Non-Alcoholic Fatty Liver Disease: The Effect of Bile Acids and Farnesoid X Receptor Agonists on Pathophysiology and Treatment
DOI:
https://doi.org/10.17140/lroj-1-106Keywords:
Bile acids, Nuclear receptors, Fatty liver disease, Lipids, CholesterolAbstract
Non-alcoholic fatty liver disease (NAFLD) is an emerging epidemic in light of its two predisposing factors, a surge in both obesity and diabetes rates with reports of between 70-80% of obese individuals in Western countries. The disease progression of NAFLD remains elusive but is generally attributed to insulin resistance, lipid metabolism dysfunction, altered immune response to name a few. Potential therapeutic strategies should target one or some of these pathological events in the liver, however currently no specific therapies for NAFLD exist. Thus novel therapeutic approaches to manage the chronic liver disease epidemic are becoming essential. In this review we discuss the evidence supporting the role of bile acid activated Farnesoid X Receptor (FXR) in promoting lipid oxidation, reducing inflammation and fibrosis in the liver. We also examine the potential of FXR agonists, as an attractive class of drugs for the safe and effective treatment of NAFLD.
References
Nie B, Park MH, Kazantzis M, et al. Specific bile acids inhibit hepatic fatty acid uptake in mice. Hepatology. 2012; 56: 1300- 1310. doi: 10.1002/hep.25797
Li T, Chiang LYJ. Nuclear receptors in bile acid metabo-lism. Drug Metab Rev. 2013; 45: 145-155. doi: 10.3109/0360 2532.2012.740048
Li Y, Jadhav K, Zhang Y. Bile acid receptors in non-alcoholic fatty liver disease. Biochemical Pharmacology. 2013; 86: 1517- 1524. doi: 10.1016/j.bcp.2013.08.015
Hylemon BP, Zhou H, Pandak MW, Ren S, Gil G, Dent P. Bile acids as regulatory molecules. Journal of lipid research. 2012; 50: 1509-1520. doi: 10.1194/jlr.R900007-JLR200
Chiang LYJ. Bile acids: regulation of synthesis. Journal of lipid research. 2009; 50: 1955-1966. doi: 10.1194/jlr.R900010- JLR200
Parks DJ, Blanchard SG, Bledsoe RK, et al. Bile acids: natu-ral ligands for an orphan nuclear receptor. Science. 1999; 284: 1365-1368.
Vlahcevic ZR, Heuman DM, Hylemon BP. Physiology and pathophysiology of enterohepatic circulation of bile acids. Hep-atology: A Textbook of Liver Disease. In: Zakim D, Boyer TD, eds. WB Sanders Co, Philadelphia, PA, USA. 1996; 376-417.
Makishima M, Okamoto YA, Repa JJ, et al. Identification of a nuclear receptor for bile acids. Science. 1999; 284: 1362-1365. doi: 10.1126/science.284.5418.1362
Staudinger JL, Goodwin B, Jones AS, et al. The nuclear recep-tor PXR is a lithocholic acid sensor that protects against liver toxicity. Proc. Natl. Acad. Sci. USA. 2001; 98: 3369-3374. doi:
1073/pnas.051551698 10. Gao B, Bataller R. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology. 2011; 141: 1572- 1585. doi: 10.1053/j.gastro.2011.09.002
Claudel T, Zollner G, Wagner M, Trauner M. Role of nuclear receptors for bile acid metabolism, bile secretion, cholestasis, and gallstone disease. Biochim Biophys Acta. 2011; 1812: 867- 878. doi: 10.1016/j.bbadis.2010.12.021
Chiang LYJ. Front. Biosci. 1998; 3: 176-193.
Mazuy C, Helleboid A, Staels B, Philippe Lefebvre. Nuclear bile acid signaling through the farnesoid X receptor. Cell Mol Life Sci. 2014; 72: 1631-1650. doi: 10.1007/s00018-014-1805-y
Russell DW. The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem. 2003; 72: 137-174. doi: 10.1146/annurev.biochem.72.121801.161712
Porez G, Prawitt J, Gross B, Staels B. Bile acid receptors as targets for the treatment of dyslipidemia and cardiovascular dis-ease: Tematic Review Series: New Lipid and Lipoprotein Tar-gets for the Treatment of Cardiometabolic Diseases. J Lipid Res. 2012; 53: 1723-1737. doi: 10.1194/jlr.R024794
Russell DW, Setchell KD. Bile acid biosynthesis. Biochem-istry. 1992; 31(1): 4737-4749.
Hofmann AF. Detoxification of lithocholic acid, a toxic bile acid: relevance to drug hepatotoxicity. Drug Metab Rev. 2004; 36: 703-722.
