentiates the nutrient-induced secretion of endogenous GLP-2 in early-weaned pigs. Bile acid-enhanced release of GLP-2, however, did not result in improved intestinal growth, morphology, or inflammation during the postweaning degenerative phase....

  13. Selective in vivo effect of chitosan on fatty acid, neutral sterol and bile acid excretion: a longitudinal study.

    Science.gov (United States)

    Santas, Jonathan; Espadaler, Jordi; Mancebo, Remedios; Rafecas, Magda

    2012-09-15

    Chitosan, a deacetylated form of chitin, is a dietary fibre known for its hypolipidemic properties, which are mainly attributed to its unique cationic characteristics. We studied the selective in vivo effect of chitosan on fat excretion in order to elucidate its hypolipidemic mechanism. A 4-week longitudinal study was conducted in guinea pigs and the effect of chitosan on fat-absorption was compared to that of a soluble fibre: digestion-resistant maltodextrin. Animals were fed with high-fat isocaloric diets containing 12/100g of cellulose, digestion-resistant maltodextrin or chitosan. Subsequently, the excretion of fatty acids, neutral sterols and bile acids was determined. Chitosan selectively reduced fat absorption in comparison to digestion-resistant maltodextrin. The excretion of lauric, myristic and palmitic fatty acids of animals fed with chitosan was more than 10-, 5- and 2-fold higher, respectively, than in the cellulose group, whereas stearic acid excretion was not significantly altered. Oleic, linoleic and α-linolenic acid excretion were also significantly higher (Pacid excretion was only increased by chitosan. Nevertheless, chitosan inhibited the intestinal bioconversion of cholesterol and primary bile acids to secondary metabolites. Hence, these results reveal that chitosan and digestion resistant maltodextrin exert their hypolipidemic activity by different mechanisms. Copyright © 2012 Elsevier Ltd. All rights reserved.

  14. Characterization of a novel bile acid-based delivery platform for microencapsulated pancreatic β-cells.

    Science.gov (United States)

    Mooranian, Armin; Negrulj, Rebecca; Arfuso, Frank; Al-Salami, Hani

    2016-01-01

    In a recent study, we confirmed good chemical and physical compatibility of microencapsulated pancreatic β-cells using a novel formulation of low viscosity sodium alginate (LVSA), Poly-L-Ornithine (PLO), and the tertiary bile acid, ursodeoxycholic acid (UDCA). This study aimed to investigate the effect of UDCA on the morphology, swelling, stability, and size of these new microcapsules. It also aimed to evaluate cell viability in the microcapsules following UDCA addition. Microencapsulation was carried out using a Büchi-based system. Two (LVSA-PLO, control and LVSA-PLO-UDCA, test) pancreatic β-cells microcapsules were prepared at a constant ratio of 10:1:3, respectively. The microcapsules' morphology, cell viability, swelling characteristics, stability, mechanical strength, Zeta potential, and size analysis were examined. The cell contents in each microcapsule and the microencapsulation efficiency were also examined. The addition of UDCA did not affect the microcapsules' morphology, stability, size, or the microencapsulation efficiency. However, UDCA enhanced cell viability in the microcapsules 24 h after microencapsulation (p cell viability in the microcapsules without affecting the microcapsules' size, morphology, or stability. It also increased the microcapsules' resistance to swelling and optimized their mechanical strength. Our findings suggest potential benefits of the bile acid UDCA in β-cell microencapsulation.

  15. Rational Design of Nucleoside–Bile Acid Conjugates Incorporating a Triazole Moiety for Anticancer Evaluation and SAR Exploration

    OpenAIRE

    Maria Luisa Navacchia; Elena Marchesi; Lara Mari; Nicola Chinaglia; Eleonora Gallerani; Riccardo Gavioli; Massimo Luigi Capobianco; Daniela Perrone

    2017-01-01

    Herein we report a study on the synthesis and biological evaluation of a library of nucleoside-bile acid conjugates prepared by combining 2′-deoxyadenosine, 2′-deoxyguanosine, 2′-deoxyuridine as well as adenosine and guanosine derivatives with cheno-, urso-, nor-cheno-, nor-urso- and taurourso-desoxycholic acid derivatives by means of the click reaction. The new nucleoside-bile acid conjugates incorporating a triazole moiety were tested in vitro against leukemic K562 and HCT116 colon carcinom...

  16. 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

  17. 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 (broiler 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.

  18. Bile Acid Control of Metabolism and Inflammation in Obesity, Type 2 Diabetes, Dyslipidemia, and Nonalcoholic Fatty Liver Disease.

    Science.gov (United States)

    Chávez-Talavera, Oscar; Tailleux, Anne; Lefebvre, Philippe; Staels, Bart

    2017-05-01

    Bile acids are signaling molecules that coordinately regulate metabolism and inflammation via the nuclear farnesoid X receptor (FXR) and the Takeda G protein-coupled receptor 5 (TGR5). These receptors activate transcriptional networks and signaling cascades controlling the expression and activity of genes involved in bile acid, lipid and carbohydrate metabolism, energy expenditure, and inflammation by acting predominantly in enterohepatic tissues, but also in peripheral organs. In this review, we discuss the most recent findings on the inter-organ signaling and interplay with the gut microbiota of bile acids and their receptors in meta-inflammation, with a focus on their pathophysiologic roles in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic steatohepatitis, and their potential therapeutic applications. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

  19. 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.

  20. HPLC and ELISA analyses of larval bile acids from Pacific and western brook lampreys.

    Science.gov (United States)

    Yun, Sang-Seon; Scott, Alexander P; Bayer, Jennifer M; Seelye, James G; Close, David A; Li, Weiming

    2003-08-01

    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 20 pg-10 ng per well. The tissue concentrations of PZS in gall bladder were 127.40, 145.86, and 276.96 micro 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.

  1. 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.

  2. 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.

  3. Concentrative biliary secretion of ceftriaxone. Inhibition of lipid secretion and precipitation of calcium ceftriaxone in bile.

    Science.gov (United States)

    Xia, Y; Lambert, K J; Schteingart, C D; GU, J J; Hofmann, A F

    1990-08-01

    The hepatic transport of ceftriaxone, a third-generation cephalosporin, was characterized in the rat and hamster; its effect on bile flow and bile acid-induced biliary lipid secretion was also measured. In anesthetized rats with biliary fistulae, the Tmax was about 5 mumol.min-1.kg-1, and in the hamster the Tmax was about 1 mumol.min-1.kg-1. The compound was not biotransformed. At high secretion rates, the concentration of cephalosporin in bile increased to 27 mmol/L, a concentration far exceeding the solubility product of its calcium salt [2 x 10(-6) (mol/L)2], which precipitated from bile. In the rat, ceftriaxone induced choleresis (22 microL/mumol ceftriaxone, the expected value for a dianionic compound). In the isolated perfused rat liver, ceftriaxone had a fractional hepatic extraction rate averaging 3%; the compound was concentratively secreted into bile, the bile-perfusate ratio ranging from 35-250. Ceftriaxone inhibited phospholipid and cholesterol secretion induced by endogenous or exogenous bile acids; the rate of inhibition was linearly proportional to the canalicular secretion rate of ceftriaxone. Hepatic transport of ceftriaxone had no influence on hepatic secretion of ursodeoxycholyltaurine. In contrast, the net hepatic transport of ursodeoxycholic acid, ursodeoxycholyltaurine, or cholyltaurine inhibited ceftriaxone transport in a dose-dependent manner. It is concluded that ceftriaxone and bile acids share a common mechanism for hepatic transport in the rat and also interact in the processes involved in biliary lipid secretion. Biliary secretion of unbiotransformed ceftriaxone occurs at high concentrations; secondary Ca2+ entry results in the formation of supersaturated canalicular bile and subsequent precipitation as a calcium salt in the biliary tract. These data explain the formation of biliary sludge that occurs in patients undergoing high-dose ceftriaxone therapy.

  4. Bile acid profiles in intrahepatic cholestasis of pregnancy: is this the solution to the enigma of intrahepatic cholestasis of pregnancy?

    Science.gov (United States)

    Sinakos, Emmanouil; Lindor, Keith D

    2010-03-01

    Intrahepatic cholestasis of pregnancy (ICP) is a rare pregnancy-related liver disease characterized by pruritus, abnormal liver function tests, and an increased risk of fetal complications. An increase in the levels of bile acids is considered to be the diagnostic hallmark of the disease. Ursodeoxycholic acid (UDCA) is currently the most effective therapy. Tribe et al. (this issue) hypothesized that measuring the longitudinal profiles of individual bile acids would provide further insight into the mechanisms of disease. They used a novel chromatography method, which allowed the simultaneous measurement of 15 serum bile acids between 16 weeks of pregnancy and 4 weeks post-partum. ICP was associated with a predominant rise in cholic acid conjugated with taurine and glycine from 24 weeks of pregnancy. UDCA treatment significantly reduced serum taurocholic and taurodeoxycholic acid concentrations. Finally, bile acid profiles were similar in normal pregnancy and pregnancy associated with pruritus gravidarum. The study by Tribe et al. (this issue) presents a significant contribution to the solution of this enigmatic disease by expanding our knowledge on the pathophysiology of ICP and proposing a convenient method for diagnosis and monitoring of this disorder.

  5. Hepatocyte MyD88 affects bile acids, gut microbiota and metabolome contributing to regulate glucose and lipid metabolism

    DEFF Research Database (Denmark)

    Duparc, Thibaut; Plovier, Hubert; Marrachelli, Vannina G

    2017-01-01

    performed microarrays and quantitative PCRs in the liver. In addition, we investigated the gut microbiota composition, bile acid profile and both liver and plasma metabolome. We analysed the expression pattern of genes in the liver of obese humans developing non-alcoholic steatohepatitis (NASH). RESULTS...... proliferator activator receptor-α, farnesoid X receptor (FXR), liver X receptors and STAT3) and bile acid profiles involved in glucose, lipid metabolism and inflammation. In addition to these alterations, the genetic deletion of MyD88 in hepatocytes changes the gut microbiota composition and their metabolomes...

  6. Bile acid profiling in human biological samples: comparison of extraction procedures and application to normal and cholestatic patients.

    Science.gov (United States)

    Humbert, Lydie; Maubert, Marie Anne; Wolf, Claude; Duboc, Henri; Mahé, Myriam; Farabos, Dominique; Seksik, Philippe; Mallet, Jean Maurice; Trugnan, Germain; Masliah, Joëlle; Rainteau, Dominique

    2012-06-15

    The role of bile acids in cell metabolism, membrane biology and cell signaling is increasingly recognized, thus making necessary a robust and versatile technique to extract, separate and quantify a large concentration range of these numerous molecular species. HPLC-MS/MS analysis provides the highest sensitivity to detect and identify bile acids. However, due to their large chemical diversity, extraction methods are critical and quite difficult to optimize, as shown by a survey of the literature. This paper compares the performances of four bile acid extraction protocols applied to either liquid (serum, urine, bile) or solid (stool) samples. Acetonitrile was found to be the best solvent for deproteinizing liquid samples and NaOH the best one for stool extraction. These optimized extraction procedures allowed us to quantitate as much as 27 distinct bile acids including sulfated species in a unique 30 min HPLC run, including both hydrophilic and hydrophobic species with a high efficiency. Tandem MS provided a non ambiguous identification of each metabolite with a good sensitivity (LOQ below 20 nmol/l except for THDCA and TLCA). After validation, these methods, successfully applied to a group of 39 control patients, detected 14 different species in serum in the range of 30-800 nmol/l, 11 species in urine in the range of 20-200 nmol/l and 25 species in stool in the range of 0.4-2000 nmol/g. The clinical interest of this method has been then validated on cholestatic patients. The proposed protocols seem suitable for profiling bile acids in routine analysis. Copyright © 2012 Elsevier B.V. All rights reserved.

  7. 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.

  8. Transcriptional regulation of human mucin MUC4 by bile acids in oesophageal cancer cells is promoter-dependent and involves activation of the phosphatidylinositol 3-kinase signalling pathway.

    Science.gov (United States)

    Mariette, Christophe; Perrais, Michaël; Leteurtre, Emmanuelle; Jonckheere, Nicolas; Hémon, Brigitte; Pigny, Pascal; Batra, Surinder; Aubert, Jean-Pierre; Triboulet, Jean-Pierre; Van Seuningen, Isabelle

    2004-02-01

    Abnormal gastro-oesophageal reflux and bile acids have been linked to the presence of Barrett's oesophageal premalignant lesion associated with an increase in mucin-producing goblet cells and MUC4 mucin gene overexpression. However, the molecular mechanisms underlying the regulation of MUC4 by bile acids are unknown. Since total bile is a complex mixture, we undertook to identify which bile acids are responsible for MUC4 up-regulation by using a wide panel of bile acids and their conjugates. MUC4 apomucin expression was studied by immunohistochemistry both in patient biopsies and OE33 oesophageal cancer cell line. MUC4 mRNA levels and promoter regulation were studied by reverse transcriptase-PCR and transient transfection assays respectively. We show that among the bile acids tested, taurocholic, taurodeoxycholic, taurochenodeoxycholic and glycocholic acids and sodium glycocholate are strong activators of MUC4 expression and that this regulation occurs at the transcriptional level. By using specific pharmacological inhibitors of mitogen-activated protein kinase, phosphatidylinositol 3-kinase, protein kinase A and protein kinase C, we demonstrate that bile acid-mediated up-regulation of MUC4 is promoter-specific and mainly involves activation of phosphatidylinositol 3-kinase. This new mechanism of regulation of MUC4 mucin gene points out an important role for bile acids as key molecules in targeting MUC4 overexpression in early stages of oesophageal carcinogenesis.

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

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    Ken-ichi eMukaisho

    2015-05-01

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

  10. Special features of bile acids spectral composition in patients with hyperuricemia in combination with obesity and non-alcoholic steatohepatitis

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    Олена Володимирівна Барабанчик

    2015-10-01

    Full Text Available Aim. To study changes of the bile acids spectral composition in patients with hyperuricemia combined with obesity and non-alcoholic steatohepatitis using thin-layer chromatography.Materials and methods. We examined 146 patients separated in two groups. The main group included 84 patients with hyperurecimia combined with obesity and non-alcoholic steatohepatitis. 62 patients with non-alcoholic steatohepatitis without additional factors of metabolic syndrome formed the control group. The non-alcoholic steatohepatitis (NASH was diagnosed on the base of criteria of exclusion of the chronic diffuse disease of liver of viral, autoimmune, inherited and medicamental genesis as a cause of cytolytic syndrome and also increase of exogeneity and decrease of sound conductivity of the liver according to the results of ultrasound examination.Results. Examined patients with hyperurecemia combined with NASH and obesity demonstrated the reliable increase of cholic acid level in cystic bile in 2,9 times (р<0,001 and deoxycholic acid level in 2,6 times (р<0,001. We observed decrease of taurocholic acid in cystic bile in 1,4 times (р<0,001 and decrease of glycocholic acid in 2,1 times (р<0,01. We noticed an increase of index of taurohenodeoxycholic and taurodeoxycholic acids mixture in 1,5 times (р<0,05 and also glycohenodeoxycholic and glycodeoxycholic ones in 1,3 times (р<0,01.Conclusions. So during the research there were demonstrated changes of spectral composition of bile acids in patients with hyperuricemia combined with obesity and non-alcoholic steatohepatitis. There was demonstrated an importance of defining the bile acids spectrum with the method of thin-layer chromatography for further prevention of cholelithiasis development

  11. [Optimum hepatic parenchymal dissection to prevent bile leak: a comparative study using electrosurgical and stapling devices in swine].

    Science.gov (United States)

    Ikeda, Tetsuo; Akahoshi, Tomohiko; Kawanaka, Hirofumi; Uchiyama, Hideaki; Yamashita, Yo-ichi; Morita, Masaru; Oki, Eiji; Saeki, Hiroshi; Sugimachi, Keishi; Ikegami, Toru; Yoshizumi, Tomoharu; Soejima, Yuji; Shirabe, Ken; Mimori, Koshi; Watanabe, Masayuki; Hashizume, Makoto; Maehara, Yoshihiko

    2013-12-01

    Bile leakage is a serious complication of liver resection, and its treatment is very time-consuming. In open liver resection, Glisson's sheaths are usually disconnected by ligation to the extent possible during the parenchyma dissection. However, in laparoscopic surgery, the ligation, suture, and hemostasis are more difficult than in open surgery. For this reason, in laparoscopic liver resection, liver parenchyma dissection is generally accomplished using electrosurgical or stapling devices. The purpose of this study was to verify the authenticity of electrosurgical devices attached an automatic irrigation function (AI) and stapling devices for laparoscopic liver parenchymal dissection. Four devices were used for liver parenchymal dissection in laparoscopic hepatic wedge resection, in pigs: monopolar high-frequency electric cautery attached AI (MCI) (n = 6), bipolar high-frequency electric cautery attached AI (BCI) (n = 6), bipolar tissue sealing system (LigaSure) attached AI (BSI) and an endoscopic stapling device (ECHELON FLEX ENDOPATH) (ES). In each group, burst pressures were tested using an electronic manometer, paying special attention to the location (s) of the first disruption (s). The dissected tissues were examined histologically. Pressures used in electrosurgical devices attach AI were significantly higher compared to pressures used in a ES (P automatic irrigation function are useful devices to dissect the liver parenchyma.

  12. Meconium impairs pulmonary surfactant by a combined action of cholesterol and bile acids.

    Science.gov (United States)

    Lopez-Rodriguez, Elena; Echaide, Mercedes; Cruz, Antonio; Taeusch, H William; Perez-Gil, Jesus

    2011-02-02

    Mechanisms for meconium-induced inactivation of pulmonary surfactant as part of the meconium aspiration syndrome in newborn infants, to our knowledge, are not clearly understood. Here we have studied the biophysical mechanisms of how meconium affects surface activity of pulmonary surfactant and whether the membrane-perturbing effects of meconium can be mimicked by exposure of surfactant to a mixture of bile acids and cholesterol. Surface activity of pulmonary surfactant complexes purified from animal lungs was analyzed in the absence and in the presence of meconium in standard surface balances and in a captive bubble surfactometer. We have also evaluated accumulation of surfactant at the air-liquid interface by what we believe to be a novel microtiter plate fluorescent assay, and the effect of meconium components on surfactant membrane fluidity using Laurdan fluorescence thermotropic profiles and differential scanning calorimetry thermograms. Rapid interfacial adsorption, low surface tension upon film compression, efficient film replenishment upon expansion, and thermotropic properties of surfactant complexes are all adversely affected by meconium, and, in a similar manner, they are affected by cholesterol/taurocholate mixtures but not by taurocholate alone. We conclude that inhibition of surfactant by meconium can be mimicked by a bile salt-promoted incorporation of excess cholesterol into surfactant complexes. These results highlight the potential pathogenic role of cholesterol-mobilizing agents as a crucial factor resulting in cholesterol induced alterations of structure and dynamics of surfactant membranes and films. Copyright © 2011 Biophysical Society. Published by Elsevier Inc. All rights reserved.

