Non-alcoholic fatty liver disease is one of the most rapidly rising clinical problems in the 21st century. So far no effective drug treatment has been established to cure this disease. Bile acids (BAs) have a variety of signaling properties, which can be used therapeutically for modulating hepatic metabolism and inflammation. A side-chain shorted derivative of ursodeoxycholic acid (UDCA) is 24 nor-ursodeoxycholic acid (NorUDCA) and it represents a new class of drugs for treatment of liver diseases. NorUDCA has unique biochemical and therapeutic properties, since it is relatively resistant to conjugation with glycine or taurine compared to UDCA. NorUDCA undergoes cholehepatic shunting, resulting in ductular targeting, bicarbonate-rich hypercholeresis, and cholangiocyte protection. Furthermore, it showed anti-fibrotic, anti-inflammatory, and anti-lipotoxic properties in several animal models. As such, NorUDCA is a promising new approach in the treatment of cholestatic and metabolic liver diseases. This review is a summary of current BA-based therapeutic approaches in the treatment of the fatty liver disease.

Do A, Lim JK: Epidemiology of nonalcoholic fatty liver disease: a primer. Clin Liver Dis 2016;7:106-108.
Bellentani S, Scaglioni F, Marino M, Bedogni G: Epidemiology of non-alcoholic fatty liver disease. Dig Dis 2010;28:155-161.
Anstee QM, Targher G, Day CP: Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol 2013;10:330-344.
Kolly P, Dufour JF: Surveillance for hepatocellular carcinoma in patients with NASH. Diagnostics (Basel) 2016;6:pii:E22.
Michelotti GA, Machado MV, Diehl AM: NAFLD, NASH and liver cancer. Nat Rev Gastroenterol Hepatol 2013;10:656-665.
Wong RJ, Aguilar M, Cheung R, Perumpail RB, Harrison SA, Younossi ZM, Ahmed A: Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology 2015;148:547-555.
Bugianesi E, McCullough AJ, Marchesini G: Insulin resistance: a metabolic pathway to chronic liver disease. Hepatology 2005;42:987-1000.
Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, Boerwinkle E, et al: Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008;40:1461-1465.
Kozlitina J, Smagris E, Stender S, Nordestgaard BG, Zhou HH, Tybjaerg-Hansen A, Vogt TF, et al: Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2014;46:352-356.
Hofmann AF, Hagey LR: Bile acids: chemistry, pathochemistry, biology, pathobiology, and therapeutics. Cell Mol Life Sci 2008;65:2461-2483.
Hofmann AF: Enterohepatic Circulation of Bile Acids. In: Comprehensive Physiology: John Wiley & Sons, Inc., 2010.
Arab JP, Karpen SJ, Dawson PA, Arrese M, Trauner M: Bile acids and nonalcoholic fatty liver disease: molecular insights and therapeutic perspectives. Hepatology 2016, Epub ahead of print.
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.
Wu X, Ge H, Lemon B, Vonderfecht S, Weiszmann J, Hecht R, Gupte J, et al: FGF19-induced hepatocyte proliferation is mediated through FGFR4 activation. J Biol Chem 2010;285:5165-5170.
Schreuder TC, Marsman HA, Lenicek M, van Werven JR, Nederveen AJ, Jansen PL, Schaap FG: 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:G440-G445.
Wahlström A, Sayin SI, Marschall HU, Bäckhed F: Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab 2016;24:41-50.
Lindor KD, Dickson ER, Baldus WP, Jorgensen RA, Ludwig J, Murtaugh PA, Harrison JM, et al: Ursodeoxycholic acid in the treatment of primary biliary cirrhosis. Gastroenterology 1994;106:1284-1290.
Poupon RE, Poupon R, Balkau B: Ursodiol for the long-term treatment of primary biliary cirrhosis. The UDCA-PBC study group. N Engl J Med 1994;330:1342-1347.
Hirschfield GM, Mason A, Luketic V, Lindor K, Gordon SC, Mayo M, Kowdley KV, et al: Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology 2015;148:751-761 e758.
Laurin J, Lindor KD, Crippin JS, Gossard A, Gores GJ, Ludwig J, Rakela J, et al: Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology 1996;23:1464-1467.
Lindor KD, Kowdley KV, Heathcote EJ, Harrison ME, Jorgensen R, Angulo P, Lymp JF, et al: Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology 2004;39:770-778.
