Bile Acid Metabolism

  • John Y. L. Chiang
Part of the Molecular Pathology Library book series (MPLB, volume 5)


Bile acids are physiological agents that facilitate biliary secretion of lipids and metabolites, and intestinal absorption of fat and nutrients. Bile acids are also signaling molecules that activate nuclear receptors and cell signaling pathways to regulate hepatic lipid metabolism and homeostasis. Bile acids are synthesized from cholesterol in the liver, stored in the gallbladder, secreted to the intestine and reabsorbed in the ileum, and transported back to the liver. This physiological process of enterohepatic circulation of bile acids is regulated by a complex network of membrane transport systems in the hepatocytes, cholangiocytes, and enterocytes. Bile acid-activated nuclear receptors, farnesoid X receptor (FXR), pregnane X receptor (PXR), and vitamin D receptor (VDR), play critical roles in regulation of key regulatory genes involved in bile acid metabolism in the liver and intestine. The bile acid receptors also regulate lipid, glucose, drugs, and energy metabolism. Inborn errors of bile acid synthesis cause neonatal liver diseases. Disruption of bile flow causes cholestatic liver diseases. Bile acids are therapeutic agents that have great potential for treating cholestasis, gallstone, fatty liver, cardiovascular diseases, obesity, and diabetes in humans.


Bile Acid Cholic Acid Bile Acid Synthesis Cholestatic Liver Disease Bile Acid Metabolism 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This research is supported by NIH grants DK44442 and DK58379


  1. 1.
    Chiang JYL. Regulation of bile acid synthesis. Front Biosci. 1998;3:D176–93.PubMedGoogle Scholar
  2. 2.
    Russell DW. The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem. 2003;72:137–74.PubMedCrossRefGoogle Scholar
  3. 3.
    Chiang JY. Regulation of bile acid synthesis: pathways, nuclear receptors, and mechanisms. J Hepatol. 2004;40(3):539–51.PubMedCrossRefGoogle Scholar
  4. 4.
    Dawson PA, Lan T, Rao A. Bile acid transporters. J Lipid Res. 2009;50:2340–57.PubMedCrossRefGoogle Scholar
  5. 5.
    Chawla A, Repa JJ, Evans RM, Mangelsdorf DJ. Nuclear receptors and lipid physiology: opening the X-files. Science. 2001;294(5548):1866–70.PubMedCrossRefGoogle Scholar
  6. 6.
    Chiang JY. Bile Acid regulation of gene expression: roles of nuclear hormone receptors. Endocr Rev. 2002;23(4):443–63.PubMedCrossRefGoogle Scholar
  7. 7.
    Francis GA, Fayard E, Picard F, Auwerx J. Nuclear receptors and the control of metabolism. Annu Rev Physiol. 2003;65:261–311.PubMedCrossRefGoogle Scholar
  8. 8.
    Houten SM, Watanabe M, Auwerx J. Endocrine functions of bile acids. Embo J. 2006;25(7):1419–25.PubMedCrossRefGoogle Scholar
  9. 9.
    Thomas C, Pellicciari R, Pruzanski M, Auwerx J, Schoonjans K. Targeting bile-acid signalling for metabolic diseases. Nat Rev Drug Discov. 2008;7(8):678–93.PubMedCrossRefGoogle Scholar
  10. 10.
    Lefebvre P, Cariou B, Lien F, Kuipers F, Staels B. Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev. 2009;89(1):147–91.PubMedCrossRefGoogle Scholar
  11. 11.
    Chiang JY. Bile acids: regulation of synthesis. J Lipid Res. 2009;50:1955–1966.Google Scholar
  12. 12.
    Hylemon PB, Zhou H, Pandak WM, Ren S, Gil G, Dent P. Bile acids as regulatory molecules. J Lipid Res. 2009;50(8):1509–20.PubMedCrossRefGoogle Scholar
  13. 13.
    Amaral JD, Viana RJ, Ramalho RM, Steer CJ, Rodrigues CM. Bile acids: regulation of apoptosis by ursodeoxycholic acid. J Lipid Res. 2009;50:1721–34.PubMedCrossRefGoogle Scholar
  14. 14.
    Nguyen A, Bouscarel B. Bile acids and signal transduction: role in glucose homeostasis. Cell Signal. 2008;20(12):2180–97.PubMedCrossRefGoogle Scholar
  15. 15.
    Sola S, Amaral JD, Aranha MM, Steer CJ, Rodrigues CM. Modulation of hepatocyte apoptosis: cross-talk between bile acids and nuclear steroid receptors. Curr Med Chem. 2006;13(25):3039–51.PubMedCrossRefGoogle Scholar
  16. 16.