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

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    Ni Nyoman Puspawati

    2016-03-01

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

  14. Bark Extracts of Ceylon Cinnamon Possess Antilipidemic Activities and Bind Bile Acids In Vitro

    Science.gov (United States)

    Abeysekera, Walimuni Prabhashini Kaushalya Mendis; Ratnasooriya, Wanigasekera Daya

    2017-01-01

    Ethanol (95%) and dichloromethane : methanol (1 : 1) bark extracts of authenticated Ceylon cinnamon were investigated for range of antilipidemic activities (ALA): HMG-CoA reductase, lipase, cholesterol esterase, and cholesterol micellization inhibitory activities and bile acids binding in vitro. Individual compounds in bark extracts were also evaluated. Bark extracts showed ALA in all the assays studied. The IC50 (μg/mL) values ranged within 153.07 ± 8.38–277.13 ± 32.18, 297.57 ± 11.78–301.09 ± 4.05, 30.61 ± 0.79–34.05 ± 0.41, and 231.96 ± 9.22–478.89 ± 9.27, respectively, for HMG-CoA reductase, lipase, cholesterol esterase, and cholesterol micellization inhibitory activities. The bile acids binding (3 mg/mL) for taurocholate, glycodeoxycholate, and chenodeoxycholate ranged within 19.74 ± 0.31–20.22 ± 0.31, 21.97 ± 2.21–26.97 ± 1.61, and 16.11 ± 1.42–19.11 ± 1.52%, respectively. The observed ALA were moderate compared to the reference drugs studied. Individual compounds in bark extracts ranged within 2.14 ± 0.28–101.91 ± 3.61 and 0.42 ± 0.03–49.12 ± 1.89 mg/g of extract. Cinnamaldehyde and gallic acid were the highest and the lowest among the tested compounds. The ethanol extract had highest quantity of individual compounds and ALA investigated. Properties observed indicate usefulness of Ceylon cinnamon bark in managing hyperlipidemia and obesity worldwide. Further, this study provides scientific evidence for the traditional claim that Ceylon cinnamon has antilipidemic activities. PMID:28808476

  15. Bark Extracts of Ceylon Cinnamon Possess Antilipidemic Activities and Bind Bile Acids In Vitro

    Directory of Open Access Journals (Sweden)

    Walimuni Prabhashini Kaushalya Mendis Abeysekera

    2017-01-01

    Full Text Available Ethanol (95% and dichloromethane : methanol (1 : 1 bark extracts of authenticated Ceylon cinnamon were investigated for range of antilipidemic activities (ALA: HMG-CoA reductase, lipase, cholesterol esterase, and cholesterol micellization inhibitory activities and bile acids binding in vitro. Individual compounds in bark extracts were also evaluated. Bark extracts showed ALA in all the assays studied. The IC50 (μg/mL values ranged within 153.07±8.38–277.13±32.18, 297.57±11.78–301.09±4.05, 30.61±0.79–34.05±0.41, and 231.96±9.22–478.89±9.27, respectively, for HMG-CoA reductase, lipase, cholesterol esterase, and cholesterol micellization inhibitory activities. The bile acids binding (3 mg/mL for taurocholate, glycodeoxycholate, and chenodeoxycholate ranged within 19.74±0.31–20.22±0.31, 21.97±2.21–26.97±1.61, and 16.11±1.42–19.11±1.52%, respectively. The observed ALA were moderate compared to the reference drugs studied. Individual compounds in bark extracts ranged within 2.14±0.28–101.91±3.61 and 0.42±0.03–49.12±1.89 mg/g of extract. Cinnamaldehyde and gallic acid were the highest and the lowest among the tested compounds. The ethanol extract had highest quantity of individual compounds and ALA investigated. Properties observed indicate usefulness of Ceylon cinnamon bark in managing hyperlipidemia and obesity worldwide. Further, this study provides scientific evidence for the traditional claim that Ceylon cinnamon has antilipidemic activities.

  16. Bile acid profiles by capillary electrophoresis in intrahepatic cholestasis of pregnancy.

    Science.gov (United States)

    Castaño, Gustavo; Lucangioli, Silvia; Sookoian, Silvia; Mesquida, Marcelo; Lemberg, Abraham; Di Scala, Mirta; Franchi, Paula; Carducci, Clyde; Tripodi, Valeria

    2006-04-01

    ICP (intrahepatic cholestasis of pregnancy) is characterized by pruritus and biochemical cholestasis, including raised SBAs (serum bile acids) and, usually, elevated aminotransferases levels. However, AHP (asymptomatic hypercholanaemia of pregnancy) is defined as the presence of total SBA levels above the cut-off value (11 microM) in healthy pregnant women, thus elevation of total SBAs do not necessarily reflect an ICP condition. The aim of the present study was to describe clinical, obstetric, perinatal and biochemical findings, as well as the SBA profile, in pregnant women studied in the third trimester of pregnancy in order to define characteristic patterns of individual bile acids that enable women with ICP to be distinguished from AHP and healthy pregnancies. Free and conjugated ursodeoxycholic (UDCA), cholic (CA), lithocholic (LCA), deoxycholic (DCA) and chenodeoxycholic (CDCA) acids were evaluated by CE (capillary electrophoresis) in 41 patients (15 of them simultaneously by HPLC), in 30 healthy pregnant women and in 10 non-pregnant women. A highly significant correlation between CE and HPLC for total SBAs (r=0.990) and for individual SBAs was found. Normal pregnant women had higher total SBA levels than non-pregnant women (due to an increase in taurine-conjugated dihydroxy SBAs). Women with ICP had higher levels of total SBAs, the free/conjugated ratio, LCA, CA, CDCA and DCA than normal pregnant women. Newborns from women with ICP had lower birth weight and gestational age. Women with AHP had higher levels of conjugated dihydroxy SBAs than normocholanaemic patients, without any evidence of a clinical difference. In conclusion, the present study has shown a clear difference in SBA profiles between ICP and normal pregnancies (including AHP), involving a shift towards a characteristic hydrophobic composition in women with ICP.

  17. Comparative studies on the uptake of 14C-bile acids and 3H-demethylphalloin in isolated rat liver cells.

    Science.gov (United States)

    Petzinger, E; Frimmer, M

    1980-03-01

    The inward transport of bile acids in isolated hepatocytes completes with the uptake of phallotoxins. Cholate, taurocholate and glycocholate added 30 s prior to phallotoxins reduce their uptake in a concentration dependent manner. 100 microM bile acids suppress the uptake of phallotoxins completely. Several compounds known to inhibit the bile acid transport reduce the phallotoxin uptake to similar degree. Hepatocytes exposed to reagents reacting preferentially with amino groups of proteins lose their up take of both bile acids and phallotoxins. In hepatocytes isolated from 5 day old rats the uptake of both phallotoxins and cholate is reduced as compared to cells from adult controls. AS-30D ascites hepatoma cells, known to be insensitive to phallotoxins are unable to take up both phallotoxins and cholate. The results are consistent with our working hypothesis of a very similar mechanism for the uptake of bile acids and phallotoxins.

  18. Bile diversion in rats leads to a decreased plasma concentration of linoleic acid which is not due to decreased net intestinal absorption of dietary linoleic acid.

    Science.gov (United States)

    Minich, D M; Kalivianakis, M; Havinga, R; van Goor, H; Stellaard, F; Vonk, R J; Kuipers, F; Verkade, H J

    1999-04-19

    Decreased bile secretion into the intestine has been associated with low plasma concentrations of essential fatty acids (EFA) in humans. We studied the mechanism behind this relationship by determining the status and absorption of the major dietary EFA, linoleic acid (LA), in control and 1-week bile-diverted rats. The absorption of LA was quantified by a balance method and by measuring plasma concentrations of [13C]LA after its intraduodenal administration. Absolute and relative concentrations of LA in plasma were decreased in bile-diverted rats (Pabsorption of LA was similar between bile-diverted and control rats (1.96+/-0.14 vs. 1.91+/-0.07 mmol/day, respectively; P>0.05). After intraduodenal administration of [13C]LA, plasma concentrations were approximately 3-4-fold lower in bile-diverted rats for at least 6 h (Pacid and [13C]arachidonic acid were increased in bile-diverted rats (Pabsorption of LA, but may be related to increased metabolism of LA.

  19. Tauro-β-muricholic acid restricts bile acid-induced hepatocellular apoptosis by preserving the mitochondrial membrane potential.

    Science.gov (United States)

    Denk, Gerald Ulrich; Kleiss, Carl Philipp; Wimmer, Ralf; Vennegeerts, Timo; Reiter, Florian Paul; Schulz, Sabine; Zischka, Hans; Rust, Christian

    2012-08-10

    β-Muricholic acid (βMCA) is a trihydroxylated bile acid that constitutes the major bile acid in rat and mouse. βMCA is more hydrophilic than ursodeoxycholic acid and has been evaluated for dissolution of cholesterol gallstones. Since it is unknown if βMCA has beneficial effects on hepatocyte cell death we determined the effect of tauro-βMCA (TβMCA) on apoptosis in vitro. Human Ntcp-transfected HepG2 cells and primary hepatocytes from rat and mouse were incubated with the proapoptotic glycochenodeoxycholic acid (GCDCA) as well as the free fatty acid palmitate in the absence and presence of TβMCA. Apoptosis was quantified using caspase 3/7-assays and after Hoechst 33342 staining. The mitochondrial membrane potential (MMP) was measured fluorometrically using JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-benzimidazol-carbocyaniniodide). Immunoblotting was performed against the proapoptotic Bcl-2-protein Bax. In Ntcp-HepG2 cells, GCDCA markedly increased apoptosis after 4h. Co-incubation with TβMCA reduced apoptosis to 49% (p<0.01 vs. GCDCA, each; n=6). While GCDCA (100μmol/L) reduced the MMP to 34% after 6h, combination treatment with TβMCA restored the MMP to control levels at all time points (n=4). TβMCA also restored breakdown of the MMP induced by palmitate. GCDCA induced a translocation of Bax from the cytosol to mitochondria that was inhibited by simultaneous treatment with TβMCA in eqimolar concentrations. TβMCA restricts hepatocellular apoptosis induced by low micromolar concentrations of GCDCA or palmitate via inhibition of Bax translocation to mitochondria and preservation of the MMP. Thus, further studies are warranted to evaluate a potential use of TβMCA in ameliorating liver injury in cholestasis. Copyright © 2012 Elsevier Inc. All rights reserved.

  20. Characterization of basal hepatic bile flow and the effects of intravenous cholecystokinin on the liver, sphincter, and gallbladder in patients with sphincter of Oddi spasm

    Energy Technology Data Exchange (ETDEWEB)

    Krishnamurthy, Gerbail T.; Krishnamurthy, Shakuntala [Department of Nuclear Medicine, Tuality Community Hospital, 335 SE 8th Avenue, OR 97123, Hillsboro (United States); Watson, Randy D. [Department of Gastroenterology, Tuality Community Hospital, Hillsboro, OR (United States)

    2004-01-01

    The major objectives of this project were to establish the pattern of basal hepatic bile flow and the effects of intravenous administration of cholecystokinin on the liver, sphincter of Oddi, and gallbladder, and to identify reliable parameters for the diagnosis of sphincter of Oddi spasm (SOS). Eight women with clinically suspected sphincter of Oddi spasm (SOS group), ten control subjects (control group), and ten patients who had recently received an opioid (opioid group) were selected for quantitative cholescintigraphy with cholecystokinin. Each patient was studied with 111-185 MBq (3-5 mCi) technetium-99m mebrofenin after 6-8 h of fasting. Hepatic phase images were obtained for 60 min, followed by gallbladder phase images for 30 min. During the gallbladder phase, 10 ng/kg octapeptide of cholecystokinin (CCK-8) was infused over 3 min through an infusion pump. Hepatic extraction fraction, excretion half-time, basal hepatic bile flow into the gallbladder, gallbladder ejection fraction, and post-CCK-8 paradoxical filling (>30% of basal counts) were identified. Seven of the patients with SOS were treated with antispasmodics (calcium channel blockers), and one underwent endoscopic sphincterotomy. Mean ({+-}SD) hepatic bile entry into the gallbladder (versus GI tract) was widely variable: it was lower in SOS patients (32%{+-}31%) than in controls (61%{+-}36%) and the opioid group (61%{+-}25%), but the difference was not statistically significant. Hepatic extraction fraction, excretion half-time, and pattern of bile flow through both intrahepatic and extrahepatic ducts were normal in all three groups. Gallbladder mean ejection fraction was 9%{+-}4% in the opioid group; this was significantly lower (P<0.0001) than the values in the control group (54%{+-}18%) and the SOS group (48%{+-}29%). Almost all of the bile emptied from the gallbladder refluxed into intrahepatic ducts; it reentered the gallbladder after cessation of CCK-8 infusion (paradoxical gallbladder filling

  1. Role of Inflammatory and Oxidative Stress, Cytochrome P450 2E1, and Bile Acid Disturbance in Rat Liver Injury Induced by Isoniazid and Lipopolysaccharide Cotreatment.

    Science.gov (United States)

    Hassan, Hozeifa Mohamed; Guo, Hongli; Yousef, Bashir Alsiddig; Guerram, Mounia; Hamdi, Aida Mejda; Zhang, Luyong; Jiang, Zhenzhou

    2016-09-01

    Isoniazid (INH) remains the core drug in tuberculosis management, but serious hepatotoxicity and potentially fatal liver injury continue to accompany INH consumption. Among numerous theories that have been established to explain INH-induced liver injury, an inflammatory stress theory has recently been widely used to explain the idiosyncrasy. Inflammatory stress usually sensitizes tissues to a drug's toxic consequences. Therefore, the present study was conducted to verify whether bacterial lipopolysaccharide (LPS)-induced inflammation may have a role in enhancing INH hepatotoxicity. While single INH or LPS administration showed no major toxicity signs, INH-LPS cotreatment intensified liver toxicity. Both blood biomarkers and histological evaluations clearly showed positive signs of severe liver damage accompanied by massive necrosis, inflammatory infiltration, and hepatic steatosis. Furthermore, elevated serum levels of bile acid associated with the repression of bile acid synthesis and transport regulatory parameters were observed. Moreover, the principal impact of cytochrome P450 2E1 (CYP2E1) on INH toxicity could be anticipated, as its protein expression showed enormous increases in INH-LPS-cotreated animals. Furthermore, the crucial role of CYP2E1 in the production of reactive oxygen species (ROS) was clearly obvious in the repression of hepatic antioxidant parameters. In summary, these results confirmed that this LPS-induced inflammation model might prove valuable in revealing the hepatotoxic mechanisms of INH and the crucial role played by CYP2E1 in the initiation and propagation of INH-induced liver damage, information which could be very useful to clinicians in understanding the pathogenesis of drug-induced liver injury. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  2. Biosynthesis and trafficking of the bile salt export pump, BSEP: therapeutic implications of BSEP mutations.

    Science.gov (United States)

    Soroka, Carol J; Boyer, James L

    2014-06-01

    The bile salt export pump (BSEP, ABCB11) is the primary transporter of bile acids from the hepatocyte to the biliary system. This rate-limiting step in bile formation is essential to the formation of bile salt dependent bile flow, the enterohepatic circulation of bile acids, and the digestion of dietary fats. Mutations in BSEP are associated with cholestatic diseases such as progressive familial intrahepatic cholestasis type 2 (PFIC2), benign recurrent intrahepatic cholestasis type 2 (BRIC2), drug-induced cholestasis, and intrahepatic cholestasis of pregnancy. Development of clinical therapies for these conditions necessitates a clear understanding of the cell biology of biosynthesis, trafficking, and transcriptional and translational regulation of BSEP. This chapter will focus on the molecular and cell biological aspects of this critical hepatic membrane transporter. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. Bile acid sequestration normalizes plasma cholesterol and reduces atherosclerosis in hypercholesterolemic mice. No additional effect of physical activity

    NARCIS (Netherlands)

    Meissner, Maxi; Wolters, Henk; de Boer, Rudolf A.; Havinga, Rick; Boverhof, Renze; Bloks, Vincent W.; Kuipers, Folkert; Groen, Albert K.

    Aims: Bile acid sequestrants (BAS) and physical activity (RUN) decrease incidence of cardiovascular events. Both treatments are often prescribed, yet it is not known whether their beneficial effects are additive. We assessed the effects of BAS treatment alone and in combination with RUN on

  4. Decreased phalloidin response, phallotoxin uptake and bile acid transport in hepatocytes prepared from wistar rats treated chronically with diethylnitrosamine.

    Science.gov (United States)

    Ziegler, K; Petzinger, E; Frimmer, M

    1980-01-01

    Isolated hepatocytes prepared from rats pretreated with diethylnitrosamine (0.5 mg/kg DENA/DAY P.O.) are less sensitive to phalloidin poisoning. They take up lower amounts of both phallotoxins and bile acids than controls. The degree of inhibition depends on the period of pretreatment.

  5. 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...

  6. 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...

  7. 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...

  8. Bile acid receptor TGR5 overexpression is associated with decreased intestinal mucosal injury and epithelial cell proliferation in obstructive jaundice.

    Science.gov (United States)

    Ji, Chen-Guang; Xie, Xiao-Li; Yin, Jie; Qi, Wei; Chen, Lei; Bai, Yun; Wang, Na; Zhao, Dong-Qiang; Jiang, Xiao-Yu; Jiang, Hui-Qing

    2017-04-01

    Bile acids stimulate intestinal epithelial proliferation in vitro. We sought to investigate the role of the bile acid receptor TGR5 in the protection of intestinal epithelial proliferation in obstructive jaundice. Intestinal tissues and serum samples were obtained from patients with malignant obstructive jaundice and from bile duct ligation (BDL) rats. Intestinal permeability and morphological changes in the intestinal mucosa were observed. The functions of TGR5 in cell proliferation in intestinal epithelial injury were determined by overexpression or knockdown studies in Caco-2 and FHs 74 Int cells pretreated with lipopolysaccharide (LPS). Internal biliary drainage was superior to external biliary drainage in recovering intestinal permeability and mucosal histology in patients with obstructive jaundice. In BDL rats, feeding of chenodeoxycholic acid (CDCA) decreased intestinal mucosa injury. The levels of PCNA, a marker of proliferation, increased in response to CDCA feeding and were paralleled by elevated TGR5 expression. CDCA upregulated TGR5 expression and promoted proliferation in Caco-2 and FHs 74 Int cells pretreated with LPS. Overexpression of TGR5 resulted in increased PCNA, cell viability, EdU incorporation, and the proportion of cells in S phase, whereas knockdown of TGR5 had the opposite effect. Our data indicate that bile acids promote intestinal epithelial cell proliferation and decrease mucosal injury by upregulating TGR5 expression in obstructive jaundice. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Attempt to Determine the Prevalence of Two Inborn Errors of Primary Bile Acid Synthesis : Results of a European Survey

    NARCIS (Netherlands)

    Jahnel, Jörg; 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

  10. Hepatocyte MyD88 affects bile acids, gut microbiota and metabolome contributing to regulate glucose and lipid metabolism

    DEFF Research Database (Denmark)

    Duparc, Thibaut; Plovier, Hubert; Marrachelli, Vannina G

    2017-01-01

    performed microarrays and quantitative PCRs in the liver. In addition, we investigated the gut microbiota composition, bile acid profile and both liver and plasma metabolome. We analysed the expression pattern of genes in the liver of obese humans developing non-alcoholic steatohepatitis (NASH). RESULTS...

  11. 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.

