Advertisement

FXR Agonists as Therapeutic Agents for Non-alcoholic Fatty Liver Disease

  • Rotonya M. CarrEmail author
  • Andrea E. Reid
Nonstatin Drugs (EM deGoma, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Nonstatin Drugs

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and a risk factor for both cardiovascular and hepatic related morbidity and mortality. The increasing prevalence of this disease requires novel therapeutic approaches to prevent disease progression. Farnesoid X receptors are bile acid receptors with roles in lipid, glucose, and energy homeostasis. Synthetic farnesoid X receptor (FXR) agonists have been developed to specifically target these receptors for therapeutic use in NAFLD patients. Here, we present a review of bile acid physiology and how agonism of FXR receptors has been examined in pre-clinical and clinical NAFLD. Early evidence suggests a potential role for synthetic FXR agonists in the management of NAFLD; however, additional studies are needed to clarify their effects on lipid and glucose parameters in humans.

Keywords

FXR Obetacholic acid Bile acid NAFLD NASH Alcoholic hepatitis 

Notes

Acknowledgments

This study was supported by the National Institutes of Health (NIH) grant funding from the following sources: K08-AA021424, P30-DK-50306 pilot, and feasibility grant program and Robert Wood Johnson Foundation, Harold Amos Medical Faculty Development Award, 71586 (RMC)

