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Targeting bile-acid signalling for metabolic diseases

Nature Reviews Drug Discovery volume 7, pages 678693 (2008) | Download Citation

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Abstract

Bile acids are increasingly being appreciated as complex metabolic integrators and signalling factors and not just as lipid solubilizers and simple regulators of bile-acid homeostasis. It is therefore not surprising that a number of bile-acid-activated signalling pathways have become attractive therapeutic targets for metabolic disorders. Here, we review how the signalling functions of bile acids can be exploited in the development of drugs for obesity, type 2 diabetes, hypertriglyceridaemia and atherosclerosis, as well as other associated chronic diseases such as non-alcoholic steatohepatitis.

Key points

  • Hepatic synthesis of bile acids is the primary pathway for cholesterol catabolism. The cholesterol 7α-hydroxylase enzyme (encoded by CYP7A1) represents the rate-limiting step of the multi-enzymatic bile-acid biosynthetic pathway.

  • Bile acids play a crucial role in dietary lipid digestion and absorption, and also act as versatile signalling molecules through the activation of the nuclear hormone receptor farnesoid X receptor-α (FXR-α) and the recently identified G-protein-coupled receptor TGR5.

  • Bile-acid-mediated activation of FXR-α-signalling pathways regulate the enterohepatic recycling of bile acids, protect against their accumulation in the liver and inhibit their own biosynthesis.

  • Through their endocrine function, bile acids also activate TGR5 signalling pathways in multiple cells, through which they control immune function, liver and gall-bladder physiology and glucose and energy homeostasis.

  • The development of TGR5 agonists could have benefits to combat many aspects of the metabolic syndrome, whereas FXR-α agonists could hold promise for reducing hypertriglyceridaemia and modulating glucose metabolism. Pharmaceutical activation of these bile-acid-signalling pathways is therefore a novel way to improve metabolism.

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References

  1. 1.

    & The enterohepatic nuclear receptors are major regulators of the enterohepatic circulation of bile salts. Ann. Med. 36, 482–491 (2004).

  2. 2.

    Circadian distribution of bile acids in the enterohepatic circulatory system in rats. Am. J. Physiol. 230, 1331–1335 (1976).

  3. 3.

    , & Within-day fluctuations in serum bile-acid concentrations among normal control subjects and patients with hepatic disease. Am. J. Clin. Pathol. 73, 196–201 (1980).

  4. 4.

    Steady-state kinetics of serum bile acids in healthy human subjects: single and dual isotope techniques using stable isotopes and mass spectrometry. J. Lipid Res. 28, 238–252 (1987).

  5. 5.

    The enzymes, regulation, and genetics of bile acid synthesis. Annu. Rev. Biochem. 72, 137–174 (2003).

  6. 6.

    et al. Disruption of cholesterol 7α-hydroxylase gene in mice. II. Bile acid deficiency is overcome by induction of oxysterol 7α-hydroxylase. J. Biol. Chem. 271, 18024–18031 (1996).

  7. 7.

    , , , & Disruption of cholesterol 7α-hydroxylase gene in mice. I. Postnatal lethality reversed by bile acid and vitamin supplementation. J. Biol. Chem. 271, 18017–18023 (1996).

  8. 8.

    , & Human CYP7A1 deficiency: progress and enigmas. J. Clin. Invest. 110, 29–31 (2002).

  9. 9.

    et al. Human cholesterol 7α-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype. J. Clin. Invest. 110, 109–117 (2002).

  10. 10.

    Cholestanol deposition in cerebrotendinous xanthomatosis. A possible mechanism. Ann. Intern. Med. 75, 843–851 (1971).

  11. 11.

    & The metabolism of cholestanol, cholesterol, and bile acids in cerebrotendinous xanthomatosis. J. Clin. Invest. 52, 2822–2835 (1973).

  12. 12.

    & The metabolism of chenodeoxycholic acid to β-muricholic acid in rat liver. Eur. J. Biochem. 134, 191–196 (1983).

  13. 13.

    et al. Identification of membrane-type receptor for bile acids (M-BAR). Biochem. Biophys. Res. Commun. 298, 714–719 (2002).

  14. 14.

    et al. A G protein-coupled receptor responsive to bile acids. J. Biol. Chem. 278, 9435–9440 (2003). References 13 and 14 report the identification of TGR5, a GPCR dedicated to bile acids..