  12. Nutritional regulation of bile acid metabolism is associated with improved pathological characteristics of the metabolic syndrome

    DEFF Research Database (Denmark)

    Liaset, Bjørn; Hao, Qin; Jørgensen, Henry

    2011-01-01

    with induction of genes involved in energy metabolism and uncoupling, Dio2, Pgc-1, and Ucp1, in interscapular brown adipose tissue. Interestingly, the same transcriptional pattern was found in white adipose tissue depots of both abdominal and subcutaneous origin. Accordingly, rats fed SPH-based diet exhibited...... increased whole body energy expenditure and heat dissipation. In skeletal muscle, expressions of the peroxisome proliferatoractivated receptor / target genes (Cpt-1b, Angptl4, Adrp, and Ucp3) were induced. Pharmacological removal of BAs by inclusion of 0.5 weight % cholestyramine to the high fat SPH diet...... attenuated the reduction in abdominal obesity, the reduction in liver TAG, and the decrease in nonfasted plasma TAG and glucose levels. Induction of Ucp3 gene expression in muscle by SPH treatment was completely abolished by cholestyramine inclusion. Taken together, our data provide evidence that bile acid...

  13. Inactivation of Bacillus cereus vegetative cells by gastric acid and bile during in vitro gastrointestinal transit

    Science.gov (United States)

    2012-01-01

    Background The foodborne pathogen Bacillus cereus can cause diarrhoeal food poisoning by production of enterotoxins in the small intestine. The prerequisite for diarrhoeal disease is thus survival during gastrointestinal passage. Methods Vegetative cells of 3 different B. cereus strains were cultivated in a real composite food matrix, lasagne verde, and their survival during subsequent simulation of gastrointestinal passage was assessed using in vitro experiments simulating transit through the human upper gastrointestinal tract (from mouth to small intestine). Results No survival of vegetative cells was observed, despite the high inoculum levels of 7.0 to 8.0 log CFU/g and the presence of various potentially protective food components. Significant fractions (approx. 10% of the consumed inoculum) of B. cereus vegetative cells survived gastric passage, but they were subsequently inactivated by bile exposure in weakly acidic intestinal medium (pH 5.0). In contrast, the low numbers of spores present (up to 4.0 log spores/g) showed excellent survival and remained viable spores throughout the gastrointestinal passage simulation. Conclusion Vegetative cells are inactivated by gastric acid and bile during gastrointestinal passage, while spores are resistant and survive. Therefore, the physiological form (vegetative cells or spores) of the B. cereus consumed determines the subsequent gastrointestinal survival and thus the infective dose, which is expected to be much lower for spores than vegetative cells. No significant differences in gastrointestinal survival ability was found among the different strains. However, considerable strain variability was observed in sporulation tendency during growth in laboratory medium and food, which has important implications for the gastrointestinal survival potential of the different B. cereus strains. PMID:23034184

  14. Effects of difructose anhydride III (DFA III) administration on bile acids and growth of DFA III-assimilating bacterium Ruminococcus productus on rat intestine.

    Science.gov (United States)

    Minamida, Kimiko; Kaneko, Maki; Ohashi, Midori; Sujaya, I Nengah; Sone, Teruo; Wada, Masaru; Yokota, Atsushi; Hara, Hiroshi; Asano, Kozo; Tomita, Fusao

    2005-06-01

    The growth of DFA III-assimilating bacteria in the intestines of rats fed 3% DFA III for 2 weeks was examined. Sixty-four percent of the DFA III intake had been assimilated on day 3 of ingestion, and almost all of the DFA III was assimilated at the end of the experiment. The DFA III-assimilating bacterium, Ruminococcus productus, in DFA III-fed rats was in the stationary state of 10(8)-10(9) cells/g dry feces within a week from 10(6) cells/g dry feces on day 1 of DFA III ingestion. The number of R. productus cells was associated with the amount of DFA III excreted in the feces. The acetic acid produced from DFA III by R. productus lowered the cecal pH to 5.8. In control-fed rats and DFA III-fed rats, 94% of secondary bile acids and 94% of primary bile acids, respectively, were accounted for in the total bile acids analyzed. DFA III ingestion increased the ratio of primary bile acids and changed the composition of fecal bile acids. In conclusion, R. productus assimilated DFA III, produced short chain fatty acids, and the cecal pH was lowered. The acidification of rat intestine perhaps inhibited secondary bile acid formation and decreased the ratio of secondary bile acids. Therefore, it is expected that DFA III may prevent colorectal cancer and be a new prebiotic candidate.

  15. Multimodal Treatment of Hepatic Metastasis in the Form of a Bile Duct Tumor Thrombus from Pancreatic Acinar Cell Carcinoma: Case Report of Successful Resection after Chemoradiation Therapy

    Directory of Open Access Journals (Sweden)

    Hirotada Kittaka

    2012-07-01

    Full Text Available Pancreatic acinar cell carcinoma (ACC is a rare tumor, and its pathophysiology has not been well understood. Treatment strategies for hepatic metastasis originating from ACC remain controversial. We report the case of a 66-year-old woman who had undergone total pancreatectomy from ACC 7 years prior to clinical presentation. Contrast-enhanced computed tomography imaging revealed a tumorous lesion measuring 7 cm in length and 1 cm in diameter and extending along the intrahepatic bile duct (B6, which showed mild enhancement in the early phase and modest washout in the late phase. This lesion was diagnosed as hepatic metastasis primarily in the form of a bile duct tumor thrombus originating from the prior ACC by the pathological evaluation of the fine needle biopsy specimen. The patient underwent preoperative gemcitabine-based chemoradiation therapy followed by subsequent surgical resection, which included subsegmentectomy (S6 of the liver and complete removal of the bile duct tumor thrombus. The patient has had no recurrence during the past 8 months since her last surgery. Multimodal treatment including preoperative chemoradiation therapy might be beneficial especially for marginally resectable cases of ACC.

  16. Bile acids and lipids in isolated rat hepatocytes. II. Source of cholesterol used for bile acid formation, estimated by incorporation of tritium from tritiated water, and by the effect of ML-236B

    NARCIS (Netherlands)

    Kempen, H.J.; Vos Van Holstein, M.; Lange, J.de

    1983-01-01

    Chemicals/CAS: cholesterol, 57-88-5; cholic acid, 32500-01-9, 361-09-1, 81-25-4; colestyramine, 11041-12-6, 58391-37-0; compactin, 73573-88-3; lipid, 66455-18-3; tritium oxide, 14940-65-9; Bile Acids and Salts; Cholesterol, 57-88-5; Cholestyramine, 11041-12-6; compactin, 73573-88-3; Lipids;

  17. Adaptation of Intestinal and Bile Acid Physiology Accompany the Metabolic Benefits Following Ileal Interposition in the Rat.

    Science.gov (United States)

    Zhao, Ping; Wendt, Donna; Goodin, Sean Z; Ravichandran, Shwetha; Chouinard, Tara E; Strader, April D

    2017-08-31

    Ileal interposition recapitulates many of the metabolic improvements similar to Roux-en-Y gastric bypass. We aimed to determine whether the metabolic improvements seen following ileal interposition were conferred solely by the interposed segment by examining changes in neighboring intestinal segments as well as the composition of the bile acid pool. Adult male rats were treated with either sham or ileal interposition surgeries. Glucose tolerance tests, body composition analysis, polymer chain reaction, enzyme-linked immunosorbent assay, and mass spectrometry were done after the surgeries. This study showed that ileal interposition improved glucose tolerance and enhanced both fasting and glucose-stimulated GLP-1 secretion in diabetic rats. Total bile acid pool was similar between groups but the composition favored glycine-conjugation in rats with ileal interposition. Insulin secretion was highly correlated with the 12-alpha-hydroxylase index of activity. The interposed ileum exhibited an increase in mRNA for preproglucagon and peptide YY; however, the bile acid transporter, apical sodium bile acid transporter, was dramatically reduced compared to sham rats. The interposed segment becomes jejunized in its new location as indicated by an increase in Glut2 and Pepck mRNA, genes predominantly synthesized within the jejunum. Ileal relocation alone can significantly alter the bile acid pool to favor a more insulin-sensitive metabolism in association with intestinal wide alterations in mRNA for a variety of genes. Ileal interposition may confer metabolic improvement via both the interposed segment and the associated intestinal changes in all segments of the intestine, including the colon.

  18. High expression of L-type amino acid transporter 1 as a prognostic marker in bile duct adenocarcinomas.

    Science.gov (United States)

    Yanagisawa, Nobuyuki; Hana, Kiyomi; Nakada, Norihiro; Ichinoe, Masaaki; Koizumi, Wasaburo; Endou, Hitoshi; Okayasu, Isao; Murakumo, Yoshiki

    2014-10-01

    Oncocytic L-type amino acid transporter (LAT) 1 may be a prognostic indicator and target of new molecular therapeutic agents against malignancies. To investigate whether LAT1 expression influence the outcomes of patients with bile duct cancer, the expression of LAT1, LAT2, CD98, and Ki-67 was investigated immunohistochemically in 134 surgically resected bile duct adenocarcinomas, including 84 distal extrahepatic bile duct adenocarcinomas, 21 hilar cholangiocarcinomas, 15 intrahepatic cholangiocarcinomas, and 14 ampullary adenocarcinomas. LAT1 expression was weakly correlated with CD98 expression and Ki-67 labeling index (LI). Kaplan-Meier analysis showed a significant difference in prognosis between patients with bile duct adenocarcinomas having LAT1-high and -low scores, whereas LAT2 and CD98 expression and Ki-67 LI were not predictive of poor prognosis. Prognosis tended to be worse in patients having tumors with LAT1-high/LAT2-low than LAT1-low/LAT2-high scores (P = 0.0686). Multivariable analyses revealed that LAT1 expression, surgical margin, pT stage were independent prognostic factors. In conclusion, aberrant overexpression of LAT1 in bile duct adenocarcinoma predicts poor prognosis, suggesting that LAT1 may be a potential target of anticancer therapy. © 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  19. Bile diversion in rats leads to a decreased plasma concentration of linoleic acid which is not due to decreased net intestinal absorption of dietary linoleic acid

    NARCIS (Netherlands)

    Minich, DM; Kalivianakis, M; Havinga, R; van Goor, H; Stellaard, F; Vonk, RJ; Kuipers, F; Verkade, HJ

    1999-01-01

    Decreased bile secretion into the intestine has been associated with low plasma concentrations of essential fatty acids (EFA) in humans. We studied the mechanism behind this relationship by determining the status and absorption of the major dietary EFA, linoleic acid (LA), in control and 1-week

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

    DEFF Research Database (Denmark)

    Fan, Weiwei; Xia, Dengning; Zhu, Quanlei

    2018-01-01

    Oral absorption of protein/peptide-loaded nanoparticles is often limited by multiple barriers of the intestinal epithelium. In addition to mucus translocation and apical endocytosis, highly efficient transepithelial absorption of nanoparticles requires successful intracellular trafficking......, especially to avoid lysosomal degradation, and basolateral release. Here, the functional material, deoxycholic acid-conjugated chitosan, is synthesized and loaded with the model protein drug insulin into deoxycholic acid-modified nanoparticles (DNPs). The DNPs designed in this study are demonstrated...... to overcome multiple barriers of the intestinal epithelium by exploiting the bile acid pathway. In Caco-2 cell monolayers, DNPs are internalized via apical sodium-dependent bile acid transporter (ASBT)-mediated endocytosis. Interestingly, insulin degradation in the epithelium is significantly prevented due...

  1. 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.

  2. Are Postprandial Bile Acid Levels Helpful in Predicting Perinatal Complications in Patients with Intrahepatic Cholestasis of Pregnancy?

    OpenAIRE

    Kudret Erkenekli; Can Tekin iskender; Hasan Onur Topcu; Tugba Ensari; Dilek Uygur; Nuri Danisman

    2015-01-01

    Purpose: To determine the outcomes of Iintrahepatic cholestasis of pregnancy and the role of postprandial serum bile acid levels in the prediction of perinatal complications. Material and Methods: This retrospective study consisted of 103 patients with intrahepatic cholestasis of pregnancy between January 2008 and June 2013. Maternal age, obstetric history, pregnancy outcome, maternal and neonatal complications, ursodeoxycholic acid treatment during pregnancy and serum laboratory tests w...

  3. Bile acid metabolism in hereditary forms of hypertriglyceridemia: evidence for an increased synthesis rate in monogenic familial hypertriglyceridemia.

    OpenAIRE

    Angelin, B; Hershon, K S; Brunzell, J D

    1987-01-01

    This study was undertaken to characterize bile acid metabolism in hereditary forms of hypertriglyceridemia. Ten hypertriglyceridemic patients (type IV phenotype) with familial combined hyperlipidemia and 7 patients with monogenic familial hypertriglyceridemia (FHTG) were compared with 18 healthy controls; all subjects were males. Pool size, synthesis rate, and fractional catabolic rate of cholic and chenodeoxycholic acids were determined with an isotope dilution technique. Patients with FHTG ...

  4. Affinity labels for membrane components involved in the uptake of bile acids and of phallotoxins by hepatocytes. Development of covalently binding derivatives of bile acids and of compounds related to cholecystographic agents.

    Science.gov (United States)

    Ziegler, K; Frimmer, M; Möller, W; Fasold, H

    1982-06-01

    A series of covalently binding derivatives of bile acids, fusidic acid and of compounds similar to cholecystographic agents were synthesized. Nearly all of them inhibited the development of protrusions on the surface of isolated hepatocytes regularly seen after treatment with phalloidin. The same compounds inhibited the uptake of demethylphalloin and of cholate in a concentration dependent manner. Two kinds of effects could be distinguished: The irreversible part of the inhibition depended on the incubation period and could not be removed by washing procedures. The reversible one was independent on the duration of the preincubation. Final results indicated that the tested derivatives inhibited either both transports, and the phalloidin response of liver cells to the same degree and in the same manner, or were found to be ineffective in all tests. The above parallelism supports the hypothesis that phallotoxins may be translocated by a carrier system normally responsible for the uptake of bile acids from the portal blood.

  5. 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.

  6. Hepatic Farnesoid X-Receptor Isoforms α2 and α4 Differentially Modulate Bile Salt and Lipoprotein Metabolism in Mice

    NARCIS (Netherlands)

    Boesjes, Marije; Bloks, Vincent W.; Hageman, Jurre; Bos, Trijnie; van Dijk, Theo H.; Havinga, Rick; Wolters, Henk; Jonker, Johan W.; Kuipers, Folkert; Groen, Albert K.

    2014-01-01

    The nuclear receptor FXR acts as an intracellular bile salt sensor that regulates synthesis and transport of bile salts within their enterohepatic circulation. In addition, FXR is involved in control of a variety of crucial metabolic pathways. Four FXR splice variants are known, i.e. FXR alpha 1-4.

  7. Are Postprandial Bile Acid Levels Helpful in Predicting Perinatal Complications in Patients with Intrahepatic Cholestasis of Pregnancy?

    Directory of Open Access Journals (Sweden)

    Kudret Erkenekli

    2015-06-01

    Results: Gestational diabetes and preterm delivery occurred more frequently in patients with intrahepatic cholestasis of pregnancy patients. The rate of primary cesarean delivery was more common in in patients with intrahepatic cholestasis of pregnancy patients. The rate of growth-restricted infants was higher in the patients who received ursodeoxycholic acid. Nenoatal intensive care unit admissions and overall neonatal complications, as well as spontaneous preterm deliveries, were similar among in patients with intrahepatic cholestasis of pregnancy regardless of ursodeoxycholic acid therapy. In the receiver operating characteristic analysis, the area under curve values for postprandial and fasting bile acids to predict neonatal complications were 0.64 and 0.70, respectively. Conclusion: Intrahepatic cholestasis of pregnancy patients increases certain perinatal complications, such as preterm deliveries and neonatal morbidity. Postprandial serum bile acid levels are inferior to fasting serum bile acid levels in the prediction of obstetric complications. ursodeoxycholic acid does not seem to improve perinatal outcomes. [Cukurova Med J 2015; 40(2.000: 212-220

  8. Differential regulation of bile acid and cholesterol metabolism by the farnesoid X receptor in Ldlr −/− mice versus hamsters[S

    Science.gov (United States)

    Gardès, Christophe; Chaput, Evelyne; Staempfli, Andreas; Blum, Denise; Richter, Hans; Benson, G. Martin

    2013-01-01

    Modulating bile acid synthesis has long been considered a good strategy by which to improve cholesterol homeostasis in humans. The farnesoid X receptor (FXR), the key regulator of bile acid synthesis, was, therefore, identified as an interesting target for drug discovery. We compared the effect of four, structurally unrelated, synthetic FXR agonists in two fat-fed rodent species and observed that the three most potent and selective agonists decreased plasma cholesterol in LDL receptor-deficient (Ldlr −/−) mice, but none did so in hamsters. Detailed investigation revealed increases in the expression of small heterodimer partner (Shp) in their livers and of intestinal fibroblast growth factor 15 or 19 (Fgf15/19) in mice only. Cyp7a1 expression and fecal bile acid (BA) excretion were strongly reduced in mice and hamsters by all four FXR agonists, whereas bile acid pool sizes were reduced in both species by all but the X-Ceptor compound in hamsters. In Ldlr −/− mice, the predominant bile acid changed from cholate to the more hydrophilic β-muricholate due to a strong repression of Cyp8b1 and increase in Cyp3a11 expression. However, FXR agonists caused only minor changes in the expression of Cyp8b1 and in bile acid profiles in hamsters. In summary, FXR agonist-induced decreases in bile acid pool size and lipophilicity and in cholesterol absorption and synthesis could explain the decreased plasma cholesterol in Ldlr −/− mice. In hamsters, FXR agonists reduced bile acid pool size to a smaller extent with minor changes in bile acid profile and reductions in sterol absorption, and consequently, plasma cholesterol was unchanged. PMID:23431047

  9. 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.

  10. Rational Design of Nucleoside–Bile Acid Conjugates Incorporating a Triazole Moiety for Anticancer Evaluation and SAR Exploration

    Directory of Open Access Journals (Sweden)

    Maria Luisa Navacchia

    2017-10-01

    Full Text Available Herein we report a study on the synthesis and biological evaluation of a library of nucleoside-bile acid conjugates prepared by combining 2′-deoxyadenosine, 2′-deoxyguanosine, 2′-deoxyuridine as well as adenosine and guanosine derivatives with cheno-, urso-, nor-cheno-, nor-urso- and taurourso-desoxycholic acid derivatives by means of the click reaction. The new nucleoside-bile acid conjugates incorporating a triazole moiety were tested in vitro against leukemic K562 and HCT116 colon carcinoma, as well as on normal fibroblast cells. Six compounds displayed interesting anti-proliferative activity against the selected cancer lines and no cytotoxic effects against normal fibroblasts. A possible structure activity relationship was also investigated.

  11. Profile of preoperative fecal organic acids closely predicts the incidence of postoperative infectious complications after major hepatectomy with extrahepatic bile duct resection: Importance of fecal acetic acid plus butyric acid minus lactic acid gap.