Compliance with Ethics Guidelines

Conflict of Interest

Rotonya M. Carr and Andrea E. Reid declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Bellentani S et al. Epidemiology of non-alcoholic fatty liver disease. Dig Dis. 2010;28(1):155–61.PubMedGoogle Scholar
  2. 2.
    Browning JD et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004;40(6):1387–95.PubMedGoogle Scholar
  3. 3.
    Marchesini G et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology. 2003;37(4):917–23.PubMedGoogle Scholar
  4. 4.•
    Stepanova M. Independent association between nonalcoholic fatty liver disease and cardiovascular disease in the US population. Clin Gastroenterol Hepatol: Off Clin Pract J Am Gastroenterol Assoc. 2012;10(6):646–50. This study is an analysis of NHANES III data examining cardiovascular disease risk in NAFLD patients by comparing ultrasound and mortality data.Google Scholar
  5. 5.
    Adams LA et al. NAFLD as a risk factor for the development of diabetes and the metabolic syndrome: an eleven-year follow-up study. Am J Gastroenterol. 2009;104(4):861–7.PubMedGoogle Scholar
  6. 6.
    Rafiq N et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol: Off Clin Pract J Am Gastroenterol Assoc. 2009;7(2):234–8.Google Scholar
  7. 7.
    Charlton MR et al. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology. 2011;141(4):1249–53.PubMedGoogle Scholar
  8. 8.••
    Chalasani N et al. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55(6):2005–23. This guideline establishes the standard of care for management of NAFLD patients.PubMedGoogle Scholar
  9. 9.
    Kleiner DE et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41(6):1313–21.PubMedGoogle Scholar
  10. 10.
    Promrat K et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology. 2010;51(1):121–9.PubMedCentralPubMedGoogle Scholar
  11. 11.
    Svetkey LP et al. Comparison of strategies for sustaining weight loss: the weight loss maintenance randomized controlled trial. JAMA. 2008;299(10):1139–48.PubMedGoogle Scholar
  12. 12.
    Kotronen A, Yki-Jarvinen H. Fatty liver: a novel component of the metabolic syndrome. Arterioscler Thromb Vasc Biol. 2008;28(1):27–38.PubMedGoogle Scholar
  13. 13.
    Harrison SA et al. Orlistat for overweight subjects with nonalcoholic steatohepatitis: A randomized, prospective trial. Hepatology. 2009;49(1):80–6.PubMedGoogle Scholar
  14. 14.
    Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology. 2010;52(5):1836–46.PubMedGoogle Scholar
  15. 15.
    Zhou G et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108(8):1167–74.PubMedCentralPubMedGoogle Scholar
  16. 16.
    Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011;34(3):274–85.PubMedGoogle Scholar
  17. 17.
    Belfort R et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355(22):2297–307.PubMedGoogle Scholar
  18. 18.
    Aithal GP et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology. 2008;135(4):1176–84.PubMedGoogle Scholar
  19. 19.
    Sanyal AJ et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362(18):1675–85.PubMedCentralPubMedGoogle Scholar
  20. 20.
    Harrison SA et al. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am J Gastroenterol. 2003;98(11):2485–90.PubMedGoogle Scholar
  21. 21.
    Saremi A, Arora R. Vitamin E and cardiovascular disease. Am J Ther. 2010;17(3):e56–65.PubMedGoogle Scholar
  22. 22.
    Lippman SM et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2009;301(1):39–51.PubMedCentralPubMedGoogle Scholar
  23. 23.
    Lefebvre P et al. Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev. 2009;89(1):147–91.PubMedGoogle Scholar
  24. 24.
    Hollman DA et al. Anti-inflammatory and metabolic actions of FXR: insights into molecular mechanisms. Biochim Biophys Acta. 2012;1821(11):1443–52.PubMedGoogle Scholar
  25. 25.
    Makishima M et al. Identification of a nuclear receptor for bile acids. Science. 1999;284(5418):1362–5.PubMedGoogle Scholar
  26. 26.
    Parks DJ et al. Bile acids: natural ligands for an orphan nuclear receptor. Science. 1999;284(5418):1365–8.PubMedGoogle Scholar
  27. 27.
    Wang H et al. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell. 1999;3(5):543–53.PubMedGoogle Scholar
  28. 28.
    Kawamata Y et al. A G protein-coupled receptor responsive to bile acids. J Biol Chem. 2003;278(11):9435–40.PubMedGoogle Scholar
  29. 29.
    Reddy JK, Rao MS. Lipid metabolism and liver inflammation. II. Fatty liver disease and fatty acid oxidation. Am J Physiol Gastrointest Liver Physiol. 2006;290(5):G852–8.PubMedGoogle Scholar
  30. 30.
    Ridlon JM, Kang DJ, Hylemon PB. Bile salt biotransformations by human intestinal bacteria. J Lipid Res. 2006;47(2):241–59.PubMedGoogle Scholar
  31. 31.