  15. 15.

    et al. Identification of nuclear receptors for bile acids. Science 284, 1362–1365 (1999).

  16. 16.

    et al. Bile acids: natural ligands for orphan nuclear receptors. Science 284, 1365–1368 (1999).

  17. 17.

    , , , & Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol. Cell 3, 543–553 (1999). References15–17 identify bile acids as endogenous ligands of the nuclear receptor FXR.

  18. 18.

    et al. Identification of a nuclear receptor that is activated by Farnesol metabolites. Cell 81, 687–693 (1995).

  19. 19.

    , & Isolation of proteins that interact specifically with retinoid X receptor: two novel orphan receptors. Mol. Endocrinol. 9, 72–85 (1995).

  20. 20.

    et al. Identification of farnesoid X receptor beta as a novel mammalian nuclear receptor sensing lanosterol. Mol. Cell Biol. 23, 864–872 (2003).

  21. 21.

    et al. Generation of multiple farnesoid-X-receptor isoforms through the use of alternative promoters. Gene 290, 35–43 (2002).

  22. 22.

    , & Natural structural variants of the nuclear receptor farnesoid X receptor affect transcriptional activation. J. Biol. Chem. 278, 104–110 (2003).

  23. 23.

    , , , & Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) regulates triglyceride metabolism by activation of the nuclear receptor FXR. Genes Dev. 18, 157–169 (2004).

  24. 24.

    et al. Structural basis for bile acid binding and activation of the nuclear receptor FXR. Mol. Cell 11, 1093–1100 (2003).

  25. 25.

    et al. A chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR. Mol. Cell 11, 1079–1092 (2003).

  26. 26.

    et al. The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proc. Natl Acad. Sci. USA 98, 3369–3374 (2001).

  27. 27.

    et al. An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids. Proc. Natl Acad. Sci. USA 98, 3375–3380 (2001).

  28. 28.

    et al. Vitamin D receptor as an intestinal bile acid sensor. Science 296, 1313–1316 (2002).

  29. 29.

    , , & Role of nuclear receptors in the adaptive response to bile acids and cholestasis: pathogenetic and therapeutic considerations. Mol. Pharm. 3, 231–251 (2006).

  30. 30.

    & Coordinate transcriptional regulation of bile acid homeostasis and drug metabolism. Arch. Biochem. Biophys. 433, 397–412 (2005).

  31. 31.

    et al. Farnesoid X receptor regulates bile acid-amino acid conjugation. J. Biol. Chem. 278, 27703–27711 (2003).

  32. 32.

    , & Prevention of cholesterol gallstone disease by FXR agonists in a mouse model. Nature Med. 10, 1352–1358 (2004). An elegant study demonstrating that the activation of the FXR-signalling pathway prevents the formation of cholesterol gallstones.

  33. 33.

    Bile acid regulation of gene expression: roles of nuclear hormone receptors. Endocr. Rev. 23, 443–463 (2002).

  34. 34.

    et al. Identification of a bile acid-responsive element in the human ileal bile acid-binding protein gene. Involvement of the farnesoid X receptor/9-cis-retinoic acid receptor heterodimer. J. Biol. Chem. 274, 29749–29754 (1999).

  35. 35.

    , , & The nuclear receptor for bile acids, FXR, transactivates human organic solute transporter-α and -β genes. Am. J. Physiol. Gastrointest. Liver Physiol. 290, G476–G485 (2006).

  36. 36.

    et al. FXR regulates organic solute transporters alpha and beta in the adrenal gland, kidney, and intestine. J. Lipid Res. 47, 201–214 (2006).

  37. 37.

    et al. Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. Genes Dev. 17, 1581–1591 (2003).

  38. 38.

    et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell. Metab. 2, 217–225 (2005). References 37 and 38 identify intestinal FGF15/FGF19 as a key regulator of bile-acid synthesis.

  39. 39.

    , , & Transcriptional corepression by SHP: molecular mechanisms and physiological consequences. Trends Endocrinol. Metab. 16, 478–488 (2005).

  40. 40.

    , , , & In vivo imaging of farnesoid X receptor activity reveals the ileum as the primary bile acid signaling tissue. Mol. Endocrinol. 21, 1312–1323 (2007).