    Science.gov (United States)

    Yokoyama, Yukihiro; Mizuno, Takashi; Sugawara, Gen; Asahara, Takashi; Nomoto, Koji; Igami, Tsuyoshi; Ebata, Tomoki; Nagino, Masato

    2017-10-01

    To investigate the association between preoperative fecal organic acid concentrations and the incidence of postoperative infectious complications in patients undergoing major hepatectomy with extrahepatic bile duct resection for biliary malignancies. The fecal samples of 44 patients were collected before undergoing hepatectomy with bile duct resection for biliary malignancies. The concentrations of fecal organic acids, including acetic acid, butyric acid, and lactic acid, and representative fecal bacteria were measured. The perioperative clinical characteristics and the concentrations of fecal organic acids were compared between patients with and without postoperative infectious complications. Among 44 patients, 13 (30%) developed postoperative infectious complications. Patient age and intraoperative bleeding were significantly greater in patients with postoperative infectious complications compared with those without postoperative infectious complications. The concentrations of fecal acetic acid and butyric acid were significantly less, whereas the concentration of fecal lactic acid tended to be greater in the patients with postoperative infectious complications. The calculated gap between the concentrations of fecal acetic acid plus butyric acid minus lactic acid gap was less in the patients with postoperative infectious complications (median 43.5 vs 76.1 μmol/g of feces, P = .011). Multivariate analysis revealed that an acetic acid plus butyric acid minus lactic acid gap acid profile (especially low acetic acid, low butyric acid, and high lactic acid) had a clinically important impact on the incidence of postoperative infectious complications in patients undergoing major hepatectomy with extrahepatic bile duct resection. Copyright © 2017. Published by Elsevier Inc.

  12. 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.

  13. Free fatty acids increase hepatic glycogen content in obese males

    NARCIS (Netherlands)

    Allick, G.; Sprangers, F.; Weverling, G. J.; Ackermans, M. T.; Meijer, A. J.; Romijn, J. A.; Endert, E.; Bisschop, P. H.; Sauerwein, H. P.

    2004-01-01

    Obesity is associated with increased hepatic glycogen content. In vivo and in vitro data suggest that plasma free fatty acids (FFA) may cause this increase. In this study we investigated the effect of physiological plasma FFA levels on hepatic glycogen metabolism by studying intrahepatic glucose

  14. 1,2-Dibromo-4-(1,2-dibromoethyl)-cyclohexane and tris(methylphenyl) phosphate cause significant effects on development, mRNA expression, and circulating bile acid concentrations in chicken embryos

    Energy Technology Data Exchange (ETDEWEB)

    Crump, Doug, E-mail: doug.crump@ec.gc.ca [National Wildlife Research Centre, Environment Canada, Ottawa, ON K1A 0H3 (Canada); Porter, Emily; Egloff, Caroline; 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)

    2014-06-15

    1,2-Dibromo-4-(1,2-dibromoethyl)-cyclohexane (DBE-DBCH; formerly abbreviated as TBECH) and tris(methylphenyl) phosphate (TMPP; formerly abbreviated as TCP) are additive flame retardants that are detected in the environment and biota. A recent avian in vitro screening study of 16 flame retardants identified DBE-DBCH and TMPP as important chemicals for follow-up in ovo evaluation based on their effects on cytotoxicity and mRNA expression in avian hepatocytes. In this study, technical mixtures of DBE-DBCH and TMPP were injected into the air cell of chicken embryos at concentrations ranging from 0 to 54,900 ng/g and from 0 to 261,400 ng/g, respectively, to determine effects on pipping success, development, hepatic mRNA expression, thyroid hormone levels, and circulating bile acid concentrations. Both compounds were detectable in embryos at pipping and the β-DBE-DBCH isomer was depleted more rapidly than the α-isomer in tissue samples. DBE-DBCH had limited effects on the endpoints measured, with the exception of the up-regulation of two phase I metabolizing enzymes, CYP3A37 and CYP2H1. TMPP exposure caused embryonic deformities, altered growth, increased liver somatic index (LSI) and plasma bile acid concentrations, and altered mRNA expression levels of genes associated with xenobiotic and lipid metabolism and the thyroid hormone pathway. Overall, TMPP elicited more adverse molecular and phenotypic effects than DBE-DBCH albeit at concentrations several orders of magnitude greater than those detected in the environment. The increase in plasma bile acid concentrations was a useful phenotypic anchor as it was associated with a concomitant increase in LSI, discoloration of the liver tissue, and modulation of hepatic genes involved with xenobiotic and lipid metabolism. - Highlights: • DBE-DBCH and TMPP are not embryolethal to chicken embryos. • TMPP caused deformities, morphometric alterations, and increased plasma bile acids. • DBE-DBCH and TMPP altered mRNA levels

  15. Role of mitogen-activated protein kinases in tauroursodeoxycholic acid-induced bile formation in cholestatic rat liver.

    Science.gov (United States)

    Denk, Gerald Ulrich; Hohenester, Simon; Wimmer, Ralf; Böhland, Claudia; Rust, Christian; Beuers, Ulrich

    2008-07-01

    Ursodeoxycholic acid exerts anticholestatic effects in various cholestatic disorders and experimental models of cholestasis. Its taurine conjugate (TUDCA) stimulates bile salt secretion in isolated perfused rat livers (IPRL) under physiological, non-cholestatic conditions, in part by mitogen-activated protein kinase (MAPK)-dependent mechanisms. The role of MAPK in the anticholestatic effect of TUDCA, however, is unclear. Therefore, we studied the role of MAPK in the anticholestatic effect of TUDCA in IPRL and isolated rat hepatocytes (IRH) in taurolithocholic acid (TLCA)-induced cholestasis. Bile flow, biliary levels of 2,4-dinitrophenyl-S-glutathione (GS-DNP) as a marker of hepatobiliary organic anion secretion and activity of lactate dehydrogenase (LDH) in hepatovenous effluate as a marker of hepatocellular damage in IPRL perfused with TUDCA and/or TLCA were determined in the presence or absence of MAPK inhibitors. In addition, phosphorylation of Erk 1/2 and p38(MAPK) induced by TUDCA and/or TLCA was studied by Western immunoblot in IPRL and IRH. TUDCA-induced bile flow was impaired by the Erk 1/2 inhibitor PD98059 in normal livers (-28%), but not in livers made cholestatic by TLCA. GS-DNP secretion was unaffected by PD98059 under both conditions. TUDCA-induced bile formation and organic anion secretion both in the presence and absence of TLCA were unaffected by the p38(MAPK) inhibitor SB202190. Erk 1/2 phosphorylation in liver tissue was unchanged after bile salt exposure for 70 min, but was transiently enhanced by TUDCA in IRH. MAPK do not mediate the anticholestatic effects of TUDCA in TLCA-induced cholestasis.

  16. Identification of miR-26a as a target gene of bile acid receptor GPBAR-1/TGR5.

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    Xiaosong Chen

    Full Text Available GPBAR1/TGR5 is a G protein-coupled receptor of bile acids. TGR5 is known to regulate the BA homeostasis and energy metabolism. Recent studies highlight an important role of TGR5 in alleviating obesity and improving glucose regulation, however, the mechanism of which is still unclear. Here we report that TGR5 is involved in mediating the anti-obesity and anti-hyperglycemia effect of a natural compound, oleanolic acid. By comparing the miRNA profiles between wild type and TGR5-/- livers after OA treatment, we identified miR-26a as a novel downstream target gene of TGR5 activation. The expression of miR-26a in the liver was induced in a TGR5-dependent manner after feeding the mice with a bile acid diet. TGR5 activation strongly increased the expression of miR-26a in macrophages, including the Kupffer cells in the liver. We further demonstrated that JNK pathway was required for miR-26a induction by TGR5 activation. Interestingly, we located the TGR5-responsive DNA element to a proximal region of miR-26's promoter, which was independent of the transcription of its host genes. These results unravel a new mechanism by which bile acid receptor TGR5 activates a miRNA gene expression.

  17. Pneumoperitoneum after Endoscopic Retrograde Cholangiopancreatography due to Rupture of Intrahepatic Bile Ducts and Glisson’s Capsule in Hepatic Metastasis: A Case Report and Review of Literature

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    Zubair Khan

    2017-10-01

    Full Text Available Introduction: Endoscopic retrograde cholangiopancreatography (ERCP has been proven to be a safe and effective method for diagnosis and treatment of biliary and pancreatic disorders. Major complications of ERCP include pancreatitis, hemorrhage, cholangitis, and duodenal perforation. We report a third case in literature of pneumoperitoneum after ERCP due to rupture of intrahepatic bile ducts and Glisson’s capsule in a peripheral hepatic lesion. Case Report: A 50-year-old male with a history of metastatic pancreatic neuroendocrine tumor and who had a partially covered metallic stent placed in the biliary tree 1 year ago presented to the oncology clinic with fatigue, abdominal pain, and hypotension. He was planned for ERCP for possible cholangitis secondary to obstructed previously placed biliary stent. However, the duodenoscope could not be advanced to the level of the major papilla because of narrowed pylorus and severely strictured duodenal sweep. Forward-view gastroscope was then passed with careful manipulation to the severely narrowed second part of the duodenum where the previously placed metallic stent was visualized. Balloon sweeping of stenting was done. Cholangiography did not show any leak. Following the procedure, the patient underwent CT scan of the abdomen that showed pneumoperitoneum which was communicating with pneumobilia through a loculated air collection in necrotic hepatic metastasis perforating Glisson’s capsule. The patient was managed conservatively. Conclusion: In our case, pneumoperitoneum resulted from rupture of intrahepatic bile ducts and Glisson’s capsule in hepatic metastasis. This case emphasizes the need for close clinical and radiological observation of patients with hepatic masses (primary or metastatic subjected to ERCP.

  18. A contribution to the study of hydrophobicity (lipophilicity of bile acids with an emphasis on oxo derivatives of 5β-cholanoic acid

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    Poša Mihalj

    2011-01-01

    Full Text Available Due to their promotory action on the transport of some drugs through various membranes (lipophilic barriers, oxo derivatives of bile acids have recently been increasingly used in biopharmacy. These compounds exhibit also a lower membranolytic (toxic activity than their hydroxy analogues. Because of that it is of special importance to find out the descriptors that would adequately describe the structure of bile acids and their biological activity and be used to model the quantitative structure-activity relationship. In view of this, the present work is concerned with the application of the chromatographic parameter RM0 obtained by normal-phase thin-layer chromatography in the solvent system toluene-butanol and silica gel as stationary phase to describe the lipophilicity of bile acids. Also, the work introduces a new molecular descriptor (ND that reflects both 2D and 3D topological characteristics of the molecule. Between the retention constant, RM0 and the descriptor ND there is a good correlation, and both RM0, and ND describe sufficiently well the structural (conformational changes that arise in the process of oxidation of the OH group of the steroid skeleton to an oxo group. On the other hand, the in silico descriptors of lipophilicity, logP (atomic-based prediction and ClogP (fragment-based prediction predict the hydrophobicity of bile acid oxo derivatives with a certain error.

  19. Nimesulide and 4'-Hydroxynimesulide as Bile Acid Transporters Inhibitors Are Contributory Factors for Drug-Induced Cholestasis.

    Science.gov (United States)

    Zhou, Lei; Pang, Xiaoyan; Jiang, Jingfang; Zhong, Dafang; Chen, Xiaoyan

    2017-05-01

    Nimesulide (NIM) is a classic nonsteroidal anti-inflammatory drug. However, some patients treated with NIM experienced cholestatic liver injury. For this reason, we investigated the potential mechanism underlying NIM-induced cholestasis by using in vivo and in vitro models. Oral administration of 100 mg/kg/day NIM to Wistar rats for 5 days increased the levels of plasma total bile acids, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase by 1.49-, 1.31-, 1.60-, and 1.29-fold, respectively. In sandwich-cultured rat hepatocytes, NIM and 4'-hydroxynimesulide (M1) reduced the biliary excretion index of d8-taurocholic acid (d8-TCA) and 5 (and 6)-carboxy-2',7'-dichlorofluorescein in a concentration-dependent manner, indicating the inhibition of the efflux transporters bile salt export pump and multidrug resistance-associated protein 2, respectively. In suspended rat hepatocytes, NIM and M1 inhibited the uptake transporters of d8-TCA for Na(+)-taurocholate cotransporting polypeptide at IC50 values of 21.3 and 25.0 μM, respectively, and for organic anion-transporting proteins at IC50 values of 45.6 and 39.4 μM, respectively. By contrast, nitro-reduced NIM and the further acetylated metabolite did not inhibit or only marginally inhibited these transporters at the maximum soluble concentrations. Inhibitory effects of NIM and M1 on human bile acid transporters were also confirmed using sandwich-cultured human hepatocytes. These data suggest that the inhibition of bile acid transporters by NIM and M1 is one of the biologic mechanisms of NIM-induced cholestasis. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  20. The bile acid membrane receptor TGR5: a valuable metabolic target.

    Science.gov (United States)

    Pols, Thijs W H; Noriega, Lilia G; Nomura, Mitsunori; Auwerx, Johan; Schoonjans, Kristina

    2011-01-01

    Bile acids (BAs) are amphipathic molecules that facilitate the uptake of lipids, and their levels fluctuate in the intestines as well as in the circulation depending on food intake. Besides their role in dietary lipid absorption, BAs function as signaling molecules that activate specific BA receptors and trigger downstream signaling cascades. The BA receptors and the signaling pathways they control are not only important in the regulation of BA synthesis and their metabolism, but they also regulate glucose homeostasis, lipid metabolism and energy expenditure - processes relevant in the context of the metabolic syndrome. In addition to the function of the nuclear receptor FXRα in regulating local effects of BAs in the organs of the enterohepatic axis, increasing evidence points to a crucial role of the G-protein-coupled receptor TGR5 in mediating systemic actions of BAs. Here we review the current knowledge on BA receptors, with a strong focus on the cell membrane receptor TGR5, which has emerged as a promising target for intervention in metabolic diseases. Copyright © 2011 S. Karger AG, Basel.

  1. Acidified bile acids enhance tumor progression and telomerase activity of gastric cancer in mice dependent on c-Myc expression.

    Science.gov (United States)

    Wang, Xiaolong; Sun, Lei; Wang, Xijing; Kang, Huafeng; Ma, Xiaobin; Wang, Meng; Lin, Shuai; Liu, Meng; Dai, Cong; Dai, Zhijun

    2017-04-01

    c-Myc overexpression has been implicated in several malignancies including gastric cancer. Here, we report that acidified bile acids enhance tumor progression and telomerase activity in gastric cancer via c-Myc activation both in vivo and in vitro. c-Myc mRNA and protein levels were assessed in ten primary and five local recurrent gastric cancer samples by quantitative real-time polymerase chain reaction and western blotting analysis. The gastric cancer cell line MGC803 was exposed to bile salts (100 μmol/L glycochenodeoxycholic acid and deoxycholic acid) in an acid medium (pH 5.5) for 10 min daily for 60 weeks to develop an MGC803-resistant cell line. Control MGC803 cells were grown without acids or bile salts for 60 weeks as a control. Cell morphology, proliferation, colony formation and apoptosis of MGC803-resistant cells were analyzed after 60 weeks. To determine the involvement of c-Myc in tumor progression and telomere aging in MGC803-resistant cells, we generated xenografts in nude mice and measured xenograft volume and in vivo telomerase activity. The c-Myc and hTERT protein and mRNA levels were significantly higher in local recurrent gastric cancer samples than in primary gastric cancer samples. MGC803-resistant cells showed a marked phenotypic change under normal growth conditions with more clusters and acini, and exhibited increased cell viability and colony formation and decreased apoptosis in vitro. These phenotypic changes were found to be dependent on c-Myc activation using the c-Myc inhibitor 10058-F4. MGC803-resistant cells also showed a c-Myc-dependent increase in xenograft growth and telomerase activity in vivo. In conclusion, these observations support the hypothesis that acidified bile acids enhance tumor progression and telomerase activity in gastric cancer and that these effects are dependent on c-Myc activity. These findings suggest that acidified bile acids play an important role in the malignant progression of local recurrent

  2. Profiling of bile acids in bovine follicular fluid by fused-core-LC-MS/MS.

    Science.gov (United States)

    Sánchez-Guijo, A; Blaschka, C; Hartmann, M F; Wrenzycki, C; Wudy, S A

    2016-09-01

    Bile acids (BAs) are present in follicular fluid (FF) from humans and cattle. This fact has triggered an interest on the role BAs might play in folliculogenesis and their possible association with fertility. To achieve a better understanding about this subject, new methods are needed to provide reliable information about concentrations of the most important BAs in FF. In this context, liquid chromatography-tandem mass spectrometry (LC-MS/MS) offers high specificity with a relatively simple sample workup. We developed and validated a new assay for the quick profiling of the 9 most abundant BAs in follicular fluid from cattle. The method uses 200μl of FF and can quantify cholic acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA) and their glycine (G) and taurine (T) conjugates. Lithocholic acid (LCA), its conjugates GLCA and TLCA, and sulfated forms, were present in some samples, but their concentration was low compared to other BAs (in average, below 60ng/ml for LCA, GLCA or TLCA and below 20ng/ml for their corresponding sulfates). Method performance was studied at three quality controls for each compound in consonance with their physiological concentration. Excellent linearity and recovery were found for all compounds at every control level. Intra-day and between-day precisions (%CV) and accuracies (relative errors) were below 15% for all the compounds. Matrix effects were negligible for most of the analytes. Samples undergoing freeze-thaw showed no degradation of their BAs. The method makes use of a fused-core phenyl column coupled to a triple quadrupole tandem mass spectrometer to achieve chromatographic separation within 5min. We quantified BAs grouped in four different follicle sizes (3-5mm, 6-8mm, 9-14mm, >15mm), obtaining a similar relative BA profile for all the sizes, with CA always in higher concentration, ranging between 1600 and 18000ng/ml, approximately, followed by its conjugate glycocholic acid, GCA, which ranged between 800 and 9000ng

  3. Fluorescence properties and sequestration of peripheral anionic site specific ligands in bile acid hosts: Effect on acetylcholinesterase inhibition activity.

    Science.gov (United States)

    Islam, Mullah Muhaiminul; Aguan, Kripamoy; Mitra, Sivaprasad

    2016-05-01

    The increase in fluorescence intensity of model acetyl cholinesterase (AChE) inhibitors like propidium iodide (PI) and ethidium bromide (EB) is due to sequestration of the probes in primary micellar aggregates of bile acid (BA) host medium with moderate binding affinity of ca. 10(2)-10(3)M(-1). Multiple regression analysis of solvent dependent fluorescence behavior of PI indicates the decrease in total nonradiative decay rate due to partial shielding of the probe from hydrogen bond donation ability of the aqueous medium in bile acid bound fraction. Both PI and EB affects AChE activity through mixed inhibition and consistent with one site binding model; however, PI (IC50=20±1μM) shows greater inhibition in comparison with EB (IC50=40±3μM) possibly due to stronger interaction with enzyme active site. The potency of AChE inhibition for both the compounds is drastically reduced in the presence of bile acid due to the formation of BA-inhibitor complex and subsequent reduction of active inhibitor fraction in the medium. Although the inhibition mechanism still remains the same, the course of catalytic reaction critically depends on equilibrium binding among several species present in the solution; particularly at low inhibitor concentration. All the kinetic parameters for enzyme inhibition reaction are nicely correlated with the association constant for BA-inhibitor complex formation. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Antitumor activity of newly synthesized oxo and ethylidene derivatives of bile acids and their amides and oxazolines.

