Endocrinol Metab.  2016 Dec;31(4):500-504. 10.3803/EnM.2016.31.4.500.

Bile Acid Nuclear Receptor Farnesoid X Receptor: Therapeutic Target for Nonalcoholic Fatty Liver Disease

• Kim SG
• Kim BK
• Kim K
• Fang S

• KMID: 2373067
• DOI: http://doi.org/10.3803/EnM.2016.31.4.500

Abstract

Nonalcoholic fatty liver disease (NAFLD) is one of the causes of fatty liver, occurring when fat is accumulated in the liver without alcohol consumption. NAFLD is the most common liver disorder in advanced countries. NAFLD is a spectrum of pathology involving hepatic steatosis with/without inflammation and nonalcoholic steatohepatitis with accumulation of hepatocyte damage and hepatic fibrosis. Recent studies have revealed that NAFLD results in the progression of cryptogenic cirrhosis that leads to hepatocarcinoma and cardiovascular diseases such as heart failure. The main causes of NAFLD have not been revealed yet, metabolic syndromes including obesity and insulin resistance are widely accepted for the critical risk factors for the pathogenesis of NAFLD. Nuclear receptors (NRs) are transcriptional factors that sense environmental or hormonal signals and regulate expression of genes, involved in cellular growth, development, and metabolism. Several NRs have been reported to regulate genes involved in energy and xenobiotic metabolism and inflammation. Among various NRs, farnesoid X receptor (FXR) is abundantly expressed in the liver and a key regulator to control various metabolic processes in the liver. Recent studies have shown that NAFLD is associated with inappropriate function of FXR. The impact of FXR transcriptional activity in NAFLD is likely to be potential therapeutic strategy, but still requires to elucidate underlying potent therapeutic mechanisms of FXR for the treatment of NAFLD. This article will focus the physiological roles of FXR and establish the correlation between FXR transcriptional activity and the pathogenesis of NAFLD.

Keyword

Bile acids and salts; Receptors, cytoplasmic and nuclear; Farnesoid X receptor; Non-alcoholic fatty liver disease; Obeticholic acid

MeSH Terms

Alcohol Drinking
Bile Acids and Salts
Bile*
Cardiovascular Diseases
Fatty Liver
Fibrosis
Heart Failure
Hepatocytes
Inflammation
Insulin Resistance
Liver
Metabolism
Non-alcoholic Fatty Liver Disease*
Obesity
Pathology
Receptors, Cytoplasmic and Nuclear
Risk Factors
Bile Acids and Salts
Receptors, Cytoplasmic and Nuclear

Reference

1. Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology. 2011; 140:124–131.

2. Lazo M, Hernaez R, Eberhardt MS, Bonekamp S, Kamel I, Guallar E, et al. Prevalence of nonalcoholic fatty liver disease in the United States: the Third National Health and Nutrition Examination Survey, 1988-1994. Am J Epidemiol. 2013; 178:38–45.

3. Bonapace S, Valbusa F, Bertolini L, Pichiri I, Mantovani A, Rossi A, et al. Nonalcoholic fatty liver disease is associated with aortic valve sclerosis in patients with type 2 diabetes mellitus. PLoS One. 2014; 9:e88371.

4. El Azeem HA, Khalek el-SA, El-Akabawy H, Naeim H, Khalik HA, Alfifi AA. Association between nonalcoholic fatty liver disease and the incidence of cardiovascular and renal events. J Saudi Heart Assoc. 2013; 25:239–246.

5. Lin XF, Shi KQ, You J, Liu WY, Luo YW, Wu FL, et al. Increased risk of colorectal malignant neoplasm in patients with nonalcoholic fatty liver disease: a large study. Mol Biol Rep. 2014; 41:2989–2997.

6. Targher G, Chonchol M, Zoppini G, Abaterusso C, Bonora E. Risk of chronic kidney disease in patients with non-alcoholic fatty liver disease: is there a link? J Hepatol. 2011; 54:1020–1029.