  41. 41.

    et al. International Union of Pharmacology. XLVI. G protein-coupled receptor list. Pharmacol. Rev. 57, 279–288 (2005).

  42. 42.

    et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 439, 484–489 (2006). A key paper identifying bile acids as endocrine factors that induce energy expenditure by promoting intracellular thyroid hormone activation through the activation of the TGR5-signalling pathway.

  43. 43.

    et al. Targeted deletion of Gpbar1 protects mice from cholesterol gallstone formation. Biochem. J. 398, 423–430 (2006).

  44. 44.

    et al. The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells. Hepatology 45, 695–704 (2007).

  45. 45.

    , & Bile acids promote glucagon-like peptide-1 secretion through TGR5 in a murine enteroendocrine cell line STC-1. Biochem. Biophys. Res. Commun. 329, 386–390 (2005).

  46. 46.

    et al. Targeted disruption of G protein-coupled bile acid receptor 1 (Gpbar1/M-Bar) in mice. J. Endocrinol. 191, 197–205 (2006).

  47. 47.

    et al. Bile acid-induced TGR5-dependent c-Jun-N terminal kinase activation leads to enhanced caspase 8 activation in hepatocytes. Biochem. Biophys. Res. Commun. 361, 156–161 (2007).

  48. 48.

    et al. Involvement of membrane-type bile acid receptor M-BAR/TGR5 in bile acid-induced activation of epidermal growth factor receptor and mitogen-activated protein kinases in gastric carcinoma cells. Biochem. Biophys. Res. Commun. 354, 154–159 (2007).

  49. 49.

    et al. Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol. Cell 6, 507–515 (2000).

  50. 50.

    et al. A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol. Cell 6, 517–526 (2000). References49 and 50 illustrate the molecular basis for feedback regulation of bile-acid biosynthesis.

  51. 51.

    , , , & The small heterodimer partner (SHP) interacts with the Liver X receptor α (LXRα) and represses its transcriptional activity. Mol. Endocrinol. 16, 2065–2076 (2002).

  52. 52.

    et al. Compromised intestinal lipid absorption in mice with a liver-specific deficiency of liver receptor homolog 1. Mol. Cell Biol. 27, 8330–8339 (2007).

  53. 53.

    et al. Liver receptor homolog-1 regulates bile acid homeostasis but is not essential for feedback regulation of bile acid synthesis. Mol. Endocrinol. 22, 1345–1356 (2008).

  54. 54.

    , & Identification of a bile acid response element in the cholesterol 7 α-hydroxylase gene CYP7A. Am. J. Physiol. 273, G508–G517 (1997).

  55. 55.

    et al. The negative effects of bile acids and tumor necrosis factor-α on the transcription of cholesterol 7α-hydroxylase gene (CYP7A1) converge to hepatic nuclear factor-4: a novel mechanism of feedback regulation of bile acid synthesis mediated by nuclear receptors. J. Biol. Chem. 276, 30708–30716 (2001).

  56. 56.

    & Transcriptional regulation of the human sterol 12α-hydroxylase gene (CYP8B1): roles of hepatocyte nuclear factor 4α in mediating bile acid repression. J. Biol. Chem. 276, 41690–41699 (2001).

  57. 57.

    et al. Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4α. J. Lipid Res. 47, 215–227 (2006).

  58. 58.

    et al. Identification of a hormonal basis for gallbladder filling. Nature Med. 12, 1253–1255 (2006).

  59. 59.

    et al. Impaired negative feedback suppression of bile acid synthesis in mice lacking βKlotho. J. Clin. Invest. 115, 2202–2208 (2005).

  60. 60.

    et al. Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. Mol. Cell Biol. 27, 3417–3428 (2007).

  61. 61.

    et al. Co-receptor requirements for fibroblast growth factor-19 signaling. J. Biol. Chem. 282, 29069–29072 (2007).

  62. 62.

    , , & Liver-specific activities of FGF19 require Klotho β. J. Biol. Chem. 282, 27277–27284 (2007).

  63. 63.

    et al. Differential regulation of rat and human CYP7A1 by the nuclear oxysterol receptor liver X receptor-α. Mol. Endocrinol. 17, 386–394 (2003).

  64. 64.

    & Chenodiol (chenodeoxycholic acid) for dissolution of gallstones: the National Cooperative Gallstone Study. A controlled trial of efficacy and safety. Ann. Intern. Med. 95, 257–282 (1981).