    Hofmann AF, Hagey LR. Bile acids: chemistry, pathochemistry, biology, pathobiology, and therapeutics. Cell Mol Life Sci. 2008;65(16):2461–83.PubMedCrossRefGoogle Scholar
  17. 17.
    Repa JJ, Mangelsdorf DJ. The role of orphan nuclear receptors in the regulation of cholesterol homeostasis. Annu Rev Cell Dev Biol. 2000;16:459–81.PubMedCrossRefGoogle Scholar
  18. 18.
    Duane WC, Javitt NB. 27-Hydroxycholesterol. Production rates in normal human subjects. J Lipid Res. 1999;40(7):1194–9.PubMedGoogle Scholar
  19. 19.
    Honda A, Yoshida T, Xu G, et al. Significance of plasma 7alpha-hydroxy-4-cholesten-3-one and 27-hydroxycholesterol concentrations as markers for hepatic bile acid synthesis in cholesterol-fed rabbits. Metabolism. 2004;53(1):42–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Hofmann AF. Detoxification of lithocholic acid, a toxic bile acid: relevance to drug hepatotoxicity. Drug Metab Rev. 2004;36(3–4):703–22.PubMedCrossRefGoogle Scholar
  21. 21.
    Lehmann JM, Kliewer SA, Moore LB, et al. Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J Biol chem. 1997;272:3137–40.PubMedCrossRefGoogle Scholar
  22. 22.
    Peet DJ, Turley SD, Ma W, et al. Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha. Cell. 1998;93(5):693–704.PubMedCrossRefGoogle Scholar
  23. 23.
    Chiang JY, Kimmel R, Stroup D. Regulation of cholesterol 7α-hydroxylase gene (CYP7A1) transcription by the liver orphan receptor (LXR α). Gene. 2001;262(1–2):257–65.PubMedCrossRefGoogle Scholar
  24. 24.
    Makishima M, Okamoto AY, Repa JJ, et al. Identification of a nuclear receptor for bile acids. Science. 1999;284:1362–5.PubMedCrossRefGoogle Scholar
  25. 25.
    Makishima M, Lu TT, Xie W, et al. Vitamin D receptor as an intestinal bile acid sensor. Science. 2002;296(5571):1313–6.PubMedCrossRefGoogle Scholar
  26. 26.
    Claudel T, Staels B, Kuipers F. The Farnesoid X receptor: a molecular link between bile acid and lipid and glucose metabolism. Arterioscler Thromb Vasc Biol. 2005;25(10):2020–30.PubMedCrossRefGoogle Scholar
  27. 27.
    Sinal CJ, Tohkin M, Miyata M, Ward JM, Lambert G, Gonzalez FJ. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell. 2000;102(6):731–44.PubMedCrossRefGoogle Scholar
  28. 28.
    Zollner G, Trauner M. Nuclear receptors as therapeutic targets in cholestatic liver diseases. Br J Pharmacol. 2009;156(1):7–27.PubMedCrossRefGoogle Scholar
  29. 29.
    Tu H, Okamoto AY, Shan B. FXR, a bile acid receptor and biological sensor. Trends Cardiovasc Med. 2000;10(1):30–5.PubMedCrossRefGoogle Scholar
  30. 30.
    Dawson PA, Hubbert M, Haywood J, et al. The heteromeric organic solute transporter alpha-beta, Ostalpha -Ostbeta, is an ileal basolateral bile acid transporter. J Biol Chem. 2005;280:6960–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Ballatori N, Christian WV, Lee JY, et al. OSTalpha-OSTbeta: a major basolateral bile acid and steroid transporter in human intestinal, renal, and biliary epithelia. Hepatology. 2005;42(6):1270–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Ballatori N, Fang F, Christian WV, Li N, Hammond CL. Ostalpha-Ostbeta is required for bile acid and conjugated steroid disposition in the intestine, kidney, and liver. Am J Physiol Gastrointest Liver Physiol. 2008;295(1):G179–86.PubMedCrossRefGoogle Scholar
  33. 33.
    Frankenberg T, Rao A, Chen F, Haywood J, Shneider BL, Dawson PA. Regulation of the mouse organic solute transporter alpha-beta, Ostalpha-Ostbeta, by bile acids. Am J Physiol Gastrointest Liver Physiol. 2006;290(5):G912–22.PubMedCrossRefGoogle Scholar
  34. 34.
    Denson LA, Sturm E, Echevarria W, et al. The orphan nuclear receptor, shp, mediates bile acid-induced inhibition of the rat bile acid transporter, ntcp. Gastroenterology. 2001;121(1):140–7.PubMedCrossRefGoogle Scholar
  35. 35.
    Kullak-Ublick GA, Meier PJ. Mechanisms of cholestasis. Clin Liver Dis. 2000;4(2):357–85.PubMedCrossRefGoogle Scholar
  36. 36.