Pandak WM , Ren S, Marques D, et al. Transport of choles-terol into mitochondria is rate-limiting for bile acid synthesis via the alternative pathway in primary rat hepatocytes. J Biol Chem. 2002; 277: 48158 -48164. doi: 10.1074/jbc.M205244200
Hofmann AF, Hagey LR. Bile acids: chemistry, pathochem-istry, biology, pathobiology, and therapeutics. Cell Mol Life Sci. 2008; 65: 2461-2483. doi: 10.1007/s00018-008-7568-6
Bernstein C, Holubec H, Bhattacharyya KA, et al. Carcino-genicity of deoxycholate, a secondary bile acid. Archives of Tox-icology. 2011; 85: 863-871. doi: 10.1007/s00204-011-0648-7
Hofmann FA. The Continuing Importance of Bile Acids in Liver and Intestinal Disease. JAMA. 1999; 159: 2647-2658. doi: 10.1001/archinte.159.22.2647
Changbumrung S, Tungtrongchitr R, Migasena P, Cham-roenngan S. Serum unconjugated primary and secondary bile acids in patients with cholangiocarcinoma and hepatocellular carcinoma. J Med Assoc Thai. 1990; 73: 81-90.
Boyer JL. New concepts of mechanisms of hepatocyte bile formation. Physiol Rev. 1980; 60: 303-326.
Ananthanarayanan M, Balasubramanian VN, Makishima M, Mangelsdorf JD, Suchy JF. Human bile salt export pump (BSEP) promoter is transactivated by the farnesoid X receptor/bile acid receptor (FXR/BAR). J Biol Chem. 2001; 27: 28857-28865
Childs S, Yeh RL, Georges E, Ling V. Identification of a sis-ter gene to P-glycoprotein. Cancer Res. 1995; 55: 2029-2034.
Strautnieks SS, Kagalwalla AF, Tanner MS, et al. Identifica-tion of a locus for progressive familial intrahepatic cholestasis PFIC2 on chromosome 2q24. Am J Hum Genet. 1997; 61: 630- 633. doi: 10.1086/515501
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: 6960-6968. doi: 10.1074/jbc.M412752200
Song KH, Li T, Owsley E, Strom S, Chiang JYL. Bile acids activate fibroblast growth factor 19 signaling in human hepato-cytes to inhibit cholesterol hydroxylase gene expression. Hepa-tology. 2009; 49: 297-305. doi: 10.1002/hep.22627
Zhang S, Wang J, Liu Q. Farnesoid X receptor agonist WAY-362450 attenuates liver inflammation and fibrosis in murine model of non-alcoholic steatohepatitis. J Hepatol. 2009; 51: 380-388. doi: 10.1016/j.jhep.2009.03.025
Lomanaco R, Sunny NE, Bril F, Cusi K. Nonalcoholic fatty liver disease: current issues and novel treatment approaches. Drugs. 2013; 73: 1-14. doi: 10.1007/s40265-012-0004-0
McNear S, Harrison, SA. Current status of therapy in non-alcoholic fatty liver disease. Therapeutic Advances in Gastroen-terology. 2009; 2: 29-43. doi: 10.1177/1756283X08100327
Onis M, Blossner M, Borghi E. Mutation research/funda-mental and molecular mechanisms of mutagenesis. American Journal of Clinical Nutrition. 2010; 92: 1257-1264.