  65. 65.

    & Different effects of chenodeoxycholic acid and ursodeoxycholic acid on serum lipoprotein concentrations in patients with radiolucent gallstones. Scand. J. Gastroenterol. 17, 587–592 (1982).

  66. 66.

    , , & Nuclear receptors and the control of metabolism. Annu. Rev. Physiol. 65, 261–311 (2003).

  67. 67.

    , & Interruption of the enterohepatic circulation of bile acids in man: comparative effects of cholestyramine and ileal exclusion on cholesterol metabolism. J. Lab. Clin. Med. 78, 94–121 (1971).

  68. 68.

    & Changes in plasma triglyceride metabolism during withdrawal of bile. Metabolism 25, 1259–1268 (1976).

  69. 69.

    , , & Effects of cholestyramine and chenodeoxycholic acid on the metabolism of endogenous triglyceride in hyperlipoproteinemia. J. Lipid Res. 19, 1017–1024 (1978).

  70. 70.

    et al. Prevention and treatment of obesity, insulin resistance, and diabetes by bile acid-binding resin. Diabetes 56, 239–247 (2007). Reports the key observation that treatment with bile-acid-binding resin reduces obesity and insulin resistance in mice.

  71. 71.

    & Triglyceride-lowering effect of chenodeoxycholic acid in patients with endogenous hypertriglyceridaemia. Lancet 2, 929–931 (1974).

  72. 72.

    et al. Farnesoid X-activated receptor induces apolipoprotein C-II transcription: a molecular mechanism linking plasma triglyceride levels to bile acids. Mol. Endocrinol. 15, 1720–1728 (2001).

  73. 73.

    , & The nuclear bile acid receptor FXR is activated by PGC-1α in a ligand-dependent manner. Biochem. J. 382, 913–921 (2004).

  74. 74.

    et al. Regulation of carbohydrate metabolism by the farnesoid X receptor. Endocrinology 146, 984–991 (2005).

  75. 75.

    et al. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J. Clin. Invest. 113, 1408–1418 (2004). This study describes the molecular mechanism underlying the triglyceride-lowering action of bile acids.

  76. 76.

    et al. Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc. Natl Acad. Sci. USA 103, 1006–1011 (2006). An interesting study demonstrating that the FXR-signalling pathway controls glucose and lipid homeostasis.

  77. 77.

    et al. Activation of the farnesoid X receptor improves lipid metabolism in combined hyperlipidemic hamsters. Am. J. Physiol. Endocrinol. Metab. 290, E716–E722 (2006).

  78. 78.

    , & SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest. 109, 1125–1131 (2002).

  79. 79.

    et al. Insulin selectively increases SREBP-1c mRNA in the livers of rats with streptozotocin-induced diabetes. Proc. Natl Acad. Sci. USA 96, 13656–13661 (1999).

  80. 80.

    , , & Sterol regulatory element binding protein 1c is a major mediator of insulin action on the hepatic expression of glucokinase and lipogenesis-related genes. Proc. Natl Acad. Sci. USA 96, 12737–12742 (1999).

  81. 81.

    et al. Role of LXRs in control of lipogenesis. Genes Dev. 14, 2831–2838 (2000).

  82. 82.

    et al. Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRα and LXRβ. Genes Dev. 14, 2819–2830 (2000).

  83. 83.

    et al. Mutations in the small heterodimer partner gene are associated with mild obesity in Japanese subjects. Proc. Natl Acad. Sci. USA 98, 575–580 (2001).

  84. 84.

    et al. Contribution of variants in the small heterodimer partner gene to birthweight, adiposity, and insulin levels: mutational analysis and association studies in multiple populations. Diabetes 52, 1288–1291 (2003).

  85. 85.

    et al. Genetic variation in the small heterodimer partner gene and young-onset type 2 diabetes, obesity, and birth weight in U.K. subjects. Diabetes 52, 1276–1279 (2003).

  86. 86.

    et al. Redundant pathways for negative feedback regulation of bile acid production. Dev. Cell 2, 721–731 (2002).

  87. 87.

    et al. Loss of nuclear receptor SHP impairs but does not eliminate negative feedback regulation of bile acid synthesis. Dev. Cell 2, 713–720 (2002).