    Science.gov (United States)

    Bjedov, Srđan; Jakimov, Dimitar; Pilipović, Ana; Poša, Mihalj; Sakač, Marija

    2017-04-01

    Bile acid derivatives with modifications in side chain and modifications on steroid skeleton were synthetized and their antitumor activity against five human cancer cell lines was investigated. Modifications in side chain include amid group, formed in reaction with 2-amino-2-methylpropanol, and 4,4-dimethyloxazoline group, obtained after cyclization of amides. In the steroid skeleton oxo groups were introduced in position 7 (2, 2a, 2b) and 7,12 (3, 3a, 3b). Ethylidene groups were introduced regio- and stereoselectively on C-7, and/or without stereoselectivity on C-3 by Wittig reaction. By combination of these modifications, a series of 19 bile acid derivatives were synthesized. Compounds containing both C-7 ethylidene and C-12 carbonyl groups (6, 6a, 6b) shown very good antitumor activity with IC50amide or oxazoline group has positive effect on cytotoxicity. Different molecular descriptors were determined in silico and after principal component analysis was found that molecular descriptor BLTF96 can be used for fast assessment of experimental cytotoxicity of bile acid derivatives. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Free fatty acids sensitize hepatocytes to bile acid-induced apoptosis.

    Science.gov (United States)

    Pusl, Thomas; Wild, Nadine; Vennegeerts, Timo; Wimmer, Ralf; Göke, Burkhard; Brand, Stephan; Rust, Christian

    2008-07-04

    Delivery of free fatty acids to the liver in nonalcoholic fatty liver disease (NAFLD) may render hepatocytes more vulnerable to glycochenodeoxycholic acid (GCDCA)-induced apoptosis. Fat overloading was induced in HepG2-Ntcp cells and primary rat hepatocytes by incubation with palmitic or oleic acid. Apoptosis was quantified by measuring caspase 3/7 activity and transcription of interleukin (IL) 8 and IL-22 by quantitative real-time PCR. Oleic acid (500 microM) alone did not induce apoptosis, while palmitic acid (500 microM) increased apoptosis 5-fold. GCDCA did not induce significant apoptosis at low micromolar concentrations (5-30 microM) in non-steatotic cells. However, at the same concentrations, GCDCA increased apoptosis 3-fold in oleic acid-pretreated HepG2-Ntcp cells and 3.5-fold in primary rat hepatocytes. Pretreatment with oleic acid increased GCDCA-induced gene transcription of the proinflammatory cytokines IL-8 and IL-22 5-fold and 19-fold, respectively. Thus, low levels of cholestasis normally not considered harmful could advance liver injury in patients with NAFLD.

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

    Science.gov (United States)

    Mooranian, Armin; Negrulj, Rebecca; Chen-Tan, Nigel; Al-Sallami, Hesham S; Fang, Zhongxiang; Mukkur, Trilochan; Mikov, Momir; Golocorbin-Kon, Svetlana; Fakhoury, Marc; Arfuso, Frank; Al-Salami, Hani

    2014-01-01

    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 developed in our laboratory. Using sodium alginate (SA) polymer, both formulations were prepared: G-SA (control) at a ratio of 1:30, and G-DCA-SA (test) at a ratio of 1:3:30. Complete characterization of microcapsules was carried out. The new G-DCA-SA formulation was further optimized by the addition of DCA, exhibiting pseudoplastic-thixotropic rheological characteristics. The size of microcapsules remained similar after DCA addition, and these microcapsules showed no chemical interactions between the excipients. This was supported further by the spectral and microscopy studies, suggesting microcapsule stability. The new microencapsulated formulation has good structural properties and may be useful for the oral delivery of G in T1D. PMID:25114507

  7. Bile acids regulate nuclear receptor (Nur77) expression and intracellular location to control proliferation and apoptosis.

    Science.gov (United States)

    Hu, Ying; Chau, Thinh; Liu, Hui-Xin; Liao, Degui; Keane, Ryan; Nie, Yuqiang; Yang, Hui; Wan, Yu-Jui Yvonne

    2015-02-01

    Bile acids (BA) are endogenous agents capable of causing cancer throughout the gastrointestinal (GI) tract. To uncover the mechanism by which BAs exert carcinogenic effects, both human liver and colon cancer cells as well as mouse primary hepatocytes were treated with BAs and assayed for viability, genotoxic stress, and transcriptional response. BAs induced both Nur77 (NR4A1) and proinflammatory gene expression. The intracellular location of BA-induced Nur77 was time dependent; short-term (1-3 hours) exposure induced nuclear Nur77, whereas longer (1-2 days) exposure also increased cytosolic Nur77 expression and apoptosis. Inhibiting Nur77 nuclear export with leptomycin B decreased lithocholic acid (LCA)-induced apoptosis. Extended (7 days) treatment with BA generated resistance to BA with increased nuclear Nur77, viability, and mobility. While, knockdown of Nur77 in BA-resistant cells increased cellular susceptibility to LCA-induced apoptosis. Moreover, in vivo mouse xenograft experiments demonstrated that BA-resistant cells form larger tumors with elevated Nur77 expression compared with parental controls. DNA-binding and gene expression assays identified multiple survival genes (CDK4, CCND2, MAP4K5, STAT5A, and RBBP8) and a proapoptosis gene (BID) as Nur77 targets. Consistently, BA-induced upregulation of the aforementioned genes was abrogated by a lack of Nur77. Importantly, Nur77 was overexpressed in high percentage of human colon and liver cancer specimens, and the intracellular location of Nur77 correlated with elevated serum total BA levels in patients with colon cancer. These data show for the first time that BAs via Nur77 have a dual role in modulating cell survival and death. These findings establish a direct link between Nur77 and the carcinogenic effect of BAs. ©2014 American Association for Cancer Research.

  8. Viability, Acid and Bile Tolerance of Spray Dried Probiotic Bacteria and Some Commercial Probiotic Supplement Products Kept at Room Temperature.

    Science.gov (United States)

    Dianawati, Dianawati; Mishra, Vijay; Shah, Nagendra P

    2016-06-01

    Production of probiotic food supplements that are shelf-stable at room temperature has been developed for consumer's convenience, but information on the stability in acid and bile environment is still scarce. Viability and acid and bile tolerance of microencapsulated Bifidobacterium spp. and Lactobacillus acidophilus and 4 commercial probiotic supplements were evaluated. Bifidobacterium and L. acidophilus were encapsulated with casein-based emulsion using spray drying. Water activity (aw ) of the microspheres containing Bifidobacterium or L. acidophilus (SD GM product) was adjusted to 0.07 followed by storage at 25 °C for 10 wk. Encapsulated Bifidobacterium spp. and Lactobacillus acidophilus and 4 commercial probiotic supplement products (AL, GH, RE, and BM) were tested. Since commercial probiotic products contained mixed bacteria, selective media MRS-LP (containing L-cysteine and Na-propionate) and MRS-clindamycin agar were used to grow Bifidobacterium spp. or L. acidophilus, respectively, and to inhibit the growth of other strains. The results showed that aw had a strong negative correlation with the viability of dehydrated probiotics of the 6 products. Viable counts of Bifidobacterium spp. and L. acidophilus of SD GM, AL, and GH were between 8.3 and 9.2 log CFU/g, whereas that of BM and RE were between 6.7 and 7.3 log CFU/g. Bifidobacterium in SD GM, in AL, and in GH products and L. acidophilus in SD GM, in AL, and in BM products demonstrated high tolerance to acid. Most of dehydrated probiotic bacteria were able to survive in bile environment except L. acidophilus in RE product. Exposure to gastric juice influenced bacterial survivability in subsequent bile environment. © 2016 Institute of Food Technologists®

  9. The value of gadoxetic acid-enhanced MRI for differentiation between hepatic microabscesses and metastases in patients with periampullary cancer

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Seo-Youn [Soonchunhyang University College of Medicine, Bucheon Hospital, Department of Radiology, Bucheon (Korea, Republic of); Kim, Young Kon; Cha, Dong Ik; Jeong, Woo Kyoung; Lee, Won Jae [Samsung Medical Center, Sungkyunkwan University School of Medicine, Department of Radiology and Center for Imaging Science, Seoul (Korea, Republic of); Min, Ji Hye [Samsung Medical Center, Sungkyunkwan University School of Medicine, Department of Radiology and Center for Imaging Science, Seoul (Korea, Republic of); Chungnam National University Hospital, Chungnam National University College of Medicine, Department of Radiology, Daejeon (Korea, Republic of)

    2017-10-15

    We aimed to identify features that differentiate hepatic microabscess from hepatic metastasis on gadoxetic acid-enhanced MRI in patients with periampullary cancer. We included 72 patients (31 patients with 83 hepatic microabscesses and 41 patients with 71 hepatic metastases) who had a history of periampullary cancer and underwent gadoxetic acid-enhanced MRI. Image analysis was performed for margin, signal intensity, rim enhancement, perilesional hyperaemia, pattern on DWI and dynamic phases, and size discrepancy between sequences by consensus of two observers. Multivariate analysis revealed that the following significant parameters favour microabscess: a history of bile duct cancer, perilesional hyperaemia, persistent arterial rim enhancement through the transitional phase (TP), and size discrepancy between T1WI and T2WI and between T1WI and hepatobiliary phase image (HBPI). The diagnostic accuracy for microabscess was highest (90.9%) when showing a size discrepancy ≥30% between T1WI and HBPI or persistent arterial rim enhancement through the TP. When the lesion was positive for both these variables, specificity reached 100%. The combination of a size discrepancy between T1WI and HBPI and persistent arterial rim enhancement through the TP represents a reliable MRI feature for distinguishing between hepatic microabscess and metastasis in patients with periampullary cancer. (orig.)

  10. 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

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

    Directory of Open Access Journals (Sweden)

    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

  12. A Cytosolic Amphiphilic α-Helix Controls the Activity of the Bile Acid-sensitive Ion Channel (BASIC)*

    Science.gov (United States)

    Schmidt, Axel; Löhrer, Daniel; Alsop, Richard J.; Lenzig, Pia; Oslender-Bujotzek, Adrienne; Wirtz, Monika; Rheinstädter, Maikel C.; Gründer, Stefan; Wiemuth, Dominik

    2016-01-01

    The bile acid-sensitive ion channel (BASIC) is a member of the degenerin/epithelial Na+ channel (Deg/ENaC) family of ion channels. It is mainly found in bile duct epithelial cells, the intestinal tract, and the cerebellum and is activated by alterations of its membrane environment. Bile acids, one class of putative physiological activators, exert their effect by changing membrane properties, leading to an opening of the channel. The physiological function of BASIC, however, is unknown. Deg/ENaC channels are characterized by a trimeric subunit composition. Each subunit is composed of two transmembrane segments, which are linked by a large extracellular domain. The termini of the channels protrude into the cytosol. Many Deg/ENaC channels contain regulatory domains and sequence motifs within their cytosolic domains. In this study, we show that BASIC contains an amphiphilic α-helical structure within its N-terminal domain. This α-helix binds to the cytosolic face of the plasma membrane and stabilizes a closed state. Truncation of this domain renders the channel hyperactive. Collectively, we identify a cytoplasmic domain, unique to BASIC, that controls channel activity via membrane interaction. PMID:27679529

  13. Hierarchical self-assembly of photoluminescent CdS nanoparticles into a bile acid derived organogel: morphological and photophysical properties.

    Science.gov (United States)

    Chatterjee, Sayantan; Maitra, Uday

    2017-07-21

    We have described a strategy towards integrating photoluminescent semiconductor nanoparticles into a bio-surfactant derived organogel. A facially amphiphilic bile thiol was used for capping CdS nanoparticles (NPs) which were embedded in a bile acid derived new organogelator in order to furnish a soft hybrid material. The presence of CdS NPs in a well-ordered 1D array on the organogel network was confirmed using microscopic techniques. Photophysical studies of the gel-NP hybrid revealed resolved excitation and emission characteristics. Time resolved spectroscopic studies showed that the average lifetime value of the CdS NPs increased in the gel state compared to the sol phase. A kinetic model was utilized to obtain quantitative information about the different decay pathways of the photoexcited NPs in the sol and gel states.

  14. Allspice and Clove As Source of Triterpene Acids Activating the G Protein-Coupled Bile Acid Receptor TGR5

    Directory of Open Access Journals (Sweden)

    Angela Ladurner

    2017-07-01

    Full Text Available Worldwide, metabolic diseases such as obesity and type 2 diabetes have reached epidemic proportions. A major regulator of metabolic processes that gained interest in recent years is the bile acid receptor TGR5 (Takeda G protein-coupled receptor 5. This G protein-coupled membrane receptor can be found predominantly in the intestine, where it is mainly responsible for the secretion of the incretins glucagon-like peptide 1 (GLP-1 and peptide YY (PYY. The aim of this study was (i to identify plant extracts with TGR5-activating potential, (ii to narrow down their activity to the responsible constituents, and (iii to assess whether the intestinal microbiota produces transformed metabolites with a different activity profile. Chenodeoxycholic acid (CDCA served as positive control for both, the applied cell-based luciferase reporter gene assay for TGR5 activity and the biotransformation assay using mouse fecal slurry. The suitability of the workflow was demonstrated by the biotransformation of CDCA to lithocholic acid resulting in a distinct increase in TGR5 activity. Based on a traditional Tibetan formula, 19 plant extracts were selected and investigated for TGR5 activation. Extracts from the commonly used spices Syzygium aromaticum (SaroE, clove, Pimenta dioica (PdioE, allspice, and Kaempferia galanga (KgalE, aromatic ginger significantly increased TGR5 activity. After biotransformation, only KgalE showed significant differences in its metabolite profile, which, however, did not alter its TGR5 activity compared to non-transformed KgalE. UHPLC-HRMS (high-resolution mass spectrometry analysis revealed triterpene acids (TTAs as the main constituents of the extracts SaroE and PdioE. Identification and quantification of TTAs in these two extracts as well as comparison of their TGR5 activity with reconstituted TTA mixtures allowed the attribution of the TGR5 activity to TTAs. EC50s were determined for the main TTAs, i.e., oleanolic acid (2.2 ± 1.6

  15. Allspice and Clove As Source of Triterpene Acids Activating the G Protein-Coupled Bile Acid Receptor TGR5

    Science.gov (United States)

    Ladurner, Angela; Zehl, Martin; Grienke, Ulrike; Hofstadler, Christoph; Faur, Nadina; Pereira, Fátima C.; Berry, David; Dirsch, Verena M.; Rollinger, Judith M.

    2017-01-01

    Worldwide, metabolic diseases such as obesity and type 2 diabetes have reached epidemic proportions. A major regulator of metabolic processes that gained interest in recent years is the bile acid receptor TGR5 (Takeda G protein-coupled receptor 5). This G protein-coupled membrane receptor can be found predominantly in the intestine, where it is mainly responsible for the secretion of the incretins glucagon-like peptide 1 (GLP-1) and peptide YY (PYY). The aim of this study was (i) to identify plant extracts with TGR5-activating potential, (ii) to narrow down their activity to the responsible constituents, and (iii) to assess whether the intestinal microbiota produces transformed metabolites with a different activity profile. Chenodeoxycholic acid (CDCA) served as positive control for both, the applied cell-based luciferase reporter gene assay for TGR5 activity and the biotransformation assay using mouse fecal slurry. The suitability of the workflow was demonstrated by the biotransformation of CDCA to lithocholic acid resulting in a distinct increase in TGR5 activity. Based on a traditional Tibetan formula, 19 plant extracts were selected and investigated for TGR5 activation. Extracts from the commonly used spices Syzygium aromaticum (SaroE, clove), Pimenta dioica (PdioE, allspice), and Kaempferia galanga (KgalE, aromatic ginger) significantly increased TGR5 activity. After biotransformation, only KgalE showed significant differences in its metabolite profile, which, however, did not alter its TGR5 activity compared to non-transformed KgalE. UHPLC-HRMS (high-resolution mass spectrometry) analysis revealed triterpene acids (TTAs) as the main constituents of the extracts SaroE and PdioE. Identification and quantification of TTAs in these two extracts as well as comparison of their TGR5 activity with reconstituted TTA mixtures allowed the attribution of the TGR5 activity to TTAs. EC50s were determined for the main TTAs, i.e., oleanolic acid (2.2 ± 1.6 μM), ursolic

  16. Retention data of bile acids and their oxo derivatives in characterization of pharmacokinetic properties and in silico ADME modeling.

    Science.gov (United States)

    Trifunović, Jovana; Borčić, Vladan; Vukmirović, Saša; Kon, Svetlana Goločorbin; Mikov, Momir

    2016-09-20

    Information on ADME properties of examined bile acids and their oxo derivatives are scarce, although the interest for bile acids and their use in nanochemistry and macromolecular chemistry is increasing. The purpose of this research was to evaluate the lipophilicity, a crucial physicochemical parameter for describing ADME properties of selected bile acids and their oxo derivatives, and to compare two approaches: experimentally determined hydrophobicity parameters and calculated logP values. Commercially available bile acids - deoxycholic, chenodeoxycholic, hyodeoxycholic and ursodeoxycholic acid were used to synthesize oxo derivatives. Lipophilicity was evaluated in two solvent systems: toluene/ethanol and toluene/butanol. Retention parameters were acquired by normal-phase TLC. The correlations between calculated logP values obtained using five different software and experimentally determined hydrophobicity parameters (RM(0)(tol/eth), RM(0)(tol/but), b(tol/eth) and b(tol/but)) were examined. Correlation analysis confirmed significant dependence between experimental RM(0) values and software calculated parameters. Results suggest satisfactory intestinal absorption after oral administration for all of the examined compounds as well as low volumes of distribution, and high affinity for binding with plasma proteins. Penetration through blood-brain barrier and skin is not satisfactory. All of the examined compounds show high affinity for binding with G-protein coupled receptors and consequently inhibition of ionic channels. Results also suggest possible binding with nuclear receptors. Established lipophilicity testing model of studied compounds showed excellent predictive ability and might represent significant tool in development of relations between chromatographic behavior and ADME properties. Compounds 3α-hydroxy-7,12-dioxo-5β-cholanoic and 12α-hydroxy-3,7-dioxo-5β-cholanoic acid might be the most suitable candidates for further development studies (satisfactory

  17. Effects of long-term ingestion of difructose anhydride III (DFA III) on intestinal bacteria and bile acid metabolism in humans.

    Science.gov (United States)

    Minamida, Kimiko; Asakawa, Chikako; Sujaya, I Nengah; Kaneko, Maki; Abe, Ayumi; Sone, Teruo; Hara, Hiroshi; Asano, Kozo; Tomita, Fusao

    2006-02-01

    Changes in the intestinal microbiota of 10 human subjects with long-term ingestion of 3 g/d difructose anhydride III (DFA III; 4 persons, 2 months; 3 persons, 6 months; and 3 persons, 12 months) were examined by denaturing gradient gel electrophoresis (DGGE). According to the answers to questionnaires, the subjects were divided into two groups (constipated and normal). The DGGE profile was different for every individual and each subject had unique profiles of intestinal microbiota. In the DGGE profiles of constipated subjects, the intensities of bands related to Bacteroides spp. increased. Moreover, the DFA III-assimilating bacteria, Ruminococcus sp. were isolated from subjects who ingested DFA III for 12 months. These strains showed 95% similarity of their 16S rDNA sequences with that of Ruminococcus obeum ATCC 29174(T) (X85101) and produced large amounts of acetic acid. DFA III ingestion for 2 months tended to increase total organic acids in feces, and tended to decrease fecal pH and the secondary bile acid (SBA) ratio in total bile acids. The SBA ratio in total bile acids corresponded to fecal pH. The production of SBA was decreased by low pH in vitro. These results indicated that DFA III ingestion in humans tended to lower intestinal pH, inhibited bile acid 7alpha-dehydroxylation activities and also tended to decrease the SBA ratios in total bile acids. Moreover, as another cause for the decrease in the SBA ratio in total bile acids, it was suggested that the number of bile acid 7alpha-dehydroxylating bacteria were decreased by DFA III ingestion.