Durazzo M, Belci P, Collo A, Grisoglio E, Bo S. Fo-cus on therapeutic strategies of nonalcoholic fatty liver dis-ease. International Journal of Hepatology. 2012; 1: 1-9. doi: 10.1155/2012/464706
Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gas-troenterology. 1998; 114: 842-845. doi: 10.1016/S0016-5085- (98)70599-2
Marra F, Gastaldelli AS, Baroni SG, Tell G, Tiribelli C. Mo-lecular basis and mechanisms of progression of non-alcoholic steatohepatitis. Trends in molecular medicine. 2008; 14: 72-81. doi: 10.1016/j.molmed.2007.12.003
Adorini L, Pruzanski M, Shapiro D. Farnesoid X receptor targeting to treat non-alcoholic steatohepatitis. Drug Discov To-day. 2012; 17: 988-997. doi: 10.1016/j.drudis.2012.05.012
Kodama Y, Brenner DA. c-Jun N-Terminal kinase signaling in the pathogenesis of nonalcoholic fatty liver disease: multiple roles in multiple steps. Hepatology. 2008; 49: 6-8. doi: 10.1002/ hep.22710
Gyamfi D, Everitt H, Tewfik I, Clemens D, Patel V. Hepatic mitochondrial dysfunction induced by fatty acids and ethanol. Free Radical Biology and Medicine. 2012; 53: 2131-2145. doi: 10.1016/j.freeradbiomed.2012.09.024
Ratziu V, Pienar L. Pharmacological therapy for non-alco-holic steatohepatitis: How efficient are thiazolidinediones? He-patology Research. 2011; 41: 687-695. doi: 10.1111/j.1872-034- X.2011.00825.x
Aithal GP, Thomas JA, Kaye PV, et al. Randomized, pla-cebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology. 2008; 135: 1176-1184. doi: 10.1053/j.gastro.2008.06.047
Sharma AM, Staels B. Peroxisome proliferator-activated re-ceptor gamma and adipose tissue-understanding obesity-related changes in regulation of lipid and glucose metabolism. J Clin Endocrinol Metab. 2007; 92: 386-395. doi: 10.1210/jc.2006- 1268
Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepa-titis. N Engl J Med. 2006; 355: 2297-2307. doi: 10.1056/NEJ-Moa060326
Boettcher E, Csako G, Pucino F, Wesley R, Loomba R. Me-ta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2012; 35: 66-75. doi: 10.1111/j.1365-2036.2011.04912.x
Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. The New England Journal of Medicine. 2010; 362: 1675-1685. doi: 10.1056/NEJMoa0907929
Baran B, Akyuz F. Non-alcoholic fatty liver disease: What has changed in the treatment since the beginning? World J Gastroenterol. 2014; 20: 14219-14229. doi: 10.3748/wjg.v20. i39.14219
Lavine JE, Schwimmer JB, Van ML. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the tonic randomized controlled trial. JAMA. 2011; 305: 1659-1668. doi: 10.1001/jama.2011.520
Saremi A, Arora R. Vitamin E and cardiovascular disease. Am J Ther. 2010; 17: 56-65. doi: 10.1097/MJT.0b013e31819cdc9a
Yang ZX, Shen W, Sun H. Effects of nuclear receptor FXR on the regulation of liver lipid metabolism in patients with non-alcoholic fatty liver disease. Hepatol Int. 2010; 4: 741-748. doi: 10.1007/s12072-010-9202-6
Sinal CJ, Tohkin M, Miyata M, Ward JM, Lambert G, Gon-zalez FJ. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell. 2000; 102: 731- 744. doi: 10.1016/S0092-8674(00)00062-3
Abu-Shanab A, Quigley EM..The role of the gut microbiota in non-alcoholic fatty liver disease. Nat Rev GastroenterolHepa-tol. 2010; 7: 691-701. doi: 10.1038/nrgastro.2010.172
Elsharkawy AM, Mann DA. Nuclear factor-kappaB and the hepatic inflammation-fibrosis-cancer axis. Hepatology. 2007; 46: 590-597. doi: 10.1002/hep.21802
Kim I, Morimura K, Shah Y, Yang Q, Ward JM, Gonzalez FJ. Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice. Carcinogenesis. 2007; 28: 940-946. doi: 10.1093/carcin/ bgl249
Carr MR, Reid EA. Synthetic FXR agonist GW4064 prevents diet-induced hepatic steatosis and insulin resistance. Pharm Res. 2015; 17(16): 1-16.
Stayrook KR, Bramlett KS, Savkur RS, et al. Regulation of carbohydrate metabolism by the farnesoid X receptor. Endocri-nology. 2005; 146: 984-991.