  88. 88.

    et al. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 102, 731–744 (2000). Demonstrates that FXR is a crucial regulator of bile-acid homeostasis.

  89. 89.

    & FXR signaling in metabolic disease. FEBS Lett. 582, 10–18 (2008).

  90. 90.

    et al. Cholate inhibits high-fat diet-induced hyperglycemia and obesity with acyl-CoA synthetase mRNA decrease. Am. J. Physiol. 273, E37–E45 (1997).

  91. 91.

    et al. Anti-hyperglycemic activity of a TGR5 agonist isolated from Olea Europea. Biochem. Biophys. Res. Commun. 362, 793–798 (2007).

  92. 92.

    et al. Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity. Endocrinology 143, 1741–1747 (2002).

  93. 93.

    et al. The orphan nuclear receptor SHP regulates PGC-1α expression and energy production in brown adipocytes. Cell. Metab. 2, 227–238 (2005).

  94. 94.

    & Cholestyramine therapy for dyslipidemia in non-insulin-dependent diabetes mellitus. A short-term, double-blind, crossover trial. Ann. Intern. Med. 121, 416–422 (1994).

  95. 95.

    et al. The farnesoid X receptor modulates hepatic carbohydrate metabolism during the fasting-refeeding transition. J. Biol. Chem. 280, 29971–29979 (2005).

  96. 96.

    et al. 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. 278, 39124–39132 (2003).

  97. 97.

    et al. Bile acids regulate gluconeogenic gene expression via small heterodimer partner-mediated repression of hepatocyte nuclear factor 4 and Foxo1. J. Biol. Chem. 279, 23158–23165 (2004).

  98. 98.

    , , & Farnesoid X receptor is essential for normal glucose homeostasis. J. Clin. Invest. 116, 1102–1109 (2006). An interesting study demonstrating that the FXR signalling pathway controls glucose homeostasis.

  99. 99.

    et al. PGC-1 promotes insulin resistance in liver through PPAR-α-dependent induction of TRB-3. Nature Med. 10, 530–534 (2004).

  100. 100.

    et al. Transient impairment of the adaptive response to fasting in FXR-deficient mice. FEBS Lett. 579, 4076–4080 (2005).

  101. 101.

    et al. The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice. J. Biol. Chem. 281, 11039–11049 (2006).

  102. 102.

    et al. Bile acids enhance the activity of the insulin receptor and glycogen synthase in primary rodent hepatocytes. Hepatology 39, 456–463 (2004).

  103. 103.

    et al. Bile acids induce mitochondrial ROS, which promote activation of receptor tyrosine kinases and signaling pathways in rat hepatocytes. Hepatology 40, 961–971 (2004).

  104. 104.

    et al. Conjugated bile acids promote ERK1/2 and AKT activation via a pertussis toxin-sensitive mechanism in murine and human hepatocytes. Hepatology 42, 1291–1299 (2005).

  105. 105.

    et al. Conjugated bile acids regulate hepatocyte glycogen synthase activity in vitro and in vivo via Gαi signaling. Mol. Pharmacol. 71, 1122–1128 (2007).

  106. 106.

    Improving metabolism by increasing energy expenditure. Nature Med. 12, 44–45; discussion 45 (2006).

  107. 107.

    et al. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 313, 1137–1140 (2006). An interesting study demonstrating that the bile acid tauroursodeoxycholic acid restores glucose homeo-stasis by reducing endoplasmic reticulum stress.

  108. 108.

    , , , & Targeting farnesoid X receptor for liver and metabolic disorders. Trends Mol. Med. 13, 298–309 (2007).

  109. 109.

    et al. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc. Natl Acad. Sci. USA 103, 3920–3925 (2006).

  110. 110.

    et al. Farnesoid X receptor modulates renal lipid metabolism, fibrosis, and diabetic nephropathy. Diabetes 56, 2485–2493 (2007).

  111. 111.

    et al. Identification of a chemical tool for the orphan nuclear receptor FXR. J. Med. Chem. 43, 2971–2974 (2000).

  112. 112.

    et al. Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis. J. Clin. Invest. 112, 1678–1687 (2003).

  113. 113.

    et al. A synthetic farnesoid X receptor (FXR) agonist protects against diet-induced dyslipidemia. J. Clin. Lipidol. 1, 362 (2007).

  114. 114.