  18. Acute liver effects, disposition and metabolic fate of [14C]-fenclozic acid following oral administration to normal and bile-cannulated male C57BL/6J mice.

    Science.gov (United States)

    Pickup, Kathryn; Martin, Scott; Partridge, Elizabeth A; Jones, Huw B; Wills, Jonathan; Schulz-Utermoehl, Tim; McCarthy, Alan; Rodrigues, Alison; Page, Chris; Ratcliffe, Kerry; Sarda, Sunil; Wilson, Ian D

    2017-07-01

    The distribution, metabolism, excretion and hepatic effects of the human hepatotoxin fenclozic acid were investigated following single oral doses of 10 mg/kg to normal and bile duct-cannulated male C57BL/6J mice. Whole body autoradiography showed distribution into all tissues except the brain, with radioactivity still detectable in blood, kidney and liver at 72 h post-dose. Mice dosed with [14C]-fenclozic acid showed acute centrilobular hepatocellular necrosis, but no other regions of the liver were affected. The majority of the [14C]-fenclozic acid-related material recovered was found in the urine/aqueous cage wash, (49%) whilst a smaller portion (13%) was eliminated via the faeces. Metabolic profiles for urine, bile and faecal extracts, obtained using liquid chromatography and a combination of mass spectrometric and radioactivity detection, revealed extensive metabolism of fenclozic acid in mice that involved biotransformations via both oxidation and conjugation. These profiling studies also revealed the presence of glutathione-derived metabolites providing evidence for the production of reactive species by mice administered fenclozic acid. Covalent binding to proteins from liver, kidney and plasma was also demonstrated, although this binding was relatively low (less than 50 pmol eq./mg protein).

  19. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  1. Mice Abundant in Muricholic Bile Acids Show Resistance to Dietary Induced Steatosis, Weight Gain, and to Impaired Glucose Metabolism.

    Directory of Open Access Journals (Sweden)

    Ylva Bonde

    Full Text Available High endogenous production of, or treatment with muricholic bile acids, strongly reduces the absorption of cholesterol. Mice abundant in muricholic bile acids may therefore display an increased resistance against dietary induced weight gain, steatosis, and glucose intolerance due to an anticipated general reduction in lipid absorption. To test this hypothesis, mice deficient in steroid 12-alpha hydroxylase (Cyp8b1-/- and therefore abundant in muricholic acids were monitored for 11 weeks while fed a high fat diet. Food intake and body and liver weights were determined, and lipids in liver, serum and feces were measured. Further, responses during oral glucose and intraperitoneal insulin tolerance tests were evaluated. On the high fat diet, Cyp8b1-/- mice displayed less weight gain compared to wildtype littermates (Cyp8b1+/+. In addition, liver enlargement with steatosis and increases in serum LDL-cholesterol were strongly attenuated in Cyp8b1-/- mice on high fat diet. Fecal excretion of cholesterol was increased and there was a strong trend for doubled fecal excretion of free fatty acids, while excretion of triglycerides was unaltered, indicating dampened lipid absorption. On high fat diet, Cyp8b1-/- mice also presented lower serum glucose levels in response to oral glucose gavage or to intraperitoneal insulin injection compared to Cyp8b1+/+. In conclusion, following exposure to a high fat diet, Cyp8b1-/- mice are more resistant against weight gain, steatosis, and to glucose intolerance than Cyp8b1+/+ mice. Reduced lipid absorption may in part explain these findings. Overall, the results suggest that muricholic bile acids may be beneficial against the metabolic syndrome.

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

    Science.gov (United States)

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

    2015-04-01

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

  3. Branched-chain amino acids for people with hepatic encephalopathy

    DEFF Research Database (Denmark)

    Gluud, Lise Lotte; Dam, Gitte; Les, Iñigo

    2015-01-01

    -chain amino acids (BCAA) versus control interventions has evaluated if BCAA may benefit people with hepatic encephalopathy. OBJECTIVES: To evaluate the beneficial and harmful effects of BCAA versus any control intervention for people with hepatic encephalopathy. SEARCH METHODS: We identified trials through...... control, language, or publication status. DATA COLLECTION AND ANALYSIS: The authors independently extracted data based on published reports and collected data from the primary investigators. We changed our primary outcomes in this update of the review to include mortality (all cause), hepatic...

  4. Branched-chain amino acids for people with hepatic encephalopathy

    DEFF Research Database (Denmark)

    Gluud, Lise Lotte; Dam, Gitte; Les, Iñigo

    2017-01-01

    -chain amino acids (BCAA) versus control interventions has evaluated if BCAA may benefit people with hepatic encephalopathy. Objectives: To evaluate the beneficial and harmful effects of BCAA versus any control intervention for people with hepatic encephalopathy. Search methods: We identified trials through...... included randomised clinical trials, irrespective of the bias control, language, or publication status. Data collection and analysis: The authors independently extracted data based on published reports and collected data from the primary investigators. We changed our primary outcomes in this update...

  5. Feeding of the water extract from Ganoderma lingzhi to rats modulates secondary bile acids, intestinal microflora, mucins, and propionate important to colon cancer.

    Science.gov (United States)

    Yang, Yongshou; Nirmagustina, Dwi Eva; Kumrungsee, Thanutchaporn; Okazaki, Yukako; Tomotake, Hiroyuki; Kato, Norihisa

    2017-09-01

    Consumption of reishi mushroom has been reported to prevent colon carcinogenesis in rodents, although the underlying mechanisms remain unclear. To investigate this effect, rats were fed a high-fat diet supplemented with 5% water extract from either the reishi mushroom (Ganoderma lingzhi) (WGL) or the auto-digested reishi G. lingzhi (AWGL) for three weeks. Both extracts markedly reduced fecal secondary bile acids, such as lithocholic acid and deoxycholic acid (colon carcinogens). These extracts reduced the numbers of Clostridium coccoides and Clostridium leptum (secondary bile acids-producing bacteria) in a per g of cecal digesta. Fecal mucins and cecal propionate were significantly elevated by both extracts, and fecal IgA was significantly elevated by WGL, but not by AWGL. These results suggest that the reishi extracts have an impact on colon luminal health by modulating secondary bile acids, microflora, mucins, and propionate that related to colon cancer.

  6. A technique for extraction and Thin Layer Chromatography visualization of fecal bile acids applied to neotropical felid scats

    Directory of Open Access Journals (Sweden)

    Ada Virginia Cazón Narvaez

    1999-06-01

    Full Text Available Fecal bile acid patterns have been used successfully to identify scats. Neotropical felid scats are capable of this biochemical identification because they present low concentrations of plant pigments that would interfere in fecal bile acids detection. However, neotropical felid scats have poor quantities of bile acids, so we developed in this work a proper technique for their extraction, visualization and determination. Twenty eighth feces of seven different felid species, collected from Zoological and Wildlife Parks, were dried and pulverized. The procedure for analyzing feces is : Take one g of pulverized feces and shake for 3 hr at room temperature in 20 ml benzene : methanol; filter and evaporate to 5 ml. Spot on TLC plate and develop in toluene :acetic acid:water. Dry and visualize with anisaldehyde. Field collected scats could be identified by the bile acids pattern revealed by this specific technique and ,then, used as a source of information for distribution, density and food habits studies.Los patrones de ácidos biliares fecales han sido utilizados satisfactoriamente para identificar heces. Las heces de félidos neotropicales son propicias para ser identificadas bioquímicamente, ya que contienen baja concentración de pigmentos vegetales que pudieran interferir en la detección de ácidos biliares. Sin embargo los ácidos biliares se encuentran en bajas concentraciones en las heces, por lo cual desarrollamos en este trabajo una técnica apropiada para su extracción, visualización y determinación. Veintiocho heces de diferentes félidos recolectadas de Zoológicos y Estaciones de Fauna Silvestre fueron secadas y pulverizadas. El procedimiento para analizar las heces es : Tomar un gramo de feca pulverizada y agitar en 20 ml de benceno :metanol a temperatura ambiente durante 3 hr ; luego filtrar y evaporar hasta 5 ml. Sembrar en placa de TLC y desarrollar en tolueno :ác. acético :agua. Secar y revelar con anisaldehído. Las heces

  7. Free fatty acids repress small heterodimer partner (SHP) activation and adiponectin counteracts bile acid-induced liver injury in superobese patients with nonalcoholic steatohepatitis.

    Science.gov (United States)

    Bechmann, Lars P; Kocabayoglu, Peri; Sowa, Jan-Peter; Sydor, Svenja; Best, Jan; Schlattjan, Martin; Beilfuss, Anja; Schmitt, Johannes; Hannivoort, Rebekka A; Kilicarslan, Alpaslan; Rust, Christian; Berr, Frieder; Tschopp, Oliver; Gerken, Guido; Friedman, Scott L; Geier, Andreas; Canbay, Ali

    2013-04-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in industrialized countries and may proceed to steatohepatitis (NASH). Apoptosis and free fatty acid (FFA)-induced lipotoxicity are important features of NASH pathogenesis. We have shown a hepatoprotective effect of adiponectin in steatotic livers of hepatitis C virus (HCV) patients and recent data links bile acid (BA) metabolism to the pathogenesis of NAFLD. The aim of this study was to identify potential interactions between BA and FFA metabolism in NAFLD. Liver biopsies and serum samples from 113 morbidly obese patients receiving bariatric surgery, healthy individuals, and moderately obese NAFLD patients were studied. Serum FFA, BA, and M30 were increased in NASH versus simple steatosis, while adiponectin was significantly decreased. The NAFLD activity score (NAS) score correlated with BA levels and reversely with adiponectin. Adiponectin reversely correlated with CD95/Fas messenger RNA (mRNA) and hepatocellular apoptosis. The BA transporter high-affinity Na+ /taurocholate cotransporter (NTCP) and the BA synthesizing enzyme cholesterol 7 alpha-hydroxylase (CYP7A1) were significantly up-regulated in obese patients and hepatoma cells exposed to FFA. Up-regulation of NTCP and CYP7A1 indicate failure to activate small heterodimer partner (SHP) upon farnesoid X receptor (FXR) stimulation by increasing BA concentrations. In line with the NAS score, adiponectin levels were reversely correlated with BA levels. Adiponectin correlated with NTCP and affects Cyp7A1 expression both in vivo and in vitro. BA synthesis and serum BA levels correlated with disease severity in NAFLD, while adiponectin is reversely correlated. FFA exposure prevented SHP-mediated repression of NTCP and Cyp7A1 expression, which lead to increased BA synthesis and uptake. In NASH, BA accumulation induced hepatocyte cell death and late FXR activation failed to prevent hepatocyte injury due to decreased adiponectin levels. Early

  8. Effects of preventative application of metformin on bile acid metabolism in high fat-fed/streptozotocin-diabetic rats.

    Science.gov (United States)

    Ding, Lin; Qu, Zhiping; Chi, Jinfeng; Shi, Rui; Wang, Lulu; Hou, Lulu; Wang, Yan; Pang, Shuguang

    2015-01-01

    This study was designed to investigate the effects of metformin on bile acid in type 2 diabetes mellitus (T2DM). In this study, we constructed a model of T2DM by a combination of high-fat diet (HFD) and low dose of streptozotocin (STZ) intraperitoneal injection. Blood samples by tail vein and eye angular vein were withdrawn before (time 0) and 30, 60, and 120 minutes after administration of glucose before STZ injection and once a week after diabetes induction, and were analyzed to evaluate the level of the fasting blood glucose and fasting insulin using glucometer. Triglyceride, low density lipoprotein cholesterin, high density lipoprotein cholesterin were detected by automatic biochemical analyzers. Total cholesterol and total bile acid (TBA) were analyzed using ELISA kits. Before STZ injection, the TBA level in HFD group was significantly higher relative to that in standard diet (SD) group and there was a moderate reduction of the TBA level in early intervention (EI) group 6 week after metformin administration comparing with that in HFD group but was still higher than that of SD group. However, after STZ injection, the TBA level was significantly higher in DM rats relative to that in normal control (NC) rats and the TBA level in late intervention (LI) (19.92 μmol/L) and EI rats (42.97 μmol/L) with metformin administration was significantly higher comparing with that in DM rats. The effects of metformin in plasma glucose and lipid metabolism might be associated with bile acid metabolism.

  9. In vivo therapeutic effect of combination treatment with metformin and Scutellaria baicalensis on maintaining bile acid homeostasis.

    Directory of Open Access Journals (Sweden)

    Kyungsun Han

    Full Text Available The radix of Scutellaria baicalensis (SB is a herb widely used in traditional Chinese medicine to treat metabolic diseases. Several main components, including baicalin and wogonoside, possess anti-dyslipidemia, anti-obesity and anti-diabetic effects. We hypothesized that co-administration of SB extract and metformin exerts a better effect on obesity-induced insulin resistance and lipid metabolism than treatment with metformin alone. We compared the effect of metformin (100 mg/10 mL/kg/day alone with co-administration of metformin (100 mg/5 mL/kg/day and SB extract (200 mg/5 mL/kg/day on Otsuka Long Evans Tokushima Fatty rats, a useful model of type II diabetes with obesity, and used Long-Evans Tokushima Otsuka rats as a control. Weight, fasting glucose, oral glucose tolerance test, intraperitoneal insulin tolerance test, and serum total cholesterol were measured after 12 weeks of drug administration. We observed a synergetic effect of metformin and SB on lowering cholesterol level by excretion of bile acid through feces. We found that this accompanied activation of FXR, CYP7A1 and LDLR genes and repression of HMGCR in the liver. Although there were no significant changes in BSH-active gut microbiota due to high variability, functional prediction with 16S sequences showed increased primary and secondary bile acid biosynthesis in the combination treatment group. Further study is needed to find the specific strains of bacteria which contribute to FXR-related cholesterol and bile acid regulations.

  10. Effect of Bile Acid Sequestrants on the Risk of Cardiovascular Events: A Mendelian Randomization Analysis.

    Science.gov (United States)

    Ross, Stephanie; D'Mello, Matthew; Anand, Sonia S; Eikelboom, John; Stewart, Alexandre F R; Samani, Nilesh J; Roberts, Robert; Paré, Guillaume

    2015-08-01

    Statins lower low-density lipoprotein cholesterol (LDL-C) and risk of coronary artery disease (CAD), but they may be ineffective or not tolerated. Bile acid sequestrants (BAS) reduce LDL-C, yet their clinical efficacy on CAD remains controversial. We conducted a systematic review and meta-analysis of randomized controlled trials to assess the effect of cholestyramine and colesevelam. We then used Mendelian randomization to estimate the effect of BAS on reducing the risk of CAD. First, we quantified the effect of rs4299376 (ABCG5/ABCG8), which affects the intestinal cholesterol absorption pathway targeted by BAS and then we used these estimates to predict the effect of BAS on CAD. Nineteen randomized controlled trials with a total of 7021 study participants were included. Cholestyramine 24 g/d was associated with a reduction in LDL-C of 23.5 mg/dL (95% confidence interval [CI] -26.8,-20.2; N=3806) and a trend toward reduced risk of CAD (odds ratio 0.81, 95% CI 0.70-1.02; P=0.07; N=3806), whereas colesevelam 3.75 g/d was associated with a reduction in LDL-C of 22.7 mg/dL (95% CI -28.3, -17.2; N=759). Based on the findings that rs4299376 was associated with a 2.75 mg/dL decrease in LDL-C and a 5% decrease in risk of CAD outcomes, we estimated that cholestyramine was associated with an odds ratio for CAD of 0.63 (95% CI 0.52-0.77; P=6.3×10(-6)) and colesevelam with an odds ratio of 0.64 (95% CI 0.52-0.79, P=4.3×10(-5)), which were not statistically different from BAS clinical trials (P>0.05). The cholesterol lowering effect of BAS may translate into a clinically relevant reduction in CAD. © 2015 American Heart Association, Inc.

  11. [Relationship between total bile acid concentration and fetal pulmonary surfactant in intrahepatic cholestasis of pregnancy].

    Science.gov (United States)

    Yu, Ling; Ding, Yi-ling; Wang, Chang-xiu

    2011-05-01

    To explore the relationship between total bile acid (TBA) concentration and fetal pulmonary surfactant in intrahepatic cholestasis of pregnancy (ICP). Fifty five patients with ICP (ICP group) who received cesarean section from April 2008 to February 2010 in Second Xiangya Hospital, Central South University, were recruited. The general conditions of the neonates within 7 days after birth in ICP group were recorded. Those with fetal distress, neonatal asphyxia, or neonatal respiratory distress syndrome were referred as pathological neonates, others were referred as normal neonates. Over the same period, 23 healthy gravidas were recruited as control group. Enzymatic method was used to detect the TBA concentrations in maternal blood, cord blood and amniotic fluid. ELISA was employed to measure the urfactant protein A (SP-A) concentration in cord blood. High performance liquid chromatography system was used to detect the concentrations of phosphatidylcholine (PC), phosphatidylinositol (PI), lysophosphatidylcholine (LPC), and sphingomyelin (SM) in amniotic fluid. (1) The concentrations of TBA in maternal blood, cord blood and amniotic fluid were (30.1 ± 7.9), (9.3 ± 3.3) and (4.4 ± 1.5) mmol/L in ICP group, (4.8 ± 2.2), (4.9 ± 0.9) and (1.4 ± 1.1) mmol/L in control group, respectively. The differences between the two groups were significant (P neonates and 35 normal neonates in ICP group. In pathological neonates, the concentrations of TBA and SP-A in cord blood were (10.9 ± 2.2) mmol/L, (37.0 ± 5.9) µg/L, respectively; and were (8.0 ± 2.8) mmol/L, (26.7 ± 4.8) µg/L in normal neonates. The differences were significant (P 0.05). (6)The ratio of PC/LPC in ICP group (14.2 ± 3.2) was significantly lower than that in control group (16.9 ± 2.5) (P 0.05). (1) The fetal TBA concentrations in both cord blood and amniotic fluid of patients with ICP was higher than those of healthy gravidas, they were also positively correlated with maternal TBA concentration. (2) ICP

  12. Influence of pregnancy, oophorectomy and contraceptive steroids on gall bladder concentrating function and hepatic bile flow in the cat.

    OpenAIRE

    Rådberg, G; Svanvik, J

    1986-01-01

    Pregnancy and contraceptive steroids are associated with a raised incidence of cholesterol gall stone disease. In pregnancy there is an increase in the size of the gall bladder. Investigation of hepatobiliary function in man and mammals has not established if the enlarged gall bladder is simply dilated, or if the absorptive capacity of the mucosa has changed. In the present study the concentrating function of the gall bladder and bile secretion from the liver were studied in pregnant animals,...