    Schreuder TC et al. The hepatic response to FGF19 is impaired in patients with nonalcoholic fatty liver disease and insulin resistance. Am J Physiol Gastrointest Liver Physiol. 2010;298(3):G440–5.PubMedGoogle Scholar
  32. 32.
    Ikemoto S et al. Cholate inhibits high-fat diet-induced hyperglycemia and obesity with acyl-CoA synthetase mRNA decrease. Am J Physiol. 1997;273(1 Pt 1):E37–45.PubMedGoogle Scholar
  33. 33.
    Liaset B et al. Nutritional regulation of bile acid metabolism is associated with improved pathological characteristics of the metabolic syndrome. J Biol Chem. 2011;286(32):28382–95.PubMedCentralPubMedGoogle Scholar
  34. 34.
    Patti ME et al. Serum bile acids are higher in humans with prior gastric bypass: potential contribution to improved glucose and lipid metabolism. Obesity. 2009;17(9):1671–7.PubMedGoogle Scholar
  35. 35.
    Bennion LJ, Grundy SM. Effects of diabetes mellitus on cholesterol metabolism in man. N Engl J Med. 1977;296(24):1365–71.PubMedGoogle Scholar
  36. 36.
    Abrams JJ, Ginsberg H, Grundy SM. Metabolism of cholesterol and plasma triglycerides in nonketotic diabetes mellitus. Diabetes. 1982;31(10):903–10.PubMedGoogle Scholar
  37. 37.
    Brufau G et al. Improved glycemic control with colesevelam treatment in patients with type 2 diabetes is not directly associated with changes in bile acid metabolism. Hepatology. 2010;52(4):1455–64.PubMedGoogle Scholar
  38. 38.
    St-Pierre MV et al. Transport of bile acids in hepatic and non-hepatic tissues. J Exp Biol. 2001;204(Pt 10):1673–86.PubMedGoogle Scholar
  39. 39.
    van der Velden LM et al. Monitoring bile acid transport in single living cells using a genetically encoded Forster resonance energy transfer sensor. Hepatology. 2013;57(2):740–52.PubMedGoogle Scholar
  40. 40.
    Fuchs C, Claudel T, Trauner M. Bile acid-mediated control of liver triglycerides. Semin Liver Dis. 2013;33(4):330–42.PubMedGoogle Scholar
  41. 41.
    Zhang Y, Kast-Woelbern HR, Edwards PA. Natural structural variants of the nuclear receptor farnesoid X receptor affect transcriptional activation. J Biol Chem. 2003;278(1):104–10.PubMedGoogle Scholar
  42. 42.
    Huber RM et al. Generation of multiple farnesoid-X-receptor isoforms through the use of alternative promoters. Gene. 2002;290(1–2):35–43.PubMedGoogle Scholar
  43. 43.
    Sinal CJ et al. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell. 2000;102(6):731–44.PubMedGoogle Scholar
  44. 44.
    Ma K et al. Farnesoid X receptor is essential for normal glucose homeostasis. J Clin Invest. 2006;116(4):1102–9.PubMedCentralPubMedGoogle Scholar
  45. 45.
    Duran-Sandoval D et al. Glucose regulates the expression of the farnesoid X receptor in liver. Diabetes. 2004;53(4):890–8.PubMedGoogle Scholar
  46. 46.
    Heni M et al. Genetic variation in NR1H4 encoding the bile acid receptor FXR determines fasting glucose and free fatty acid levels in humans. J Clin Endocrinol Metab. 2013;98(7):E1224–9.PubMedGoogle Scholar
  47. 47.
    Postic C, Girard J. Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J Clin Invest. 2008;118(3):829–38.PubMedCentralPubMedGoogle Scholar
  48. 48.
    Watanabe M et al. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest. 2004;113(10):1408–18.PubMedCentralPubMedGoogle Scholar
  49. 49.
    Ikeda H. KK mouse. Diabetes Res Clin Pract. 1994;24(Suppl):S313–6.PubMedGoogle Scholar
  50. 50.
    Stienstra R et al. Peroxisome proliferator-activated receptor alpha protects against obesity-induced hepatic inflammation. Endocrinology. 2007;148(6):2753–63.PubMedGoogle Scholar
  51. 51.
    Pineda Torra I et al. Bile acids induce the expression of the human peroxisome proliferator-activated receptor alpha gene via activation of the farnesoid X receptor. Mol Endocrinol. 2003;17(2):259–72.PubMedGoogle Scholar
  52. 52.
    Stayrook KR et al. Regulation of carbohydrate metabolism by the farnesoid X receptor. Endocrinology. 2005;146(3):984–91.PubMedGoogle Scholar
  53. 53.
    Yang J, Kalhan SC, Hanson RW. What is the metabolic role of phosphoenolpyruvate carboxykinase? J Biol Chem. 2009;284(40):27025–9.PubMedCentralPubMedGoogle Scholar
  54. 54.
    De Fabiani E 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. 2003;278(40):39124–32.PubMedGoogle Scholar
  55. 55.
    Yamagata K 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.PubMedGoogle Scholar
  56. 56.
    Goodwin B 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.PubMedGoogle Scholar
  57. 57.
    Abu-Shanab A, Quigley EM. The role of the gut microbiota in nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol. 2010;7(12):691–701.PubMedGoogle Scholar
  58. 58.
    Elsharkawy AM, Mann DA. Nuclear factor-kappaB and the hepatic inflammation-fibrosis-cancer axis. Hepatology. 2007;46(2):590–7.PubMedGoogle Scholar
  59. 59.