Dufour JF, Oneta CM, Gonvers JJ, Bihl F, Cerny A, Cereda JM, Zala JF, et al: Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin e in nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2006;4:1537-1543.
Leuschner UF, Lindenthal B, Herrmann G, Arnold JC, Rössle M, Cordes HJ, Zeuzem S, et al: High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial. Hepatology 2010;52:472-479.
Ratziu V, de Ledinghen V, Oberti F, Mathurin P, Wartelle-Bladou C, Renou C, Sogni P, et al: A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis. J Hepatol 2011;54:1011-1019.
Kars M, Yang L, Gregor MF, Mohammed BS, Pietka TA, Finck BN, Patterson BW, et al: Tauroursodeoxycholic acid may improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women. Diabetes 2010;59:1899-1905.
Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, Görgün CZ, et al: Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 2006;313:1137-1140.
European Association for the Study of the Liver (EASL). Electronic Address:; European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO): EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016;64:1388-1402.
Fickert P, Wagner M, Marschall HU, Fuchsbichler A, Zollner G, Tsybrovskyy O, Zatloukal K, et al: 24-norUrsodeoxycholic acid is superior to ursodeoxycholic acid in the treatment of sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology 2006;130:465-481.
Beraza N, Ofner-Ziegenfuss L, Ehedego H, Boekschoten M, Bischoff SC, Mueller M, Trauner M, et al: Nor-ursodeoxycholic acid reverses hepatocyte-specific nemo-dependent steatohepatitis. Gut 2011;60:387-396.
Denk GU, Maitz S, Wimmer R, Rust C, Invernizzi P, Ferdinandusse S, Kulik W, et al: Conjugation is essential for the anticholestatic effect of NorUrsodeoxycholic acid in taurolithocholic acid-induced cholestasis in rat liver. Hepatology 2010;52:1758-1768.
Halilbasic E, Fiorotto R, Fickert P, Marschall HU, Moustafa T, Spirli C, Fuchsbichler A, et al: Side chain structure determines unique physiologic and therapeutic properties of norursodeoxycholic acid in Mdr2-/- mice. Hepatology 2009;49:1972-1981.
Moustafa T, Fickert P, Magnes C, Guelly C, Thueringer A, Frank S, Kratky D, et al: Alterations in lipid metabolism mediate inflammation, fibrosis, and proliferation in a mouse model of chronic cholestatic liver injury. Gastroenterology 2012;142:140-151.e12.
Fickert P, Moustafa T, Fuchsbichler A, Claudel T, Halilbasic E, Zatloukal K, Denk H, Trauner M: Differential effects of norUDCA and UDCA in the treatment of fatty liver and arteriosclerosis in western chow-fed ApoE knock out mice. J Hepatol 2008;48(suppl 2):S42.
Sombetzki M, Fuchs CD, Fickert P, Osterreicher CH, Mueller M, Claudel T, Loebermann M, et al: 24-nor-ursodeoxycholic acid ameliorates inflammatory response and liver fibrosis in a murine model of hepatic schistosomiasis. J Hepatol 2015;62:871-878.
Buko VU, Lukivskaya OY, Naruta EE, Belonovskaya EB, Tauschel HD: Protective effects of norursodeoxycholic acid versus ursodeoxycholic acid on thioacetamide-induced rat liver fibrosis. J Clin Exp Hepatol 2014;4:293-301.
Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall HU, Kipnes M, Adorini L, 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.
Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, Chalasani N, et al: Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 2015;385:956-965.
Pencek R, Marmon T, Roth JD, Liberman A, Hooshmand-Rad R, Young MA: Effects of obeticholic acid on lipoprotein metabolism in healthy volunteers. Diabetes Obes Metab 2016;18:936-940.
Claudel T, Sturm E, Duez H, Torra IP, Sirvent A, Kosykh V, Fruchart JC, et al: Bile acid-activated nuclear receptor FXR suppresses apolipoprotein A-I transcription via a negative FXR response element. J Clin Invest 2002;109:961-971.
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.
Gautier T, de Haan W, Grober J, Ye D, Bahr MJ, Claudel T, Nijstad N, et al: Farnesoid X receptor activation increases cholesteryl ester transfer protein expression in humans and transgenic mice. J Lipid Res 2013;54:2195-2205.
Thomas C, Pellicciari R, Pruzanski M, Auwerx J, Schoonjans K: Targeting bile-acid signalling for metabolic diseases. Nat Rev Drug Discov 2008;7:678-693.