    , & Farnesoid X receptor: from structure to potential clinical applications. J. Med. Chem. 48, 5383–5403 (2005).

  115. 115.

    et al. Guggulsterone is a farnesoid X receptor antagonist in coactivator association assays but acts to enhance transcription of bile salt export pump. J. Biol. Chem. 278, 10214–10220 (2003).

  116. 116.

    et al. Identification of gene-selective modulators of the bile acid receptor FXR. J. Biol. Chem. 278, 7027–7033 (2003).

  117. 117.

    et al. A natural product that lowers cholesterol as an antagonist ligand for FXR. Science 296, 1703–1706 (2002). This study identifies guggulsterone as an FXR antagonist and relays this property to its cholesterol-lowering effects.

  118. 118.

    et al. The hypolipidemic natural product guggulsterone acts as an antagonist of the bile acid receptor. Mol. Endocrinol. 16, 1590–1597 (2002).

  119. 119.

    et al. Guggulipid for the treatment of hypercholesterolemia: a randomized controlled trial. JAMA 290, 765–772 (2003).

  120. 120.

    , , & Is antagonism of E/Z-guggulsterone at the farnesoid X receptor mediated by a noncanonical binding site? A molecular modeling study. J. Med. Chem. 48, 6948–6955 (2005).

  121. 121.

    et al. Novel potent and selective bile acid derivatives as TGR5 agonists: biological screening, structure–activity relationships, and molecular modeling studies. J. Med. Chem. 51, 1831–1841 (2008). The first description of the structure–activity relationship of bile acids as TGR5 ligands.

  122. 122.

    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. 50, 4265–4268 (2007).

  123. 123.

    et al., Receptor antagonists. WO2004067008 (2004).

  124. 124.

    & G protein coupled receptor AXOR 109. GB2371546A (2001).

  125. 125.

    , , , & Effect of colestimide therapy for glycemic control in type 2 diabetes mellitus with hypercholesterolemia. Endocr. J. 54, 53–58 (2007).

  126. 126.

    et al. Glucuronidation converting methyl 1-(3,4-dimethoxyphenyl)-3-(3-ethylvaleryl)-4-hydroxy-6,7,8-trimethoxy-2-na phthoate (S-8921) to a potent apical sodium-dependent bile acid transporter inhibitor, resulting in a hypocholesterolemic action. J. Pharmacol. Exp. Ther. 322, 610–618 (2007).

  127. 127.

    et al. Inhibition of ileal bile acid transport lowers plasma cholesterol levels by inactivating hepatic farnesoid X receptor and stimulating cholesterol 7 α-hydroxylase. Metabolism 53, 927–932 (2004).

  128. 128.

    , , , & SC-435, an ileal apical sodium co-dependent bile acid transporter (ASBT) inhibitor lowers plasma cholesterol and reduces atherosclerosis in guinea pigs. Atherosclerosis 171, 201–210 (2003).

  129. 129.

    et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006).

  130. 130.

    et al. A top-down systems biology view of microbiome–mammalian metabolic interactions in a mouse model. Mol. Syst. Biol. 3, 112 (2007).

  131. 131.

    et al. Symbiotic gut microbes modulate human metabolic phenotypes. Proc. Natl Acad. Sci. USA 105, 2117–2122 (2008).

  132. 132.

    & Modulation of longevity by environmental sensing. Cell 131, 1231–1234 (2007).

  133. 133.

    The physiology of glucagon-like peptide 1. Physiol. Rev. 87, 1409–1439 (2007).

  134. 134.

    et al. Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science 312, 233–236 (2006).

  135. 135.

    et al. Identification of ligands for DAF-12 that govern dauer formation and reproduction in C. elegans. Cell 124, 1209–1223 (2006).

  136. 136.

    et al. A bile acid-like steroid modulates Caenorhabditis elegans lifespan through nuclear receptor signaling. Proc. Natl Acad. Sci. USA 104, 5014–5019 (2007).

  137. 137.

    , , & Feeding natural hydrophilic bile acids inhibits intestinal cholesterol absorption: studies in the gallstone-susceptible mouse. Am. J. Physiol. Gastrointest. Liver Physiol. 285, G494–G502 (2003).

  138. 138.

    , & Lithocholyltaurine interacts with cholinergic receptors on dispersed chief cells from guinea pig stomach. Am. J. Physiol. 274, G997–G1004 (1998).