    Trauner M, Meier PJ, Boyer JL. Molecular pathogenesis of cholestasis. N Engl J Med. 1998;339(17):1217–27.PubMedCrossRefGoogle Scholar
  37. 37.
    Jansen PL, Sturm E. Genetic cholestasis, causes and consequences for hepatobiliary transport. Liver Int. 2003;23(5):315–22.PubMedCrossRefGoogle Scholar
  38. 38.
    Zollner G, Marschall HU, Wagner M, Trauner M. Role of nuclear receptors in the adaptive response to bile acids and cholestasis: pathogenetic and therapeutic considerations. Mol Pharm. 2006;3(3):231–51.PubMedCrossRefGoogle Scholar
  39. 39.
    Lu TT, Makishima M, Repa JJ, et al. Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol Cell. 2000;6(3):507–15.PubMedCrossRefGoogle Scholar
  40. 40.
    Goodwin B, Jones SA, Price RR, et al. A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell. 2000;6(3):517–26.PubMedCrossRefGoogle Scholar
  41. 41.
    Zhang M, Chiang JY. Transcriptional regulation of the human sterol 12α(alpha)-hydroxylase gene (CYP8B1): Roles of hepatocyte nuclear factor 4α(alpha) (HNF4α(alpha)) in mediating bile acid repression. J Biol Chem. 2001;276:41690–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Del Castillo-Olivares A, Campos JA, Pandak WM, Gil G. Role of FTF/LRH-1 on bile acid biosynthesis. A known nuclear receptor activator that can Act as a suppressor of bile acid biosynthesis. J Biol Chem. 2004;279:16813–21.PubMedCrossRefGoogle Scholar
  43. 43.
    Kerr TA, Saeki S, Schneider M, et al. Loss of nuclear receptor shp impairs but does not eliminate negative feedback regulation of bile acid synthesis. Dev Cell. 2002;2(6):713–20.PubMedCrossRefGoogle Scholar
  44. 44.
    Wang L, Lee YK, Bundman D, et al. Redundant pathways for negative feedback regulation of bile Acid production. Dev Cell. 2002;2(6):721–31.PubMedCrossRefGoogle Scholar
  45. 45.
    Mataki C, Magnier BC, Houten SM, et al. Compromised intestinal lipid absorption in mice with a liver-specific deficiency of liver receptor homolog 1. Mol Cell Biol. 2007;27(23):8330–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Lee YK, Schmidt DR, Cummins CL, et al. Liver receptor homolog-1 regulates bile acid homeostasis but is not essential for feedback regulation of bile acid synthesis. Mol Endocrinol. 2008;22: 1345–56.PubMedCrossRefGoogle Scholar
  47. 47.
    Holt JA, Luo G, Billin AN, et al. Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. Genes Dev. 2003;17(13):1581–91.PubMedCrossRefGoogle Scholar
  48. 48.
    Inagaki T, Choi M, Moschetta A, et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab. 2005;2(4):217–25.PubMedCrossRefGoogle Scholar
  49. 49.
    Yu C, Wang F, Kan M, et al. Elevated cholesterol metabolism and bile acid synthesis in mice lacking membrane tyrosine kinase receptor FGFR4. J Biol Chem. 2000;275(20):15482–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Yu C, Wang F, Jin C, Huang X, McKeehan WL. Independent repression of bile acid synthesis and activation of c-Jun N-terminal kinase (JNK) by activated hepatocyte fibroblast growth factor receptor 4 (FGFR4) and bile acids. J Biol Chem. 2005;280(18):17707–14.PubMedCrossRefGoogle Scholar
  51. 51.
    Kim I, Ahn SH, Inagaki T, et al. Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine. J Lipid Res. 2007;48:2664–72.PubMedCrossRefGoogle Scholar
  52. 52.
    Lin BC, Wang M, Blackmore C, Desnoyers LR. Liver specific activities of FGF19 require KLOTHO beta. J Biol Chem. 2007;282:27277–84.PubMedCrossRefGoogle Scholar
  53. 53.
    Ito S, Fujimori T, Furuya A, Satoh J, Nabeshima Y. Impaired negative feedback suppression of bile acid synthesis in mice lacking betaKlotho. J Clin Invest. 2005;115(8):2202–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Lundasen T, Galman C, Angelin B, Rudling M. Circulating intestinal fibroblast growth factor 19 has a pronounced diurnal variation and modulates hepatic bile acid synthesis in man. J Intern Med. 2006;260(6):530–6.PubMedCrossRefGoogle Scholar
  55. 55.
    Song KH, Li T, Owsley E, Strom S, Chiang JY. Bile acids activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol 7alpha-hydroxylase gene expression. Hepatology. 2009;49(1):297–305.PubMedCrossRefGoogle Scholar
  56. 56.