    Wang YD et al. Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response. Hepatology. 2008;48(5):1632–43.PubMedCentralPubMedGoogle Scholar
  60. 60.
    Kim I et al. Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice. Carcinogenesis. 2007;28(5):940–6.PubMedCentralPubMedGoogle Scholar
  61. 61.
    Yang F et al. Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor. Cancer Res. 2007;67(3):863–7.PubMedGoogle Scholar
  62. 62.
    Lu Y et al. Yin Yang 1 promotes hepatic steatosis through repression of farnesoid X receptor in obese mice. Gut. 2014;63(1):170–8.PubMedGoogle Scholar
  63. 63.
    Xiong X et al. Hepatic steatosis exacerbated by endoplasmic reticulum stress-mediated downregulation of FXR in aging mice. J Hepatol. 2014;60(4):847–54.PubMedGoogle Scholar
  64. 64.
    Liu X et al. Activation of farnesoid X receptor (FXR) protects against fructose-induced liver steatosis via inflammatory inhibition and ADRP reduction. Biochem Biophys Res Commun. 2014;450(1):117–23.PubMedGoogle Scholar
  65. 65.
    Zhang S et al. Farnesoid X receptor agonist WAY-362450 attenuates liver inflammation and fibrosis in murine model of non-alcoholic steatohepatitis. J Hepatol. 2009;51(2):380–8.PubMedGoogle Scholar
  66. 66.
    Fiorucci S et al. The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis. Gastroenterology. 2004;127(5):1497–512.PubMedGoogle Scholar
  67. 67.
    Huang W et al. Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science. 2006;312(5771):233–6.PubMedGoogle Scholar
  68. 68.
    Chen WD et al. Farnesoid X receptor alleviates age-related proliferation defects in regenerating mouse livers by activating forkhead box m1b transcription. Hepatology. 2010;51(3):953–62.PubMedCentralPubMedGoogle Scholar
  69. 69.
    Zhang L et al. Significance and mechanism of CYP7a1 gene regulation during the acute phase of liver regeneration. Mol Endocrinol. 2009;23(2):137–45.PubMedCentralPubMedGoogle Scholar
  70. 70.
    Meng Z et al. FXR regulates liver repair after CCl4-induced toxic injury. Mol Endocrinol. 2010;24(5):886–97.PubMedCentralPubMedGoogle Scholar
  71. 71.
    Ahima RS, Flier JS. Leptin. Annu Rev Physiol. 2000;62:413–37.PubMedGoogle Scholar
  72. 72.
    Durham HA, Truett GE. Development of insulin resistance and hyperphagia in Zucker fatty rats. Am J Physiol Regul Integr Comp Physiol. 2006;290(3):R652–8.PubMedGoogle Scholar
  73. 73.
    Cipriani S et al. FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats. J Lipid Res. 2010;51(4):771–84.PubMedCentralPubMedGoogle Scholar
  74. 74.
    Carr RM et al. Absence of perilipin 2 prevents hepatic steatosis, glucose intolerance and ceramide accumulation in alcohol-fed mice. PLoS One. 2014;9(5):e97118.PubMedCentralPubMedGoogle Scholar
  75. 75.
    Chang BH et al. Protection against fatty liver but normal adipogenesis in mice lacking adipose differentiation-related protein. Mol Cell Biol. 2006;26(3):1063–76.PubMedCentralPubMedGoogle Scholar
  76. 76.
    Varela GM et al. Inhibition of ADRP prevents diet-induced insulin resistance. Am J Physiol Gastrointest Liver Physiol. 2008;295(3):G621–8.PubMedCentralPubMedGoogle Scholar
  77. 77.
    Bjursell M et al. Ageing Fxr deficient mice develop increased energy expenditure, improved glucose control and liver damage resembling NASH. PLoS One. 2013;8(5):e64721.PubMedCentralPubMedGoogle Scholar
  78. 78.
    Anstee QM, Goldin RD. Mouse models in non-alcoholic fatty liver disease and steatohepatitis research. Int J Exp Pathol. 2006;87(1):1–16.PubMedCentralPubMedGoogle Scholar
  79. 79.
    Tanaka N et al. Disruption of phospholipid and bile acid homeostasis in mice with nonalcoholic steatohepatitis. Hepatology. 2012;56(1):118–29.PubMedGoogle Scholar
  80. 80.
    Vignozzi L et al. Farnesoid X receptor activation improves erectile function in animal models of metabolic syndrome and diabetes. J Sex Med. 2011;8(1):57–77.PubMedGoogle Scholar
  81. 81.
    Mencarelli A et al. Antiatherosclerotic effect of farnesoid X receptor. Am J Physiol Heart Circ Physiol. 2009;296(2):H272–81.PubMedGoogle Scholar
  82. 82.
    Perez Tamayo R. Is cirrhosis of the liver experimentally produced by CCl4 and adequate model of human cirrhosis? Hepatology. 1983;3(1):112–20.PubMedGoogle Scholar
  83. 83.
    Kountouras J, Billing BH, Scheuer PJ. Prolonged bile duct obstruction: a new experimental model for cirrhosis in the rat. Br J Exp Pathol. 1984;65(3):305–11.PubMedCentralPubMedGoogle Scholar
  84. 84.
    Bhunchet E, Wake K. Role of mesenchymal cell populations in porcine serum-induced rat liver fibrosis. Hepatology. 1992;16(6):1452–73.PubMedGoogle Scholar
  85. 85.
    Ascha MS et al. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology. 2010;51(6):1972–8.PubMedGoogle Scholar
  86. 86.