  13. Bile acid receptor TGR5 agonism induces NO production and reduces monocyte adhesion in vascular endothelial cells.

    Science.gov (United States)

    Kida, Taiki; Tsubosaka, Yoshiki; Hori, Masatoshi; Ozaki, Hiroshi; Murata, Takahisa

    2013-07-01

    TGR5 is a G-protein-coupled receptor for bile acids. So far, little is known about the function of TGR5 in vascular endothelial cells. In bovine aortic endothelial cells, treatment with a bile acid having a high affinity to TGR5, taurolithocholic acid (TLCA), significantly increased NO production. This effect was abolished by small interfering RNA-mediated depletion of TGR5. TLCA-induced NO production was also observed in human umbilical vein endothelial cells measured via intracellular cGMP accumulation. TLCA increased endothelial NO synthase(ser1177) phosphorylation in human umbilical vein endothelial cells. This response was accompanied by increased Akt(ser473) phosphorylation and intracellular Ca(2+). Inhibition of these signals significantly decreased TLCA-induced NO production. We next examined whether TGR5-mediated NO production affects inflammatory responses of endothelial cells. In human umbilical vein endothelial cells, TLCA significantly reduced tumor necrosis factor-α-induced adhesion of monocytes, vascular cell adhesion molecule-1 expression, and activation of nuclear factor-κB. TLCA also inhibited lipopolysaccharide-induced monocyte adhesion to mesenteric venules in vivo. These inhibitory effects of TLCA were abrogated by NO synthase inhibition. TGR5 agonism induces NO production via Akt activation and intracellular Ca(2+) increase in vascular endothelial cells, and this function inhibits monocyte adhesion in response to inflammatory stimuli.

  14. Bile duct adenoma and von Meyenburg complex-like duct arising in hepatitis and cirrhosis: pathogenesis and histological characteristics.

    Science.gov (United States)

    Aishima, Shinichi; Tanaka, Yuki; Kubo, Yuichiro; Shirabe, Ken; Maehara, Yoshihiko; Oda, Yoshinao

    2014-11-01

    Morphologic features and neoplastic potentials of bile duct adenoma (BDA) and von Meyenburg complex (VMC)-like duct arising in chronic liver disease were unknown. Thirty-five BDAs and 12 VMC-like duct lesions were observed in 39 cases with chronic liver disease. BDAs were divided into the EMA-cytoplasmic type (n = 14) and EMA-luminal type (n = 21). EMA-cytoplasmic BDA composed of a proliferation of cuboidal to low-columnar cells forming an open lumen with NCAM(+)/MUC6(-), resembling an interlobular bile duct. EMA-luminal BDA showed uniform cuboidal cells with narrow lumen, and NCAM(++)/MUC6(++), resembling a ductular reaction. VMC-like duct showed positive MUC1 expression and negative MUC6. The expression of S100P, glucose transporter-1 (GLUT-1) and insulin-like growth factor II mRNA-binding protein 3 (IMP-3) were not detected in three lesions. p16 expression was higher than those of the ductular reaction, and the Ki67 and p53 indexes were very low (bile duct type; BDA, ductular/peribiliary gland type; and VMC-like duct. They may be reactive proliferation rather than neoplastic lesions. © 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.

  15. Uric acid contributes greatly to hepatic antioxidant capacity besides protein.

    Science.gov (United States)

    Mikami, T; Sorimachi, M

    2017-12-20

    Uric acid is the end-product of purine nucleotide metabolism and an increase in uric acid concentration in the body results in hyperuricemia, ultimately leading to gout. However, uric acid is a potent antioxidant and interacts with reactive oxygen species (ROS) to be non-enzymatically converted to allantoin. Uric acid accounts for approximately 60 % of antioxidant capacity in the plasma; however, its contribution to tissue antioxidant capacity is unknown. In this study, the contribution of uric acid to tissue antioxidant capacity and its conversion to allantoin by scavenging ROS in tissue were examined. The results showed that a decrease in hepatic uric acid content via allopurinol administration significantly reduced hepatic total-radical trapping antioxidant parameter (TRAP) content in protein-free cytosol. Additionally, treating protein-free cytosol with uricase led to a further reduction of hepatic TRAP content. Allantoin was also detected in the solution containing protein-free cytosol that reacted with ROS. These findings suggest that in the absence of protein, uric acid contributes greatly to antioxidant capacity in the liver, where uric acid is converted to allantoin by scavenging ROS.

  16. The effect of bile acids and piroxicam on MHC antigen expression in rat colonocytes during colon cancer development.

    Science.gov (United States)

    Rigas, B; Tsioulias, G J; Allan, C; Wali, R K; Brasitus, T A

    1994-10-01

    The effect of bile acids and piroxicam on the expression of major histocompatibility complex (MHC) antigens in colonocytes was evaluated in rats treated with the colonic carcinogen azoxymethane (AOM). Male Fischer-344 rats were fed a basal diet (AIN-76) supplemented with 0.4% cholic acid, 0.4% ursodeoxycholic acid, 0.2% ursodeoxycholic acid plus 0.2% cholic acid, or 75 p.p.m. piroxicam. Rats were injected subcutaneously once a week for 2 weeks with AOM (15 mg/kg body weight/week) or vehicle, after being fed their respective diets for two weeks. The rats were killed at 16 weeks, while parallel identical groups of rats were killed at 28 weeks, and colon tumours were counted. None of the rats treated with AOM-vehicle developed tumours at 28 weeks, while in the AOM-treated rats the frequency of colonic tumours was as follows: AOM alone 50%, cholic acid 74%, ursodeoxycholic acid 17%, piroxicam 28%, ursodeoxycholic plus cholic acid 46%. The expression of RT1A, RT1B and RT1D was determined in isolated colonocytes by immune fluocytometry. Normal rat colonocytes express all three MHC antigens strongly. Neither the bile acids nor piroxicam affected MHC antigen expression in AOM-vehicle-treated rats. AOM did not effect MHC antigen expression compared to normal controls. Cholic acid had no significant effect on the expression of MHC antigens in AOM-treated rats. Ursodeoxycholic acid alone or in combination with cholic acid increased the expression of RT1A compared to normal controls, of RT1B compared to AOM-treated rats, and of RT1D compared to controls or AOM-treated rats. Piroxicam increased the expression of all three antigens compared to either control or AOM-treated rats. These findings indicate that (1) ursodeoxycholic acid and piroxicam up-regulate colonic MHC antigen expression in the AOM model of colonic carcinogenesis; (2) the colon of rats exposed to AOM responds differently than the normal colon with respect to MHC regulation; and (3) the protective effect of

  17. 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.

  18. Amaranth oil increased fecal excretion of bile Acid but had no effect in reducing plasma cholesterol in hamsters.

    Science.gov (United States)

    de Castro, Luíla Ivini Andrade; Soares, Rosana Aparecida Manólio; Saldiva, Paulo H N; Ferrari, Roseli A; Miguel, Ana M R O; Almeida, Claudia A S; Arêas, José Alfredo Gomes

    2013-06-01

    Hamsters were fed for 4 weeks on four different diets: control (C) (balanced diet containing 20 % corn oil as the lipid source), hypercholesterolemic (H) (identical to C but containing 12 % coconut oil, 8 % corn oil and 0.1 % cholesterol as the lipid source), amaranth oil (A) (identical to H without corn oil but with amaranth oil), and squalene (S) (identical to H but admixed with squalene in the ratio found in amaranth oil). There were no significant differences in lipid profile, and in the cholesterol excreted in the animals' feces from amaranth oil (A) and squalene (S) groups. Fecal excretion of bile acids was greater in the amaranth oil (A) and squalene groups (S) as compared to the other groups. The scores of steatosis and parenchymal inflammation observed in the amaranth oil (A) and squalene groups (S) were superior to the ones observed in the other groups. Our findings demonstrated that amaranth oil, and its component squalene, increased the excretion of bile acids but did not have a hypocholesterolemic effect in hamsters fed on a diet containing high amounts of saturated fat and cholesterol.

  19. 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.

  20. Absorption enhancement, mechanistic and toxicity studies of medium chain fatty acids, cyclodextrins and bile salts as peroral absorption enhancers.

    Science.gov (United States)

    Sharma, Pradeep; Varma, Manthena V S; Chawla, Harmander P S; Panchagnula, Ramesh

    2005-01-01

    The objective of the present investigation was to evaluate an oral 'drug delivery' approach, which involves co-administration of absorption enhancers (AEs). The representative low permeable hydrophilic (biopharmaceutic classification system (BCS) Class III) drugs used in the study comprised of cefotaxime sodium and ceftazidime pentahydrate, whereas low permeable lipophilic (BCS Class IV) drugs include cyclosporin A and lovastatin. AEs from three different chemical classes, namely, medium chain fatty acids (sodium caprylate and caprate), cyclodextrins (beta-cyclodextrin, hydroxypropyl beta-cyclodextrin) and bile salts (sodium cholate and deoxycholate) were evaluated for absorption enhancement efficacy, mechanism of action and toxicity using in vitro everted intestinal sac model. These AEs were found to enhance intestinal permeability of drugs from 2- to 27-fold. Light microscopy studies of intestinal sac incubated with AEs for 120 min revealed morphological changes in absorptive mucosa and rank order of toxicity were cyclodextrins>bile salts congruent with medium chain fatty acids. Fluorescence polarization studies indicated that brush bordered membrane vesicles labeled with lipophilic (DPH, 12AS) and hydrophilic dyes (ANS), when treated with AEs exhibited concentration and time dependent decrease in fluorescence polarization. Total protein released in presence of AEs was more than control but considerably less than EDTA (0.58% w/v), which is known to cause toxic release of proteins from cell. Overall, AEs were found to significantly enhance drug permeability by decreasing lipid membrane fluidity and/or interacting with hydrophilic domains of membrane, and has the potential to improve oral delivery.

  1. Effect of sulfonylureas on hepatic fatty acid oxidation

    Energy Technology Data Exchange (ETDEWEB)

    Patel, T.B.

    1986-08-01

    In isolated rat livers perfused with oleic acid (0.1 mM), infusion of tolbutamide or glyburide decreased the rate of ketogenesis in a dose-dependent manner. The inhibition of fatty acid oxidation was maximal at 2.0 mM and 10 M concentrations of tolbutamide and glyburide, respectively. Neither tolbutamide nor glyburide inhibited ketogenesis in livers perfused with octanoate. The inhibition of hepatic ketogenesis by sulfonylureas was independent of perfusate oleic acid concentration. Additionally, in rat livers perfused with oleic acid in the presence of L-(-)-carnitine (10 mM), submaximal concentrations of tolbutamide and glyburide did not inhibit hepatic ketogenesis. Finally, glyburide infusion into livers perfused with (U- $C)oleic acid (0.1 mM) increased the rate of UC label incorporation into hepatic triglycerides by 2.5-fold. These data suggest that both tolbutamide and glyburide inhibit long-chain fatty acid oxidation by inhibition the key regulatory enzyme, carnitine palmitoyltransferase I, most probably by competing with L-(-)-carnitine.

  2. The influence of severity of bile flow reduction, cycloheximide, and methyl isobutyl ketone pretreatment on the kinetics of taurolithocholic acid disposition in the rat.

    Science.gov (United States)

    Dahlström-King, L; du Souich, P; Couture, J; Plaa, G L

    1990-06-15

    Pretreatment of rats with methyl isobutyl ketone (MIBK) potentiates the effect of taurolithocholic acid (TLCA) on bile flow, while cycloheximide pretreatment diminishes the cholestatic response. Experiments were performed to determine if the effects of the pretreatments were related to changes in the kinetic disposition of TLCA. Groups of rats were pretreated daily with either 7.5 mmol MIBK/kg po for 3 days or 3.55 mumol cycloheximide/kg ip for 2 days prior to an iv challenge of TLCA. Bile and blood samples were collected for 3 hr and the blood concentrations and biliary excretion of TLCA monitored. The severity of the bile flow reduction had a marked effect on the kinetic pattern of TLCA. The volume of distribution and bile disposition constant of TLCA decreased inversely with the severity of bile flow reduction, while the blood disposition constant increased. The total clearance of TLCA was not affected, but increasing the severity of the cholestasis altered the contribution of biliary and extrabiliary clearance to total clearance. The changes in the kinetics of TLCA observed in MIBK- and cycloheximide-pretreated rats were consistent with the effects the pretreatments exerted on TLCA-induced reduction in bile flow. They were interpreted to be the result of the effects of the pretreatments rather than their cause. Thus, pretreatment with MIBK and cycloheximide appears to exert a modulating effect on TLCA-induced cholestasis by mechanisms unrelated to an alteration of TLCA kinetic profile.

  3. 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...... (T2D) patients and 12 normal glucose tolerant (NGT) subjects participated in the study. Intervention: A 4-hour liquid meal test was performed before and 1 week, 3 months, and 1 year after RYGB. Main Outcome Measures: We measured fasting and postprandial TBA and FGF19 concentrations. Results: Fasting...... TBA concentrations decreased in NGT subjects (P

  4. Synthesis, Spectroscopic and Theoretical Studies of New Quasi-Podands from Bile Acid Derivatives Linked by 1,2,3-Triazole Rings

    Directory of Open Access Journals (Sweden)

    Tomasz Pospieszny

    2014-02-01

    Full Text Available A novel method for the synthesis of bile acid derivatives has been developed using “click chemistry”. Intermolecular 1,3-dipolar cycloaddition of the propargyl ester of bile acids and azide groups of 1,3,5-tris(azidomethylbenzene gave a new quasi-podands with 1,2,3-triazole rings. The structures of the products were confirmed by spectral (1H-NMR, 13C-NMR, and FT-IR analysis, mass spectrometry and PM5 semiempirical methods. Estimation of the pharmacotherapeutic potential has been accomplished for synthesized compounds on the basis of Prediction of Activity Spectra for Substances (PASS.

  5. [Neutralizing capacity, pepsin inactivation and binding to bile acids and lysolecithin of the antacid magaldrate (author's transl)].

    Science.gov (United States)

    Baur, C; Becker, A; Linder, R; Schwan, T

    1981-01-01

    The neutralizing capacity of pentaaluminum-decamagnesiumhentriacontahydroxide-bis(sulfate)-hydrate (magaldrate, Riopan), a stable Al-Mg-hydroxide mono-substance, determined by a modification of the method described in literature, surpasses the efficacy index (mval divided by g) of various commercial antacids. These results coincide with the findings of other workers. The intragastric pH is rapidly and consistently raised to a value between 3 and 5 which is not exceeded (no acid rebound). Due to this fact, pepsin is inactivated and finally adsorbed by magaldrate. Moreover, magaldrate binds a considerable amount of substances contained in duodeno-gastric reflux, such as bile acids and lysolecithin (aggressors in case of gastritis, peptic ulcer, stress ulcer, peptic esophagitis).

  6. The importance of serum bile acid level analysis and treatment with ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a case series from central Europe.

    Science.gov (United States)

    Ambros-Rudolph, Christina M; Glatz, Martin; Trauner, Michael; Kerl, Helmut; Müllegger, Robert R

    2007-06-01

    Intrahepatic cholestasis of pregnancy (ICP) is a severely pruritic form of reversible cholestasis that is associated with significant fetal risks. Because precise diagnostic and therapeutic guidelines are lacking, we performed a retrospective investigation of dermatologic and biochemical features, treatment, and neonatal outcome in patients with ICP seen from 2000 through 2005 at a university-based dermatologic hospital in central Europe. The 13 observed cases of ICP (11 patients) represented 6% of all pregnancy-associated dermatoses at our department. Intrahepatic cholestasis of pregnancy started at a mean+/-SD of 30+/-4 weeks' gestation, with pruritus as the leading symptom, followed by secondary skin lesions in 11 cases (85%). Total serum bile acid levels were markedly elevated in all patients and correlated with impaired fetal prognosis. Only 10 cases (77%) had other liver function test result abnormalities. Fetal distress occurred in 3 pregnancies (23%). In the 10 cases treated with ursodeoxycholic acid, 3 (30%) involved preterm deliveries compared with a 100% preterm delivery rate in the cases not treated with ursodeoxycholic acid. Severe pruritus with or without skin changes in the second half of pregnancy should alert the physician to the possibility of ICP. Elevated total serum bile acid levels are the clue to diagnosis, which should be established as early as possible. Close obstetric surveillance and prompt treatment with ursodeoxycholic acid are warranted.

  7. Hepatic Fatty Acid Oxidation Restrains Systemic Catabolism during Starvation

    Directory of Open Access Journals (Sweden)

    Jieun Lee

    2016-06-01

    Full Text Available The liver is critical for maintaining systemic energy balance during starvation. To understand the role of hepatic fatty acid β-oxidation on this process, we generated mice with a liver-specific knockout of carnitine palmitoyltransferase 2 (Cpt2L−/−, an obligate step in mitochondrial long-chain fatty acid β-oxidation. Fasting induced hepatic steatosis and serum dyslipidemia with an absence of circulating ketones, while blood glucose remained normal. Systemic energy homeostasis was largely maintained in fasting Cpt2L−/− mice by adaptations in hepatic and systemic oxidative gene expression mediated in part by Pparα target genes including procatabolic hepatokines Fgf21, Gdf15, and Igfbp1. Feeding a ketogenic diet to Cpt2L−/− mice resulted in severe hepatomegaly, liver damage, and death with a complete absence of adipose triglyceride stores. These data show that hepatic fatty acid oxidation is not required for survival during acute food deprivation but essential for constraining adipocyte lipolysis and regulating systemic catabolism when glucose is limiting.

  8. High fat feeding induces hepatic fatty acid elongation in mice.

    Directory of Open Access Journals (Sweden)

    Maaike H Oosterveer

    Full Text Available BACKGROUND: High-fat diets promote hepatic lipid accumulation. Paradoxically, these diets also induce lipogenic gene expression in rodent liver. Whether high expression of these genes actually results in an increased flux through the de novo lipogenic pathway in vivo has not been demonstrated. METHODOLOGY/PRINCIPAL FINDINGS: To interrogate this apparent paradox, we have quantified de novo lipogenesis in C57Bl/6J mice fed either chow, a high-fat or a n-3 polyunsaturated fatty acid (PUFA-enriched high-fat diet. A novel approach based on mass isotopomer distribution analysis (MIDA following 1-(13C acetate infusion was applied to simultaneously determine de novo lipogenesis, fatty acid elongation as well as cholesterol synthesis. Furthermore, we measured very low density lipoprotein-triglyceride (VLDL-TG production rates. High-fat feeding promoted hepatic lipid accumulation and induced the expression of lipogenic and cholesterogenic genes compared to chow-fed mice: induction of gene expression was found to translate into increased oleate synthesis. Interestingly, this higher lipogenic flux (+74 microg/g/h for oleic acid in mice fed the high-fat diet was mainly due to an increased hepatic elongation of unlabeled palmitate (+66 microg/g/h rather than to elongation of de novo synthesized palmitate. In addition, fractional cholesterol synthesis was increased, i.e. 5.8+/-0.4% vs. 8.1+/-0.6% for control and high fat-fed animals, respectively. Hepatic VLDL-TG production was not affected by high-fat feeding. Partial replacement of saturated fat by fish oil completely reversed the lipogenic effects of high-fat feeding: hepatic lipogenic and cholesterogenic gene expression levels as well as fatty acid and cholesterol synthesis rates were normalized. CONCLUSIONS/SIGNIFICANCE: High-fat feeding induces hepatic fatty acid synthesis in mice, by chain elongation and subsequent desaturation rather than de novo synthesis, while VLDL-TG output remains unaffected

  9. Control of bovine hepatic fatty acid oxidation

    Energy Technology Data Exchange (ETDEWEB)

    Jesse, B.W.; Emery, R.S.; Thomas, J.W.