    Stravitz RT, Vlahcevic ZR, Gurley EC, Hylemons PB. Repression of cholesterol 7a-hydroxylase transcription by bile acids is mediated through protein kinase C in primary cultures of rat hepatocytes. J Lipid Res. 1995;36:1359–68.PubMedGoogle Scholar
  57. 57.
    Gupta S, Stravitz RT, Dent P, Hylemon PB. Down-regulation of cholesterol 7alpha -hydroxylase (CYP7A1) gene expression by bile acids in primary rat hepatocytes is mediated by the c-Jun N-terminal kinase pathway. J Biol Chem. 2001;276(19):15816–22.PubMedCrossRefGoogle Scholar
  58. 58.
    Miyake JH, Wang SL, Davis RA. Bile acid induction of cytokine expression by macrophages correlates with repression of hepatic cholesterol 7alpha-hydroxylase. J Biol Chem. 2000;275(29):21805–8.PubMedCrossRefGoogle Scholar
  59. 59.
    Jahan A, Chiang JY. Cytokine regulation of human sterol 12{alpha}-hydroxylase (CYP8B1) gene. Am J Physiol Gastrointest Liver Physiol. 2005;288:G685–95.PubMedCrossRefGoogle Scholar
  60. 60.
    Li T, Jahan A, Chiang JY. Bile acids and cytokines inhibit the human cholesterol 7alpha-hydroxylase gene via the JNK/c-jun pathway in human liver cells. Hepatology. 2006;43(6):1202–10.PubMedCrossRefGoogle Scholar
  61. 61.
    Dent P, Fang Y, Gupta S, et al. Conjugated bile acids promote ERK1/2 and AKT activation via a pertussis toxin-sensitive mechanism in murine and human hepatocytes. Hepatology. 2005;42(6):1291–9.PubMedCrossRefGoogle Scholar
  62. 62.
    Fang Y, Han SI, Mitchell C, et al. Bile acids induce mitochondrial ROS, which promote activation of receptor tyrosine kinases and signaling pathways in rat hepatocytes. Hepatology. 2004;40(4):961–71.PubMedGoogle Scholar
  63. 63.
    Fang Y, Studer E, Mitchell C, et al. Conjugated bile acids regulate hepatocyte glycogen synthase activity in vitro and in vivo via Galphai signaling. Mol Pharmacol. 2007;71(4):1122–8.PubMedCrossRefGoogle Scholar
  64. 64.
    Li T, Chiang JY. A novel role of transforming growth factor beta1 in transcriptional repression of human cholesterol 7alpha-hydroxylase gene. Gastroenterology. 2007;133(5):1660–9.PubMedCrossRefGoogle Scholar
  65. 65.
    Wilkinson DS, Ogden SK, Stratton SA, et al. A direct intersection between p53 and transforming growth factor beta pathways targets chromatin modification and transcription repression of the alpha-fetoprotein gene. Mol Cell Biol. 2005;25(3):1200–12.PubMedCrossRefGoogle Scholar
  66. 66.
    Cordenonsi M, Montagner M, Adorno M, et al. Integration of TGF-beta and Ras/MAPK signaling through p53 phosphorylation. Science. 2007;315(5813):840–3.PubMedCrossRefGoogle Scholar
  67. 67.
    Maeda Y, Seidel SD, Wei G, Liu X, Sladek FM. Repression of hepatocyte nuclear factor 4alpha tumor suppressor p53: involvement of the ligand-binding domain and histone deacetylase activity. Mol Endocrinol. 2002;16(2):402–10.PubMedCrossRefGoogle Scholar
  68. 68.
    Song KH, Ellis E, Strom S, Chiang JY. Hepatocyte growth factor signaling pathway inhibits cholesterol 7alpha-hydroxylase and bile acid synthesis in human hepatocytes. Hepatology. 2007;46(6):1993–2002.PubMedCrossRefGoogle Scholar
  69. 69.
    Angelin B, Einarsson K, Hellstrom K, Leijd B. Bile acid kinetics in relation to endogenous triglyceride metabolism in various types of hyperlipoproteinemia. J Lipid Res. 1978;19:1004–16.PubMedGoogle Scholar
  70. 70.
    Kast HR, Nguyen CM, Sinal CJ, et al. Farnesoid x-activated receptor induces apolipoprotein c-ii transcription: a molecular mechanism linking plasma triglyceride levels to bile acids. Mol Endocrinol. 2001;15(10):1720–8.PubMedCrossRefGoogle Scholar
  71. 71.
    Zhang Y, Castellani LW, Sinal CJ, Gonzalez FJ, Edwards PA. Peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) regulates triglyceride metabolism by activation of the nuclear receptor FXR. Genes Dev. 2004;18(2):157–69.PubMedCrossRefGoogle Scholar
  72. 72.
    Zhang Y, Lee FY, Barrera G, et al. Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc Natl Acad Sci U S A. 2006;103(4):1006–11.PubMedCrossRefGoogle Scholar
  73. 73.