    Deuschle U et al. FXR controls the tumor suppressor NDRG2 and FXR agonists reduce liver tumor growth and metastasis in an orthotopic mouse xenograft model. PLoS One. 2012;7(10):e43044.PubMedCentralPubMedGoogle Scholar
  87. 87.
    Campana G et al. Regulation of ileal bile acid-binding protein expression in Caco-2 cells by ursodeoxycholic acid: role of the farnesoid X receptor. Biochem Pharmacol. 2005;69(12):1755–63.PubMedGoogle Scholar
  88. 88.
    Amaral JD et al. Bile acids: regulation of apoptosis by ursodeoxycholic acid. J Lipid Res. 2009;50(9):1721–34.PubMedCentralPubMedGoogle Scholar
  89. 89.
    Lindor KD et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology. 2004;39(3):770–8.PubMedGoogle Scholar
  90. 90.
    Ratziu V et al. A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis. J Hepatol. 2011;54(5):1011–9.PubMedGoogle Scholar
  91. 91.
    Pellicciari R et al. Bile acid derivatives as ligands of the farnesoid X receptor. Synthesis, evaluation, and structure-activity relationship of a series of body and side chain modified analogues of chenodeoxycholic acid. J Med Chem. 2004;47(18):4559–69.PubMedGoogle Scholar
  92. 92.••
    Mudaliar S et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology. 2013;145(3):574–82 e1. This is the first clinical trial of the first-in-class FXR synthetic agonist OCA in diabetic NAFLD patients that establishes the safety of OCA in NAFLD patients.PubMedGoogle Scholar
  93. 93.
    Marchesini G et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes. 2001;50(8):1844–50.PubMedGoogle Scholar
  94. 94.
    Feldstein AE et al. Cytokeratin-18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: a multicenter validation study. Hepatology. 2009;50(4):1072–8.PubMedCentralPubMedGoogle Scholar
  95. 95.••
    Neuschwander-Tetri BA, et al., Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2014. This is the first clinical trial of OCA in NASH patients.Google Scholar
  96. 96.
    Angulo P, The prognostic relevance of liver histology features in nonalcoholic fatty liver disease: the PRELHIN study. AASLD 2014. Abstract. 2014.Google Scholar
  97. 97.
    Janssen I, Katzmarzyk PT, Ross R. Waist circumference and not body mass index explains obesity-related health risk. Am J Clin Nutr. 2004;79(3):379–84.PubMedGoogle Scholar
  98. 98.
    Hu M et al. The farnesoid X receptor -1G > T polymorphism influences the lipid response to rosuvastatin. J Lipid Res. 2012;53(7):1384–9.PubMedCentralPubMedGoogle Scholar
  99. 99.
    Alemi F et al. The TGR5 receptor mediates bile acid-induced itch and analgesia. J Clin Invest. 2013;123(4):1513–30.PubMedCentralPubMedGoogle Scholar
  100. 100.
    Intercept Provides 2014 Year-End Update and Planned 2015 Milestones. Jan. 15, 2015 Accessed January 26, 2015]; Available from: http://ir.interceptpharma.com/releasedetail.cfm?releaseid=890713.
  101. 101.
    Carr RM et al. Temporal effects of ethanol consumption on energy homeostasis, hepatic steatosis, and insulin sensitivity in mice. Alcohol Clin Exp Res. 2013;37(7):1091–9.PubMedCentralPubMedGoogle Scholar
  102. 102.
    Wu W et al. Activation of farnesoid X receptor attenuates hepatic injury in a murine model of alcoholic liver disease. Biochem Biophys Res Commun. 2014;443(1):68–73.PubMedGoogle Scholar
  103. 103.
    Livero FA et al. The FXR agonist 6ECDCA reduces hepatic steatosis and oxidative stress induced by ethanol and low-protein diet in mice. Chem Biol Interact. 2014;217:19–27.PubMedGoogle Scholar
  104. 104.
    Dunn W et al. MELD accurately predicts mortality in patients with alcoholic hepatitis. Hepatology. 2005;41(2):353–8.PubMedGoogle Scholar
  105. 105.
    Kowdley KV, Jones D, Luketic V, C.R.B.A., et al., An International Study Evaluating the Farnesoid X Receptor Agonist Obeticholic Acid as Monotherapy in PBC. J Hepatol. 2011(Suppl 1): p. S13.Google Scholar
  106. 106.
    Lambert G et al. The farnesoid X-receptor is an essential regulator of cholesterol homeostasis. J Biol Chem. 2003;278(4):2563–70.PubMedGoogle Scholar
  107. 107.
    Hambruch E et al. Synthetic farnesoid X receptor agonists induce high-density lipoprotein-mediated transhepatic cholesterol efflux in mice and monkeys and prevent atherosclerosis in cholesteryl ester transfer protein transgenic low-density lipoprotein receptor (−/−) mice. J Pharmacol Exp Ther. 2012;343(3):556–67.PubMedGoogle Scholar
  108. 108.
    Rohrl C et al. Bile acids reduce endocytosis of high-density lipoprotein (HDL) in HepG2 cells. PLoS One. 2014;9(7):e102026.PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Division of GastroenterologyUniversity of PennsylvaniaPhiladelphiaUSA
  2. 2.Gastroenterology, Hepatology and Nutrition SectionWashington DC VA Medical CenterWashingtonUSA

Personalised recommendations