  139. 139.

    , & Muscarinic acetylcholine receptors: mutant mice provide new insights for drug development. Nature Rev. Drug Discov. 6, 721–733 (2007).

  140. 140.

    et al. A critical role for beta cell M3 muscarinic acetylcholine receptors in regulating insulin release and blood glucose homeostasis in vivo. Cell. Metab. 3, 449–461 (2006).

  141. 141.

    , & Formyl-peptide receptors revisited. Trends Immunol. 23, 541–548 (2002).

  142. 142.

    et al. Characterization of chenodeoxycholic acid as an endogenous antagonist of the G-coupled formyl peptide receptors. Inflamm. Res. 49, 744–755 (2000).

  143. 143.

    et al. Effect of cholestasis and bile acids on interferon-induced 2′,5′-adenylate synthetase and NK cell activities. Gastroenterology 108, 1192–1198 (1995).

  144. 144.

    , , & Pharmacophore model for bile acids recognition by the FPR receptor. J. Comput. Aided Mol. Des. 20, 295–303 (2006).

  145. 145.

    et al. Bile acid regulation of C/EBPβ, CREB, and c-Jun function, via the extracellular signal-regulated kinase and c-Jun NH2-terminal kinase pathways, modulates the apoptotic response of hepatocytes. Mol. Cell Biol. 23, 3052–3066 (2003).

  146. 146.

    et al. Bile acid-mediated induction of cyclooxygenase-2 and Mcl-1 in hepatic stellate cells. Biochem. Biophys. Res. Commun. 342, 1108–1113 (2006).

  147. 147.

    , & Activation and role of mitogen-activated protein kinases in deoxycholic acid-induced apoptosis. Carcinogenesis 22, 35–41 (2001).

  148. 148.

    , , & Down-regulation of cholesterol 7α-hydroxylase (CYP7A1) gene expression by bile acids in primary rat hepatocytes is mediated by the c-Jun N-terminal kinase pathway. J. Biol. Chem. 276, 15816–15822 (2001).

  149. 149.

    Three hypotheses linking bile to carcinogenesis in the gastrointestinal tract: certain bile salts have properties that may be used to complement chemotherapy. Med. Hypotheses 59, 398–405 (2002).

  150. 150.

    et al. Expression of sterol 12α-hydroxylase alters bile acid pool composition in primary rat hepatocytes and in vivo. Gastroenterology 120, 1801–1809 (2001).

  151. 151.

    et al. Cholic acid mediates negative feedback regulation of bile acid synthesis in mice. J. Clin. Invest. 110, 1191–1200 (2002).

  152. 152.

    et al. Molecular cloning and expression of rat liver bile acid CoA ligase. J. Lipid Res. 43, 2062–2071 (2002).

  153. 153.

    et al. Bile acid coenzyme A: amino acid N-acyltransferase in the amino acid conjugation of bile acids. Methods Enzymol. 400, 374–394 (2005).

  154. 154.

    , & Rat liver bile acid CoA:amino acid N-acyltransferase: expression, characterization, and peroxisomal localization. J. Lipid Res. 44, 2242–2249 (2003).

  155. 155.

    & Bile salt transporters. Annu. Rev. Physiol. 64, 635–661 (2002).

  156. 156.

    & Bile salt transporters: molecular characterization, function, and regulation. Physiol. Rev. 83, 633–671 (2003).

  157. 157.

    et al. The organic solute transporter α-β, Ostα-Ostβ, is essential for intestinal bile acid transport and homeostasis. Proc. Natl Acad. Sci. USA 105, 3891–3896 (2008).

  158. 158.

    & Nuclear bile acid receptor FXR as pharmacological target: are we there yet? FEBS Lett. 580, 5492–5499 (2006).

  159. 159.

    et al. 6α-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J. Med. Chem. 45, 3569–3572 (2002).

  160. 160.

    , , , & The farnesoid X receptor FXRα/NR1H4 acquired ligand specificity for bile salts late in vertebrate evolution. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293, R1400–R1409 (2007).