    Watanabe M, Houten SM, Wang L, et al. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest. 2004;113(10):1408–18.PubMedGoogle Scholar
  74. 74.
    De Fabiani E, Mitro N, Gilardi F, Caruso D, Galli G, Crestani M. Coordinated control of cholesterol catabolism to bile acids and of gluconeogenesis via a novel mechanism of transcription regulation linked to the fasted-to-fed cycle. J Biol Chem. 2003;278:39124–32.PubMedCrossRefGoogle Scholar
  75. 75.
    Yamagata K, Daitoku H, Shimamoto Y, et al. Bile acids regulate gluconeogenic gene expression via small heterodimer partner-mediated repression of hepatocyte nuclear factor 4 and Foxo1. J Biol Chem. 2004;279(22):23158–65.PubMedCrossRefGoogle Scholar
  76. 76.
    Ma K, Saha PK, Chan L, Moore DD. Farnesoid X receptor is essential for normal glucose homeostasis. J Clin Invest. 2006;116(4):1102–9.PubMedCrossRefGoogle Scholar
  77. 77.
    Duran-Sandoval D, Cariou B, Percevault F, et al. The farnesoid X receptor modulates hepatic carbohydrate metabolism during the fasting-refeeding transition. J Biol Chem. 2005;280(33):29971–9.PubMedCrossRefGoogle Scholar
  78. 78.
    Shin DJ, Campos JA, Gil G, Osborne TF. PGC-1a activates CYP7A1 and bile acid biosynthesis. J Biol Chem. 2003;278:50047–52.PubMedCrossRefGoogle Scholar
  79. 79.
    Galman C, Angelin B, Rudling M. Bile acid synthesis in humans has a rapid diurnal variation that is asynchronous with cholesterol synthesis. Gastroenterology. 2005;129(5):1445–53.PubMedCrossRefGoogle Scholar
  80. 80.
    Song KH, Chiang JY. Glucagon and cAMP inhibit cholesterol 7alpha-hydroxylase (CYP7a1) gene expression in human hepatocytes: Discordant regulation of bile acid synthesis and gluconeogenesis. Hepatology. 2006;43:117–25.PubMedCrossRefGoogle Scholar
  81. 81.
    Fu L, John LM, Adams SH, et al. Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes. Endocrinology. 2004;145(6):2594–603.PubMedCrossRefGoogle Scholar
  82. 82.
    Tomlinson E, Fu L, John L, et al. Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity. Endocrinology. 2002;143(5):1741–7.PubMedCrossRefGoogle Scholar
  83. 83.
    Cariou B, Bouchaert E, Abdelkarim M, et al. FXR-deficiency confers increased susceptibility to torpor. FEBS Lett. 2007;581(27):5191–8.PubMedCrossRefGoogle Scholar
  84. 84.
    Bhatnagar S, Damron HA, Hillgartner FB. Fibroblast growth factor-19, a novel factor that inhibits hepatic fatty acid synthesis. J Biol Chem. 2009;284(15):10023–33.PubMedCrossRefGoogle Scholar
  85. 85.
    Wang L, Liu J, Saha P, et al. The orphan nuclear receptor SHP regulates PGC-1alpha expression and energy production in brown adipocytes. Cell Metab. 2005;2(4):227–38.PubMedCrossRefGoogle Scholar
  86. 86.
    Maruyama T, Miyamoto Y, Nakamura T, et al. Identification of membrane-type receptor for bile acids (M-BAR). Biochem Biophys Res Commun. 2002;298(5):714–9.PubMedCrossRefGoogle Scholar
  87. 87.
    Kawamata Y, Fujii R, Hosoya M, et al. A G protein-coupled receptor responsive to bile acids. J Biol Chem. 2003;278:9435–40.PubMedCrossRefGoogle Scholar
  88. 88.
    Keitel V, Reinehr R, Gatsios P, et al. The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells. Hepatology. 2007;45(3):695–704.PubMedCrossRefGoogle Scholar
  89. 89.
    Keitel V, Cupisti K, Ullmer C, Knoefel WT, Kubitz R, Haussinger D. The membrane-bound bile acid receptor TGR5 is localized in the epithelium of human gallbladders. Hepatology. 2009;50:861–70.PubMedCrossRefGoogle Scholar
  90. 90.
    Watanabe M, Houten SM, Mataki C, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature. 2006;439:484–9.PubMedCrossRefGoogle Scholar
  91. 91.
    Maruyama T, Tanaka K, Suzuki J, et al. Targeted disruption of G protein-coupled bile acid receptor 1 (Gpbar1/M-Bar) in mice. J Endocrinol. 2006;191(1):197–205.PubMedCrossRefGoogle Scholar
  92. 92.