Maloney PR, Parks DJ, Haffner CD, Fivush AM, Chandra G, Plunket KD, Creech KL, et al: Identification of a chemical tool for the orphan nuclear receptor FXR. J Med Chem 2000;43:2971-2974.
Dussault I, Beard R, Lin M, Hollister K, Chen J, Xiao JH, Chandraratna R, et al: Identification of gene-selective modulators of the bile acid receptor FXR. J Biol Chem 2003;278:7027-7033.
Abel U, Schluter T, Schulz A, Hambruch E, Steeneck C, Hornberger M, Hoffmann T, et al: Synthesis and pharmacological validation of a novel series of non-steroidal FXR agonists. Bioorg Med Chem Lett 2010;20:4911-4917.
Hambruch E, Miyazaki-Anzai S, Hahn U, Matysik S, Boettcher A, Perovic-Ottstadt S, Schluter T, 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;343:556-567.
Downes M, Verdecia MA, Roecker AJ, Hughes R, Hogenesch JB, Kast-Woelbern HR, Bowman ME, et al: A chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR. Mol Cell 2003;11:1079-1092.
Fang S, Suh JM, Reilly SM, Yu E, Osborn O, Lackey D, Yoshihara E, et al: Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med 2015;21:159-165.
Zhang L, Xie C, Nichols RG, Chan SH, Jiang C, Hao R, Smith PB, et al: Farnesoid X receptor signaling shapes the gut microbiota and controls hepatic lipid metabolism. mSystems 2016;1:pii:e00070-16.
Inagaki T, Moschetta A, Lee YK, Peng L, Zhao G, Downes M, Yu RT, 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.
Gadaleta RM, van Erpecum KJ, Oldenburg B, Willemsen EC, Renooij W, Murzilli S, Klomp LW, et al: Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. Gut 2011;60:463-472.
Modica S, Petruzzelli M, Bellafante E, Murzilli S, Salvatore L, Celli N, Di Tullio G, et al: Selective activation of nuclear bile acid receptor FXR in the intestine protects mice against cholestasis. Gastroenterology 2012;142:355-365.e1-e4.
Preitner F, Mody N, Graham TE, Peroni OD, Kahn BB: Long-term Fenretinide treatment prevents high-fat diet-induced obesity, insulin resistance, and hepatic steatosis. Am J Physiol Endocrinol Metab 2009;297:E1420-E1429.
Wu X, Ge H, Lemon B, Vonderfecht S, Baribault H, Weiszmann J, Gupte J, et al: Separating mitogenic and metabolic activities of fibroblast growth factor 19 (FGF19). Proc Natl Acad Sci U S A 2010;107:14158-14163.
Safadi R, Konikoff FM, Mahamid M, Zelber-Sagi S, Halpern M, Gilat T, Oren R, et al: The fatty acid-bile acid conjugate Aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2014;12:2085-2091.e1.
Shang Q, Saumoy M, Holst JJ, Salen G, Xu G: Colesevelam improves insulin resistance in a diet-induced obesity (F-DIO) rat model by increasing the release of GLP-1. Am J Physiol Gastrointest Liver Physiol 2010;298:G419-G424.
Potthoff MJ, Potts A, He T, Duarte JA, Taussig R, Mangelsdorf DJ, Kliewer SA, et al: Colesevelam suppresses hepatic glycogenolysis by TGR5-mediated induction of GLP-1 action in DIO mice. Am J Physiol Gastrointest Liver Physiol 2013;304:G371-G380.
Blahova T, Peterkova L, Lenicek M, Vlachova M, Zemankova K, Adamkova V, Vitek L, et al: The effect of colesevelam treatment on bile acid and lipid metabolism and glycemic control in healthy men. Physiol Res 2016, Epub ahead of print.
Ooi CP, Loke SC: Colesevelam for type 2 diabetes mellitus: an abridged cochrane review. Diabet Med 2014;31:2-14.
Le TA, Chen J, Changchien C, Peterson MR, Kono Y, Patton H, Cohen BL, et al: Effect of colesevelam on liver fat quantified by magnetic resonance in nonalcoholic steatohepatitis: a randomized controlled trial. Hepatology 2012;56:922-932.
Rao A, Kosters A, Mells JE, Zhang W, Setchell KD, Amanso AM, Wynn GM, et al: Inhibition of ileal bile acid uptake protects against nonalcoholic fatty liver disease in high-fat diet-fed mice. Sci Transl Med 2016;8:357ra122.
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