    1986-09-01

    Fatty acid oxidation by bovine liver slices and mitochondria was examined to determine potential regulatory sites of fatty acid oxidation. Conversion of 1-(/sup 14/C)palmitate to /sup 14/CO/sub 2/ and total (/sup 14/C)acid-soluble metabolites was used to measure fatty acid oxidation. Oxidation of palmitate (1 mM) was linear in both liver slice weight and incubation time. Carnitine stimulated palmitate oxidation; 2 mM dl-carnitine produced maximal stimulation of palmitate oxidation to both CO/sup 2/ and acid-soluble metabolites. Propionate (10 mM) inhibited palmitate oxidation by bovine liver slices. Propionate (.5 to 10 mM) had no effect on palmitate oxidation by mitochondria, but malonyl Coenzyme A, the first committed intermediate of fatty acid synthesis, inhibited mitochondrial palmitate oxidation (inhibition constant = .3 ..mu..M). Liver mitochonndrial carnitine palmitoyltransferase exhibited Michaelis constants for palmitoyl Coenzyme A and l-carnitine of 11.5 ..mu..M and .59 mM, respectively. Long-chain fatty acid oxidation in bovine liver is regulated by mechanisms similar to those in rats but adapted to the unique digestive physiology of the bovine.

  10. Microbiota-related Changes in Bile Acid & Tryptophan Metabolism are Associated with Gastrointestinal Dysfunction in a Mouse Model of Autism

    Directory of Open Access Journals (Sweden)

    Anna V. Golubeva

    2017-10-01

    Full Text Available Autism spectrum disorder (ASD is one of the most prevalent neurodevelopmental conditions worldwide. There is growing awareness that ASD is highly comorbid with gastrointestinal distress and altered intestinal microbiome, and that host-microbiome interactions may contribute to the disease symptoms. However, the paucity of knowledge on gut-brain axis signaling in autism constitutes an obstacle to the development of precision microbiota-based therapeutics in ASD. To this end, we explored the interactions between intestinal microbiota, gut physiology and social behavior in a BTBR T+ Itpr3tf/J mouse model of ASD. Here we show that a reduction in the relative abundance of very particular bacterial taxa in the BTBR gut – namely, bile-metabolizing Bifidobacterium and Blautia species, - is associated with deficient bile acid and tryptophan metabolism in the intestine, marked gastrointestinal dysfunction, as well as impaired social interactions in BTBR mice. Together these data support the concept of targeted manipulation of the gut microbiota for reversing gastrointestinal and behavioral symptomatology in ASD, and offer specific plausible targets in this endeavor.

  11. 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.

  12. Serum gamma glutamyl transferase as a specific indicator of bile duct lesions in the rat liver.

    Science.gov (United States)

    Leonard, T B; Neptun, D A; Popp, J A

    1984-08-01

    Serum gamma-glutamyl transferase (GGT), a marker of hepatic injury used extensively in humans, has been used rarely in rats because its specificity has not been previously defined. Studies were designed for investigation of the specificity of serum GGT activity with the use of cell type specific hepatotoxicants in Fischer 344 rats. Single necrogenic doses of CCl4, allyl alcohol (AA), and alpha-naphthylisothiocyanate (ANIT) were used to produce cell specific injury in centrilobular hepatocytes, periportal hepatocytes, and bile duct cells, respectively. Administration of CCl4 markedly increased serum activities of alanine aminotransferase (ALT), alkaline phosphatase (AP), and serum bile acid concentrations within 24 hours but had no effect on serum GGT activity. ANIT treatment increased serum GGT and AP activities and bile acid concentration 24 hours following administration. Allyl alcohol administration increased serum ALT activity but had no effect on GGT activity. Administration of ANIT in the diet at 0.01%, 0.022%, 0.047%, and 0.1% for 2, 4, and 6 weeks produced dose- and time-dependent increases in serum GGT activity which strongly correlated with quantitative increases in hepatic bile duct volume, which was determined morphometrically. These observations support the use of serum GGT activity in the rat as diagnostic of bile duct cell necrosis when increases are detected shortly after the insult and as an indicator of possible bile duct hyperplasia.

  13. Effects of pelleted or powdered diets containing soy protein or sodium caseinate on lipid concentrations and bile acid excretion in golden Syrian hamsters.

    Science.gov (United States)

    Butteiger, Dustie N; Krul, Elaine S

    2015-08-01

    Custom diets are a convenient vector for oral administration of test articles, but the processing and physical form of a diet can affect its nutritional properties and how it is consumed. Here, the authors evaluated the feeding behavior and physiology of golden Syrian hamsters fed diets of either soy or caseinate protein in pelleted or powdered forms for 28 d to determine whether dietary processing and form mediates the physiological effects of dietary proteins. The authors compared body weight, food consumption, serum cholesterol concentration, serum triglyceride concentration, fecal weight and fecal excretion of bile acids between treatment groups. Hamsters fed powdered diets showed higher food consumption than hamsters fed pelleted diets, regardless of protein source. Hamsters fed soy pelleted diets showed lower serum cholesterol concentration and higher fecal excretion of bile acid than hamsters fed caseinate pelleted diets, and serum cholesterol concentration correlated strongly with fecal excretion of bile acid. This correlation suggests that the physiological effects of soy protein on cholesterol and excretion of bile acid might be related or similarly mediated through diet. The differences observed between hamsters on different diets indicate that dietary form can influence both feeding behavior and the physiological effects of a diet in hamsters.

  14. Novel non-systemic inhibitor of ileal apical Na+-dependent bile acid transporter reduces serum cholesterol levels in hamsters and monkeys

    NARCIS (Netherlands)

    Kitayama, K.; Nakai, D.; Kono, K.; Hoop, A.G. van der; Kurata, H.; Wit, E.C. de; Cohen, L.H.; Inaba, T.; Kohama, T.

    2006-01-01

    1-{7-[(1-(3,5-Diethoxyphenyl)-3-{[(3,5-difluorophenyl)(ethyl)amino]carbo nyl}-4-oxo-1,4-dihydroquinolin-7-yl)oxy]heptyl}-1-methylpiperidinium bromide, R-146224, is a potent, specific ileum apical sodium-dependent bile acid transporter (ASBT) inhibitor; concentrations required for 50% inhibition of

  15. Acyl-coenzyme A : cholesterol acyltransferase inhibitor, avasimibe, stimulates bile acid synthesis and cholesterol 7 alpha-hydroxylase in cultured rat hepatocytes and in vivo in the rat

    NARCIS (Netherlands)

    Post, SM; Zoeteweij, JP; Bos, MHA; de Wit, ECM; Havinga, R; Kuipers, F; Princen, HMG

    Acyl-coenzyme A:cholesterol acyltransferase (ACAT) inhibitors are currently in clinical development as potential lipid-lowering and antiatherosclerotic agents. We investigated the effect of avasimibe (Cl- 1011), a novel ACAT inhibitor, on bile acid synthesis and cholesterol 7 alpha-hydroxylase in

  16. Lack of intestinal transport of [3H]-demethylphalloin: comparative studies with phallotoxins and bile acids on isolated small intestinal cells and ileal brush border membrane vesicles.

    Science.gov (United States)

    Petzinger, E; Burckhardt, G; Schwenk, M; Faulstich, H

    1982-08-01

    Several earlier studies suggested that the uptake of phallotoxins by liver cells is a carrier mediated process using a transport system normally handling bile acids (see Frimmer 1982). In this study we have shown whether ileal cells, well known to transport bile acids too, are able to take up phallotoxins. Isolated epithelial cells prepared from guinea pig ileum accumulated [14C]-cholate, whereas [3H]-demethylphalloin ([3H]-DMP) was not taken up. The same observation was made with isolated jejunal cells but the uptake of [14C]-cholate was much slower. [3H]-DMP, however, was partly bound to intestinal cells. This process was not inhibited by cholate, iodipamide, oligomycin and carbonylcyano-chlorophenylhydrazone (CCCP), compounds known to decrease the uptake of phallotoxins into liver cells. Substituting Na+ for choline+ and also Cl- for SCN- did not influence the binding of [3H]-DMP. Frozen intestinal cells from the guinea pig bound two time more [3H]-DMP after thawing compared with intact cells. Supplementary uptake experiments on isolated brush border membrane vesicles from rat ileum revealed that phalloidin does not inhibit taurocholate uptake and that taurocholate does not interfere with [3H]-DMP binding. The results suggest that [3H]-demethylphalloin is not recognized by the bile acid carrier of the guinea pig and the rat ileum. It is concluded that the transport system for bile acids present in ileal cell is different from that of liver cells.

  17. A study of the relationship between serum bile acids and propranolol pharmacokinetics and pharmacodynamics in patients with liver cirrhosis and in healthy controls

    NARCIS (Netherlands)

    Taegtmeyer, Anne B.; Haschke, Manuel; Tchambaz, Lydia; Buylaert, Mirabel; Tschöpl, Martin; Beuers, Ulrich; Drewe, Jürgen; Krähenbühl, Stephan

    2014-01-01

    The main objectives of the study were to determine the exposure and bioavailability of oral propranolol and to investigate their associations with serum bile acid concentration in patients with liver cirrhosis and in healthy controls. A further objective was to study the pharmacodynamics of

  18. 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

  19. The ABC-Type Multidrug Resistance Transporter LmrCD Is Responsible for an Extrusion-Based Mechanism of Bile Acid Resistance in Lactococcus lactis

    NARCIS (Netherlands)

    Zaidi, Arsalan Haseeb; Bakkes, Patrick J.; Lubelski, Jacek; Agustiandari, Herfita; Kuipers, Oscar P.; Driessen, Arnold J. M.

    2008-01-01

    Upon prolonged exposure to cholate and other toxic compounds, Lactococcus lactis develops a multidrug resistance phenotype that has been attributed to an elevated expression of the heterodimeric ABC-type multidrug transporter LmrCD. To investigate the molecular basis of bile acid resistance in L.

  20. In Oesophageal Squamous Cells Exposed to Acidic Bile Salt Medium, Omeprazole Inhibits IL-8 Expression through Effects on Nuclear Factor-κB and Activator Protein-1

    Science.gov (United States)

    Huo, Xiaofang; Zhang, Xi; Yu, Chunhua; Zhang, Qiuyang; Cheng, Edaire; Wang, David H.; Pham, Thai H.; Spechler, Stuart J.; Souza, Rhonda F.

    2013-01-01

    Objective Oesophagitis might result from the effects of chemokines produced by oesophageal cells in response to gastro-oesophageal reflux, and not solely from the direct, caustic effects of refluxed gastric juice. Proton pump inhibitors (PPIs) can block chemokine production through mechanisms independent of their antisecretory effects. We studied omeprazole effects on chemokine production by oesophageal epithelial cells exposed to acidic bile salts. Design Human primary and telomerase-immortalised oesophageal squamous cells were exposed to acidic bile salt medium with or without omeprazole pretreatment. Interleukin (IL)-8 expression was determined by RT-PCR and ELISA. IL-8 promoter activity was measured by luciferase reporter assay. Binding of NF-κB and AP-1 subunits to the IL-8 promoter was assessed by ChIP assay. Immune cell migration induced by conditioned medium was determined by a double-chamber migration assay system. Results Acidic bile salt medium caused oesophageal epithelial cells to express IL-8 mRNA and protein by activating the IL-8 promoter through NF-κB and AP-1 binding. Omeprazole inhibited that acidic bile salt-stimulated IL-8 expression by blocking the nuclear translocation of p65 (an NF-κB subunit) and by blocking the binding of p65, c-jun and c-fos (AP-1 subunits) to the IL-8 promoter. Omeprazole also blocked the ability of conditioned medium from cells exposed to acidic bile salts to induce immune cell migration. Conclusions In oesophageal squamous epithelial cells, omeprazole inhibits IL-8 expression through effects on NF-κB and AP-1 that are entirely independent of effects on gastric acid secretion. These previously unrecognized PPI effects might contribute to the healing of reflux oesophagitis. PMID:24048734

  1. Upregulation of the oncogene c-myc in Barrett’s adenocarcinoma: induction of c-myc by acidified bile acid in vitro

    Science.gov (United States)

    Tselepis, C; Morris, C D; Wakelin, D; Hardy, R; Perry, I; Luong, Q T; Harper, E; Harrison, R; Attwood, S E A; Jankowski, J A Z

    2003-01-01

    Background and aims: C-myc over expression is implicated in malignancy although to date this has not been studied in Barrett’s metaplasia. We sought to determine c-myc expression in the malignant progression of Barrett’s metaplasia and whether it may be induced by bile acids seen in gastro-oesophageal refluxate. Methods: C-myc protein and mRNA levels were assessed in 20 Barrett’s metaplasia and 20 oesophageal adenocarcinoma samples by western blotting and real time polymerase chain reaction. Levels of c-myc and proliferation were also assessed in cell lines OE21, OE33, SW-480, and TE-7 stimulated with pulses or continuous exposure to the bile acids deoxycholic acid and chenodeoxycholic acid. Results: C-myc protein was upregulated in 50% of Barrett’s metaplasia and 90% of oesophageal adenocarcinoma samples compared with squamous, gastric, and duodenal controls. C-myc immunolocalisation in Barrett’s metaplasia revealed discrete nuclear localisation, becoming more diffuse with progression from low to high grade dysplasia to adenocarcinoma. Both continual and pulsed bile acid induced c-myc at pH 4, with no effect at pH 7 or with acidified media alone. Pulsed bile acid treatment induced proliferation (p<0.05); in contrast, continuous exposure led to suppression of proliferation (p<0.05). Conclusions: We have shown upregulation of c-myc with malignant progression of Barrett’s metaplasia and suggest that acidified bile may be a novel agent responsible for induction of this oncogene. PMID:12524396

  2. Bile acid and inflammation activate gastric cardia stem cells in a mouse model of Barrett’s-like metaplasia

    Science.gov (United States)

    Quante, Michael; Bhagat, Govind; Abrams, Julian; Marache, Frederic; Good, Pamela; Lee, Michele D.; Lee, Yoomi; Friedman, Richard; Asfaha, Samuel; Dubeykovskaya, Zinaida; Mahmood, Umar; Figueiredo, Jose-Luiz; Kitajewski, Jan; Shawber, Carrie; Lightdale, Charles; Rustgi, Anil K.; Wang, Timothy C.

    2011-01-01

    Summary Esophageal adenocarcinoma (EAC) arises from Barrett esophagus (BE), intestinal-like columnar metaplasia linked to reflux esophagitis. In a transgenic mouse model of BE, esophageal overexpression of interleukin-1β phenocopies human pathology with evolution of esophagitis, Barrett’s-like metaplasia and EAC. Histopathology and gene signatures resembled closely human BE, with upregulation of TFF2, Bmp4, Cdx2, Notch1 and IL-6. The development of BE and EAC was accelerated by exposure to bile acids and/or nitrosamines, and inhibited by IL-6 deficiency. Lgr5+ gastric cardia stem cells present in BE were able to lineage trace the early BE lesion. Our data suggest that BE and EAC arise from gastric progenitors due to a tumor-promoting IL-1β-IL-6 signaling cascade and Dll1-dependent Notch signaling. PMID:22264787

  3. Total bile acid levels are associated with left atrial volume and cardiac output in patients with cirrhosis

    DEFF Research Database (Denmark)

    Voiosu, Andrei M; Wiese, Signe; Voiosu, Theodor A

    2018-01-01

    BACKGROUND AND AIMS: Bile acids (BAs) are potent signaling molecules involved in the regulation of several metabolic and functional aspects of cardiovascular homeostasis. BA pool alteration in cirrhosis may contribute toward the development of hemodynamic and cardiac disturbances. We aimed...... and diastolic dysfunction were rare in the cohort. Total BA levels associated with several echocardiographic parameters of the hyperdynamic syndrome in univariate analysis but only with left atrial volume in multivariate analysis (P=0.007). BA concentrations did not differ according to the presence...... of echocardiographically diagnosed cirrhotic cardiomyopathy in the two models tested. CONCLUSION: Total serum BA levels are associated with enlarged left atrial volume and markers of the hyperdynamic circulation in patients with cirrhosis irrespective of the etiology or the severity of liver disease....

  4. Modulation of fibroblast growth factor 19 expression by bile acids, meal replacement and energy drinks, milk, and coffee.

    Science.gov (United States)

    Styer, Amanda M; Roesch, Stephen L; Argyropoulos, George

    2014-01-01

    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. 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. 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.

  5. 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.

  6. Bile acid binding resin prevents fat accumulation through intestinal microbiota in high-fat diet-induced obesity in mice.

    Science.gov (United States)

    Kusumoto, Yukie; Irie, Junichiro; Iwabu, Kaho; Tagawa, Hirotsune; Itoh, Arata; Kato, Mari; Kobayashi, Nana; Tanaka, Kumiko; Kikuchi, Rieko; Fujita, Masataka; Nakajima, Yuya; Morimoto, Kohkichi; Sugizaki, Taichi; Yamada, Satoru; Kawai, Toshihide; Watanabe, Mitsuhiro; Oike, Yuichi; Itoh, Hiroshi

    2017-06-01

    Bile acid binding resin (BAR) absorbs intestinal bile acids, and improves obesity and metabolic disorders, but the precise mechanism remains to be clarified. Recent findings reveal that obesity is associated with skewed intestinal microbiota. Thus, we investigated the effect of BAR on intestinal microbiota and the role of microbiota in the prevention of obesity in high-fat diet-induced obesity in mice. Male Balb/c mice were fed a low-fat diet (LFD), high-fat diet (HFD), or HFD with BAR (HFD+BAR), and then metabolic parameters, caecal microbiota, and metabolites were investigated. The same interventions were conducted in germ-free and antibiotic-treated mice. The frequency of Clostridium leptum subgroup was higher in both HFD-fed and HFD+BAR-fed mice than in LFD-fed mice. The frequency of Bacteroides-Prevotella group was lower in HFD-fed mice than in LFD-fed mice, but the frequency was higher in HFD+BAR-fed mice than in HFD-fed mice. Caecal propionate was lower in HFD-fed mice than in LFD-fed mice, and higher in HFD+BAR-fed mice than in HFD-fed mice. HFD+BAR-fed mice showed lower adiposity than HFD-fed mice, and the reduction was not observed in germ-free or antibiotic-treated mice. Colonized germ-free mice showed a reduction in adiposity by BAR administration. Energy expenditure was lower in HFD-fed mice and higher in HFD+BAR-fed mice, but the increments induced by administration of BAR were not observed in antibiotic-treated mice. Modulation of intestinal microbiota by BAR could be a novel therapeutic approach for obesity. Copyright © 2017 Elsevier Inc. All rights reserved.