    Katsuma S, Hirasawa A, Tsujimoto G. Bile acids promote glucagon-like peptide-1 secretion through TGR5 in a murine enteroendocrine cell line STC-1. Biochem Biophys Res Commun. 2005;329(1): 386–90.PubMedCrossRefGoogle Scholar
  93. 93.
    Vassileva G, Golovko A, Markowitz L, et al. Targeted deletion of Gpbar1 protects mice from cholesterol gallstone formation. Biochem J. 2006;398(3):423–30.PubMedCrossRefGoogle Scholar
  94. 94.
    Setchell KD, Street JM. Inborn errors of bile acid synthesis. Semin Liver Dis. 1987;7(2):85–99.PubMedCrossRefGoogle Scholar
  95. 95.
    Wagner M, Zollner G, Trauner M. New molecular insights into the mechanisms of cholestasis. J Hepatol. 2009;51:565–80.PubMedCrossRefGoogle Scholar
  96. 96.
    Vlahcevic ZR, Hylemon PB, Chiang JYL. Hepatic cholesterol metabolism. In: Arias IM, Boyer JL, Fausto N, Jakoby WB, Schachter DA, Shafritz DA, editors. The liver: biology and pathobiology. New York: Raven; 1994.Google Scholar
  97. 97.
    Pullinger CR, Eng C, Salen G, et al. Human cholesterol 7alpha-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype. J Clin Invest. 2002;110(1):109–17.PubMedGoogle Scholar
  98. 98.
    Setchell KDR, Schwarz M, O’Connell NC, et al. Identification of a new inborn error in bile acid synthesis: mutation of the oxysterol 7α(alpha)-hydroxylase gene causes severe neonatal liver disease. J Clin Invest. 1998;102(9):1690–703.PubMedCrossRefGoogle Scholar
  99. 99.
    Clayton PT, Leonard JV, Lawson AM, et al. Familial giant cell hepatitis associated with synthesis of 3 beta, 7 alpha-dihydroxy-and 3 beta, 7 alpha, 12 alpha-trihydroxy-5-cholenoic acids. J Clin Invest. 1987;79(4):1031–8.PubMedCrossRefGoogle Scholar
  100. 100.
    Schwarz M, Wright AC, Davis DL, Nazer H, Bjorkhem I, Russell DW. The bile acid synthetic gene 3beta-hydroxy-Delta(5)-C(27)-steroid oxidoreductase is mutated in progressive intrahepatic cholestasis. J Clin Invest. 2000;106(9):1175–84.PubMedCrossRefGoogle Scholar
  101. 101.
    Cheng JB, Jacquemin E, Gerhardt M, et al. Molecular genetics of 3beta-hydroxy-Delta5-C27-steroid oxidoreductase deficiency in 16 patients with loss of bile acid synthesis and liver disease. J Clin Endocrinol Metab. 2003;88(4):1833–41.PubMedCrossRefGoogle Scholar
  102. 102.
    Setchell KD, Suchy FJ, Welsh MB, Zimmer-Nechemias L, Heubi J, Balistreri WF. Delta 4–3-oxosteroid 5 beta-reductase deficiency described in identical twins with neonatal hepatitis. A new inborn error in bile acid synthesis. J Clin Invest. 1988;82(6):2148–57.PubMedCrossRefGoogle Scholar
  103. 103.
    Shneider BL, Setchell KD, Whitington PF, Neilson KA, Suchy FJ. Delta 4–3-oxosteroid 5 beta-reductase deficiency causing neonatal liver failure and hemochromatosis [see comments]. J Pediatr. 1994;124(2):234–8.PubMedCrossRefGoogle Scholar
  104. 104.
    Lemonde HA, Custard EJ, Bouquet J, et al. Mutations in SRD5B1 (AKR1D1), the gene encoding delta(4)-3-oxosteroid 5beta-reductase, in hepatitis and liver failure in infancy. Gut. 2003;52(10):1494–9.PubMedCrossRefGoogle Scholar
  105. 105.
    Gonzales E, Cresteil D, Baussan C, Dabadie A, Gerhardt MF, Jacquemin E. SRD5B1 (AKR1D1) gene analysis in delta(4)-3-oxosteroid 5beta-reductase deficiency: evidence for primary genetic defect. J Hepatol. 2004;40(4):716–8.PubMedCrossRefGoogle Scholar
  106. 106.
    Bjorkhem I. Inborn errors of metabolism with consequences for bile acid biosynthesis. A minireview. Scand J Gastroenterol Suppl. 1994;204:68–72.PubMedCrossRefGoogle Scholar
  107. 107.
    Bjorkhem I, Leitersdorf I. Sterol 27-hydroxylase deficiency: a rare cause of Xanthomas in normocholesterolemic humans. Trends Endocrinol Metab. 2000;11(5):180–3.PubMedCrossRefGoogle Scholar
  108. 108.