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Acknowledgements

The authors acknowledge support by grants from the Centre National de la Recherche Scientifique, the Institut National de la Santé et de la Recherche Médicale, the Université Louis Pasteur, the Hôpital Universitaire de Strasbourg, the National Institutes of Health (DK59820 and DK067320), L'Agence Nationale pour la Recherche (ANR 07-PHYSIO-003-01), La Fondation pour la Recherche Médicale, Ligue contre le Cancer, Intercept Pharmaceuticals (New York, USA), the Ecole Polytechnique Federale de Lausanne and the European Union (LSHM-CT-2004-512,013), and by fellowships from Société Française de Nutrition and L'Association pour la Recherche sur le Cancer (to C.T.). We apologize to those authors whose original work could not be quoted owing to space restrictions.

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Affiliations

  1. Institute of Genetics and Molecular and Cellular Biology, 1 Rue Laurent Fries, 67404 Illkirch, France.

    • Charles Thomas
    • , Johan Auwerx
    •  & Kristina Schoonjans
  2. Department of Chemistry and Pharmaceutical Technology, University of Perugia, 06123 Perugia, Italy.

    • Roberto Pellicciari
  3. Intercept Pharmaceuticals, 18 Desbrosses Street, New York, New York 10013, USA.

    • Mark Pruzanski
  4. Mouse Clinical Institute, 1 Rue Laurent Fries, 67404 Illkirch, France.

    • Johan Auwerx
  5. Swiss Federal Institute of Technology, CH 1015 Lausanne, Switzerland.

    • Johan Auwerx
    •  & Kristina Schoonjans

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Competing interests

J.A. and R.P. are consultants for Intercept Pharmaceuticals, and M.P. is CEO of Intercept Pharmaceuticals, a company that is developing FXR-α and TGR5 ligands.

Corresponding authors

Correspondence to Johan Auwerx or Kristina Schoonjans.

Glossary

Bile canaliculus

One of the intercellular channels that occur between liver cells that form the first portion of the bile system. The different components of bile, synthesized and secreted by hepatocytes, are collected in these bile canaliculi, which merge and ultimately form bile ductules.

Atherosclerosis

A chronic inflammatory response in the walls of arteries, in large part due to the infiltration of macrophages, which accumulate cholesterol from low-density lipoproteins. Without the adequate removal of this cholesterol by high-density lipoproteins, these macrophages become foam cells.

Cerebrotendinous xanthomatosis

An inherited disorder that is associated with elevated circulating cholesterol levels and deposition of cholestanol in the brain and other tissues. This disorder is characterized by progressive cerebellar ataxia beginning after puberty, by juvenile cataracts, and by tendinous or tuberous xanthomas.

Syntenic

Describes a preserved co-localization of genes on chromosomes between different species.

Brown adipose tissue

Brown adipose tissue (BAT) is one of the two types of adipose tissue, the other being white adipose tissue. BAT is present in human newborns or small mammals. Its primary purpose is to generate body heat, owing to a high density of mitochondria.

Lithogenic diet

An experimental diet to induce cholelithiasis or cholesterol gallstones in the gall bladder.

Kupffer cells

Kupffer cells are specialized macrophages located in the liver that are part of the reticuloendothelial system.

Incretins

Incretins are gastrointestinal hormones that cause an increase in the amount of insulin released from the pancreatic β-cells after a meal. Gastric inhibitory peptide (GIP) — also known as glucose-dependent insulinotropic peptide — and glucagon-like peptide 1 (GLP1) are the two main incretins secreted by the enteroendocrine K and L cells, respectively.

Hypertriglyceridaemia

Denotes high levels of triglycerides in the blood.

Type 2 iodothyronine deiodinase

This enzyme activates thyroid hormone by converting the prohormone thyroxine (T4) by outer ring deiodination to the bioactive 3,3′,5-triiodothyronine (T3).

Diabesity

An association of obesity and type 2 diabetes.

Endoplasmic reticulum stress

Cellular disturbances causing an accumulation of unfolded proteins in the endoplasmic reticulum, which results in activation of the unfolded protein response.

Non-alcoholic steato-hepatitis

Non-alcoholic steatohepatitis (NASH) is a common and often silent liver disease, which has become one of the most prevalent alcohol-independent causes of liver cirrhosis in Western countries. Similar to non-alcoholic fatty liver disease (NAFLD), NASH is characterized by the accumulation of hepatic fat droplets, but distinguishes itself from NAFLD by the presence of a significant inflammatory component.

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DOI

https://doi.org/10.1038/nrd2619

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