Yamagata K, Daitoku H, Shimamoto Y, Matsuzaki H, Hirota K, Ishida J. Bile acids regulate gluconeogenic gene expression via small heterodimer partner mediated repression of hepatocyte nuclear factor 4 and Foxo1. J Biol Chem. 2004; 279: 23158- 23165. doi: 10.1074/jbc.M314322200
Langhi C, May CL, Kourimate S, et al. Activation of the farnesoid X receptor represses PCSK9 expression in human hepatocytes. FEBS Lett. 2008; 582: 949-955. doi: 10.1016/j. febslet.2008.02.038
Ma Y, Huang Y, Yan L, Gao M, Liu D. Synthetic FXR ago-nist GW4064 prevents diet-induced hepatic steatosis and insu-lin resistance. Pharm Res. 2013; 30: 1447-1457. doi: 10.1007/ s11095-013-0986-7
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, USA. 2006; 103: 1006-1011. doi: 10.1073/pnas.0506982103
Cariou B, Harmelen VK, Duran-Sandoval D, et al. The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice. J Biol Chem. 2006; 281: 11039-11049. doi: 10.1074/jbc.M510258200
Xiong X, Wang X, Lu Y, et al. Hepatic steatosis exacer-bated by endoplasmic reticulum stress-mediated downregula-tion of FXR in aging mice. J Hepatol. 2014; 60: 847-854. doi: 10.1016/j.jhep.2013.12.003
LiuY, Binz J, Numerick JM, et al. Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis. J Clin Invest. 2003; 112: 1678-1687. doi: 10.1172/JCI200318945
Pellicciari R, Fiorucci S, Camaioni E, et al. 6-alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem. 2002; 45: 3569-3572. doi: 10.1021/jm025529g
Mi LZ, Devarakonda S, Harp JM, et al. Structural basis for bile acid binding and activation of the nuclear receptor FXR. Mol Cell. 2003; 11: 1093-1100. doi: 10.1016/S1097-2765- (03)00112-6
Vignozzi L, Morelli A, Filippi S, et al. Farnesoid X receptor activation improves erectile function in animal models of meta-bolic syndrome and diabetes. Journal of Sexual medicine. 2011; 8: 57-77. doi: 10.1111/j.1743-6109.2010.02073.x
Cipriani S, Mencarelli A, Palladino G, Fiorucci S. FXR ac-tivation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats. J Lipid Res. 2010; 51: 771-784. doi: 10.1194/jlr.M001602
Mencarelli A, Renga B, Migliorati M, et al. The bile acid sensor farnesoid X receptor is a modulator of liver immunity in a rodent model of acute hepatitis. Journal of immunology. 2009; 183: 6657-6666. doi: 10.4049/jimmunol.0901347
Fiorucci S, Antonelli E, Rizzo G, et al. The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis. Gastroenterology. 2004; 127: 1497-1512. doi: 10.1053/j.gastro.2004.08.001
Mudaliar S, Henry RR, Sanyal AJ, et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenter-ology. 2013; 145: 574-582. doi: 10.1053/j.gastro.2013.05.042
Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farne-soid X nuclear receptor ligand obeticholic acid for non-cirrhot-ic, non-alcoholic steatohepatitis (FLINT): a multicentre, ran-domised, placebo-controlled trial. Lancet. 2014; 385: 956-1065. doi: 10.1016/S0140-6736(14)61933-4
Walters JR, Johnston IM, Nolan JD, Vassie C, Pruzanski ME, Shapiro DA. The response of patients with bile acid diarrhoea to the farnesoid X receptor agonist obeticholic acid. Aliment Phar-macol Ther. 2015; 41: 54-64. doi: 10.1111/apt.12999
Ratziu V. Treatment of NASH with ursodeoxycholic acid: Pro. Clin Res Hepatol Gastroenterol. 2012; 36(Suppl 1): S41- S45. doi: 10.1016/S2210-7401(12)70020-7
Xiang Z, Chen YP, Ma KF, et al. The role of ursodeoxycholic acid in non-alcoholic steatohepatitis: a systematic review. BMC Gastroenterol. 2013; 13: 140. doi: 10.1186/1471-230X-13-140
Lindor KD, Kowdley KV, Heathcote EJ, et al. Ursodeoxy-cholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology. 2004; 39: 770-778. doi: 10.1002/hep.20092
Adams LA, Angulo P, Petz J, Keach J. Lindor KD. A pilot trial of high-dose ursodeoxycholic acid in non-alcoholic Steato-hepatitis. Hepatol Int. 2010; 4: 628-633. doi: 10.1007/s12072- 010-9195-1
Ratziu V1, de Ledinghen V, Oberti F, et al. A randomized controlled trial of high-dose ursodesoxycholic acid for nonal-coholic steatohepatitis. J Hepatol. 2011; 54:1011-1019. doi: 10.1016/j.jhep.2010.08.030
Cho EJ, Yoon JH, Kwak MS, et al. Tauroursodeoxycholic acid attenuates progression of steatohepatitis in mice fed a meth-ionine-choline-deficient diet. Dig Dis Sci. 2014; 59: 1461-1474. doi: 10.1007/s10620-014-3217-
Hafeez S, Ahmed MH. Bariatric surgery as potential treat-ment for nonalcoholic fatty liver disease: a future treatment by choice or by chance? Journal of Obesity. 2013; Article ID 839275. doi: 10.1155/2013/839275
Ben M, Polimeni L, Baratta F, Pastori D, Loffredo L, An-gelico F. Modern approach to the clinical management of non-alcoholic fatty liver disease. World J Gastroenterol. 2014; 20: 8341-8350. doi: 10.3748/wjg.v20.i26.8341
Bower G, Toma T, Harling L, et al. Bariatric surgery and non-alcoholic fatty liver disease: a systematic review of liver biochemistry and histology. Obes Surg. 2015. doi: 10.1007/ s11695-015-1691-x
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