    Dussault I, Yoo HD, Lin M, et al. Identification of an endogenous ligand that activates pregnane X receptor-mediated sterol clearance. Proc Natl Acad Sci U S A. 2003;100:833–8.PubMedCrossRefGoogle Scholar
  109. 109.
    Bove KE, Daugherty CC, Tyson W, et al. Bile acid synthetic defects and liver disease. Pediatr Dev Pathol. 2000;3(1):1–16.PubMedCrossRefGoogle Scholar
  110. 110.
    Hanson RF, Szczepanik-Van Leeuwen P, Williams GC, Grabowski G, Sharp HL. Defects of bile acid synthesis in Zellweger’s syndrome. Science. 1979;203:1107–8.PubMedCrossRefGoogle Scholar
  111. 111.
    Ferdinandusse S, Denis S, Faust PL, Wanders RJ. Bile acids: role of peroxisomes. J Lipid Res. 2009;50:2139–47.PubMedCrossRefGoogle Scholar
  112. 112.
    Goldfisher S, Moore CL, Johnson AB, et al. Peroxisomal and mitochondrial defects in the cerebro-hepato-renal syndrome. Science. 1997;182:62–4.CrossRefGoogle Scholar
  113. 113.
    Setchell KD, Bragetti P, Zimmer-Nechemias L, et al. Oral bile acid treatment and the patient with Zellweger syndrome. Hepatology. 1992;15(2):198–207.PubMedCrossRefGoogle Scholar
  114. 114.
    Alvarez L, Jara P, Sanchez-Sabate E, et al. Reduced hepatic expression of Farnesoid X Receptor in hereditary cholestasis associated to mutation in ATP8B1. Hum Mol Genet. 2004;13:2451–60.PubMedCrossRefGoogle Scholar
  115. 115.
    Chen F, Ananthanarayanan M, Emre S, et al. Progressive familial intrahepatic cholestasis, type 1, is associated with decreased farnesoid X receptor activity. Gastroenterology. 2004;126(3):756–64.PubMedCrossRefGoogle Scholar
  116. 116.
    Frankenberg T, Miloh T, Chen FY, et al. The membrane protein ATPase class I type 8B member 1 signals through protein kinase C zeta to activate the farnesoid X receptor. Hepatology. 2008; 48(6):1896–905.PubMedCrossRefGoogle Scholar
  117. 117.
    Cai SY, Gautam S, Nguyen T, Soroka CJ, Rahner C, Boyer JL. ATP8B1 deficiency disrupts the bile canalicular membrane bilayer structure in hepatocytes, but FXR expression and activity are maintained. Gastroenterology. 2009;136(3):1060–9.PubMedCrossRefGoogle Scholar
  118. 118.
    Strautnieks SS, Bull LN, Knisely AS, et al. A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Nat Genet. 1998;20(3):233–8.PubMedCrossRefGoogle Scholar
  119. 119.
    Pauli-Magnus C, Lang T, Meier Y, et al. Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy. Pharmacogenetics. 2004;14(2):91–102.PubMedCrossRefGoogle Scholar
  120. 120.
    Noe J, Kullak-Ublick GA, Jochum W, et al. Impaired expression and function of the bile salt export pump due to three novel ABCB11 mutations in intrahepatic cholestasis. J Hepatol. 2005;43(3):536–43.PubMedCrossRefGoogle Scholar
  121. 121.
    Lang T, Haberl M, Jung D, et al. Genetic variability, haplotype structures, and ethnic diversity of hepatic transporters MDR3 (ABCB4) and bile salt export pump (ABCB11). Drug Metab Dispos. 2006;34(9):1582–99.PubMedCrossRefGoogle Scholar
  122. 122.
    Lang C, Meier Y, Stieger B, et al. Mutations and polymorphisms in the bile salt export pump and the multidrug resistance protein 3 associated with drug-induced liver injury. Pharmacogenet Genomics. 2007;17(1):47–60.PubMedCrossRefGoogle Scholar
  123. 123.
    Jacquemin E. Role of multidrug resistance 3 deficiency in pediatric and adult liver disease: one gene for three diseases. Semin Liver Dis. 2001;21(4):551–62.PubMedCrossRefGoogle Scholar
  124. 124.
    Wasmuth HE, Glantz A, Keppeler H, et al. Intrahepatic cholestasis of pregnancy: the severe form is associated with common variants of the hepatobiliary phospholipid transporter ABCB4 gene. Gut. 2007;56(2):265–70.PubMedCrossRefGoogle Scholar
  125. 125.
    Keitel V, Nies AT, Brom M, Hummel-Eisenbeiss J, Spring H, Keppler D. A common Dubin-Johnson syndrome mutation impairs protein maturation and transport activity of MRP2 (ABCC2). Am J Physiol Gastrointest Liver Physiol. 2003;284(1):G165–74.PubMedGoogle Scholar
  126. 126.