7. Sanyal AJ. NASH: a global health problem. Hepatol Res. 2011; 41:670–674.

8. Lee FY, Lee H, Hubbert ML, Edwards PA, Zhang Y. FXR, a multipurpose nuclear receptor. Trends Biochem Sci. 2006; 31:572–580.

9. Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology. 1998; 114:842–845.

10. Mantena SK, King AL, Andringa KK, Eccleston HB, Bailey SM. Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases. Free Radic Biol Med. 2008; 44:1259–1272.

11. Lefebvre P, Cariou B, Lien F, Kuipers F, Staels B. Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev. 2009; 89:147–191.

12. Chiang JY. Bile acid regulation of gene expression: roles of nuclear hormone receptors. Endocr Rev. 2002; 23:443–463.

13. 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; 25:2020–2030.

14. Stayrook KR, Bramlett KS, Savkur RS, Ficorilli J, Cook T, Christe ME, et al. Regulation of carbohydrate metabolism by the farnesoid X receptor. Endocrinology. 2005; 146:984–991.

15. Duran-Sandoval D, Cariou B, Percevault F, Hennuyer N, Grefhorst A, van Dijk TH, et al. The farnesoid X receptor modulates hepatic carbohydrate metabolism during the fasting-refeeding transition. J Biol Chem. 2005; 280:29971–29979.

16. Ma K, Saha PK, Chan L, Moore DD. Farnesoid X receptor is essential for normal glucose homeostasis. J Clin Invest. 2006; 116:1102–1109.

17. Lambert G, Amar MJ, Guo G, Brewer HB Jr, Gonzalez FJ, Sinal CJ. The farnesoid X-receptor is an essential regulator of cholesterol homeostasis. J Biol Chem. 2003; 278:2563–2570.

18. Zhang Y, Lee FY, Barrera G, Lee H, Vales C, Gonzalez FJ, et al. Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc Natl Acad Sci U S A. 2006; 103:1006–1011.

19. Yao J, Zhou CS, Ma X, Fu BQ, Tao LS, Chen M, et al. FXR agonist GW4064 alleviates endotoxin-induced hepatic inflammation by repressing macrophage activation. World J Gastroenterol. 2014; 20:14430–14441.

20. Inagaki T, Moschetta A, Lee YK, Peng L, Zhao G, Downes M, et al. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc Natl Acad Sci U S A. 2006; 103:3920–3925.

21. Ma Y, Huang Y, Yan L, Gao M, Liu D. Synthetic FXR agonist GW4064 prevents diet-induced hepatic steatosis and insulin resistance. Pharm Res. 2013; 30:1447–1457.

22. Cipriani S, Mencarelli A, Palladino G, Fiorucci S. FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats. J Lipid Res. 2010; 51:771–784.

23. Gadaleta RM, van Erpecum KJ, Oldenburg B, Willemsen EC, Renooij W, Murzilli S, et al. Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. Gut. 2011; 60:463–472.

24. Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall HU, Kipnes M, 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; 145:574–582.e1.

25. Downes M, Verdecia MA, Roecker AJ, Hughes R, Hogenesch JB, Kast-Woelbern HR, et al. A chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR. Mol Cell. 2003; 11:1079–1092.

26. Fang S, Suh JM, Reilly SM, Yu E, Osborn O, Lackey D, et al. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med. 2015; 21:159–165.

27. Urizar NL, Liverman AB, Dodds DT, Silva FV, Ordentlich P, Yan Y, et al. A natural product that lowers cholesterol as an antagonist ligand for FXR. Science. 2002; 296:1703–1706.

28. Prawitt J, Abdelkarim M, Stroeve JH, Popescu I, Duez H, Velagapudi VR, et al. Farnesoid X receptor deficiency improves glucose homeostasis in mouse models of obesity. Diabetes. 2011; 60:1861–1871.