    Bertolotti M, Carulli L, Concari M, et al. Suppression of bile acid synthesis, but not of hepatic cholesterol 7alpha-hydroxylase expression, by obstructive cholestasis in humans. Hepatology. 2001;34(2):234–42.PubMedCrossRefGoogle Scholar
  127. 127.
    Schaap FG, van der Gaag NA, Gouma DJ, Jansen PL. High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis. Hepatology. 2009;49(4):1228–35.PubMedCrossRefGoogle Scholar
  128. 128.
    Inagaki T, Moschetta A, Lee YK, et al. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc Natl Acad Sci U S A. 2006;103(10):3920–5.PubMedCrossRefGoogle Scholar
  129. 129.
    Fiorucci S, Baldelli F. Farnesoid X receptor agonists in biliary tract disease. Curr Opin Gastroenterol. 2009;25(3):252–9.PubMedCrossRefGoogle Scholar
  130. 130.
    Wang J, Gafvels M, Rudling M, et al. Critical role of cholic acid for development of hypercholesterolemia and gallstones in diabetic mice. Biochem Biophys Res Commun. 2006;342(4):1382–8.PubMedCrossRefGoogle Scholar
  131. 131.
    Staels B, Kuipers F. Bile acid sequestrants and the treatment of type 2 diabetes mellitus. Drugs. 2007;67(10):1383–92.PubMedCrossRefGoogle Scholar
  132. 132.
    Staels B. A review of bile acid sequestrants: potential mechanism(s) for glucose-lowering effects in type 2 diabetes mellitus. Postgrad Med. 2009;121(3 Suppl 1):25–30.PubMedCrossRefGoogle Scholar
  133. 133.
    Fiorucci S, Clerici C, Antonelli E, et al. Protective effects of 6-ethyl chenodeoxycholic acid, a farnesoid x receptor (FXR) ligand, in estrogen induced cholestasis. J Pharmacol Exp Ther. 2005;313:604–12.PubMedCrossRefGoogle Scholar
  134. 134.
    Pellicciari R, Sato H, Gioiello A, et al. Nongenomic actions of bile acids. Synthesis and preliminary characterization of 23- and 6, 23-alkyl-substituted bile acid derivatives as selective modulators for the G-protein coupled receptor TGR5. J Med Chem. 2007;50(18):4265–8.PubMedCrossRefGoogle Scholar
  135. 135.
    Gilat T, Leikin-Frenkel A, Goldiner I, et al. Prevention of diet-induced fatty liver in experimental animals by the oral administration of a fatty acid bile acid conjugate (FABAC). Hepatology. 2003;38(2):436–42.PubMedCrossRefGoogle Scholar
  136. 136.
    Leikin-Frenkel A, Goldiner I, Leikin-Gobbi D, et al. Treatment of preestablished diet-induced fatty liver by oral fatty acid-bile acid conjugates in rodents. Eur J Gastroenterol Hepatol. 2008;20(12): 1205–13.PubMedCrossRefGoogle Scholar
  137. 137.
    Gilat T, Leikin-Frenkel A, Goldiner I, Halpern Z, Konikoff FM. Dissolution of cholesterol gallstones in mice by the oral administration of a fatty acid bile acid conjugate. Hepatology. 2002;35(3):597–600.PubMedCrossRefGoogle Scholar
  138. 138.
    Gilat T, Leikin-Frenkel A, Goldiner L, Laufer H, Halpern Z, Konikoff FM. Arachidyl amido cholanoic acid (Aramchol) is a cholesterol solubilizer and prevents the formation of cholesterol gallstones in inbred mice. Lipids. 2001;36(10):1135–40.PubMedCrossRefGoogle Scholar
  139. 139.
    Konikoff FM, Gilat T. Effects of fatty acid bile acid conjugates (FABACs) on biliary lithogenesis: potential consequences for non-surgical treatment of gallstones. Curr Drug Targets Immune Endocr Metabol Disord. 2005;5(2):171–5.PubMedCrossRefGoogle Scholar
  140. 140.
    Gonen A, Shaish A, Leikin-Frenkel A, Gilat T, Harats D. Fatty acid bile acid conjugates inhibit atherosclerosis in the C57BL/6 mouse model. Pathobiology. 2002;70(4):215–8.PubMedCrossRefGoogle Scholar
  141. 141.
    Leikin-Frenkel A, Parini P, Konikoff FM, et al. Hypocholesterolemic effects of fatty acid bile acid conjugates (FABACs) in mice. Arch Biochem Biophys. 2008;471(1):63–71.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Integrative Medical SciencesNortheastern Ohio Universities Colleges of Medicine and PharmacyRootstownUSA

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