Glycyrrhetic Acid Derivative TY501 Protects Against Lithocholic Acid–Induced Cholestasis

Abstract

The aim of the study is to investigate the protective effects of TY501 against LCA-induced cholestasis in mice and to explore the potential mechanisms. It was demonstrated that TY501(5, 15 or 45 mg/kg, i.g.) can markedly reduced the level of ALT, AST and ALP which increased by LCA treatment. Meanwhile, TY501 also lowered total bile acids, total bilirubin and total cholesterol levels in serum. Furthermore, TY501 can protect HepG2 cell cultures from LCA-induced cytotoxicity. RT-PCR and Western Blot analysis showed that TY501 recovered the expression of BSEP, MRP2 and NTCP which were down-regulated by LCA. Moreover, mRNA and protein of FXR was also observed in TY501 treated mice significantly accumulation in nucleus. Taken together, It can be concluded that TY501 exerted beneficial effects on LCA-induced cholestasis, possibly via activation of FXR mediated upregulation of BSEP, MRP2 and NTCP.

Key words

Glycyrrhetic acid derivative - bile acid - FXR - BSEP - MRP2 - NTCP

^# These authors are corresponding authors.

^* These authors contributed equally to this article.

• References

• 1 Trauner M, Meier PJ, Boyer JL. Molecular pathogenesis of cholestasis. N Engl J Med 1998; 339: 1217-1227
• 2 Fickert P, Fuchsbichler A, Marschall HU. et al. Lithocholic acid feeding induces segmental bile duct obstruction and destructive cholangitis in mice. Am J Pathol 2006; 168: 410-422
• 3 Zeng H, Jiang Y, Chen P. et al. Schisandrol B protects against cholestatic liver injury through pregnane X receptors. Br J Pharmacol 2017; 174: 672-688
• 4 Chen P, Zeng H, Wang Y. et al. Low dose of oleanolic acid protects against lithocholic acid-induced cholestasis in mice: potential involvement of nuclear factor-E2-related factor 2-mediated upregulation of multidrug resistance-associated proteins. Drug Metab Dispos 2014; 42: 844-852
• 5 Hohenester S, Oude-Elferink RP, Beuers U. Primary biliary cirrhosis. Semin Immunopathol 2009; 31: 283-307
• 6 Kim I, Morimura K, Shah Y. et al. Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice. Carcinogenesis 2007; 28: 940-946
• 7 Vanwijngaerden YM, Wauters J, Langouche L. et al. Critical illness evokes elevated circulating bile acids related to altered hepatic transporter and nuclear receptor expression. Hepatology 2011; 54: 1741-1752
• 8 Gadaleta RM, van Erpecum KJ, Oldenburg B. et al. Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. Gut 2011; 60: 463-472
• 9 Jiang C, Xie C, Li F. et al. Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J Clin Invest 2015; 125: 386-402
• 10 Noel OF, Still CD, Argyropoulos G. et al. Bile Acids, FXR, and Metabolic effects of bariatric surgery. J Obes 2016; 2016: 4390254
• 11 Li W, Richard D. Effects of bariatric surgery on energy homeostasis. Can J Diabetes 2017; 41: 426-431
• 12 Zhang Y, Ge X, Heemstra LA. et al. Loss of FXR protects against diet-induced obesity and accelerates liver carcinogenesis in ob/ob mice. Mol Endocrinol 2012; 26: 272-280
• 13 Stieger B, Beuers U. The canalicular bile salt export pump BSEP (ABCB11) as a potential therapeutic target. Curr Drug Targets 2011; 12: 661-670
• 14 Tang ZH, Li T, Tong YG. et al. A systematic review of the anticancer properties of compounds isolated from licorice (Gancao). Planta Med 2015; 81: 1670-1687
• 15 Wu X, Zhang L, Gurley E. et al. Prevention of free fatty acid-induced hepatic lipotoxicity by 18beta-glycyrrhetinic acid through lysosomal and mitochondrial pathways. Hepatology 2008; 47: 1905-1915
• 16 Orlent H, Hansen BE, Willems M. et al. Biochemical and histological effects of 26 weeks of glycyrrhizin treatment in chronic hepatitis C: A randomized phase II trial. J Hepatol 2006; 45: 539-546
• 17 Asl MN, Hosseinzadeh H. Review of pharmacological effects of Glycyrrhiza sp. and its bioactive compounds. Phytother Res 2008; 22: 709-724
• 18 Zhang A, Jia Y, Xu Q. et al. Dioscin protects against ANIT-induced cholestasis via regulating Oatps, Mrp2 and Bsep expression in rats. Toxicol Appl Pharmacol 2016; 305: 127-135
• 19 Woolbright BL, Li F, Xie Y. et al. Lithocholic acid feeding results in direct hepato-toxicity independent of neutrophil function in mice. Toxicol Lett 2014; 228: 56-66
• 20 Liu T, Meng Q, Wang C. et al. Changes in expression of renal Oat1, Oat3 and Mrp2 in cisplatin-induced acute renal failure after treatment of JBP485 in rats. Toxicol Appl Pharmacol 2012; 264: 423-430
• 21 Fuchs CD, Paumgartner G, Wahlstrom A. et al. Metabolic preconditioning protects BSEP/ABCB11-/- mice against cholestatic liver injury. J Hepatol 2017; 66: 95-101
• 22 Kong B, Csanaky IL, Aleksunes LM. et al. Gender-specific reduction of hepatic Mrp2 expression by high-fat diet protects female mice from ANIT toxicity. Toxicol Appl Pharmacol 2012; 261: 189-195
• 23 Hayashi H, Mizuno T, Horikawa R. et al. 4-Phenylbutyrate modulates ubiquitination of hepatocanalicular MRP2 and reduces serum total bilirubin concentration. J Hepatol 2012; 56: 1136-1144
• 24 Tanaka Y, Aleksunes LM, Cui YJ. et al. ANIT-induced intrahepatic cholestasis alters hepatobiliary transporter expression via Nrf2-dependent and independent signaling. Toxicol Sci 2009; 108: 247-257
• 25 Gong L, Aranibar N, Han YH. et al. Characterization of organic anion-transporting polypeptide (Oatp) 1a1 and 1a4 null mice reveals altered transport function and urinary metabolomic profiles. Toxicol Sci 2011; 122: 587-597
• 26 Ou QQ, Qian XH, Li DY. et al. Yinzhihuang attenuates ANIT-induced intrahepatic cholestasis in rats through upregulation of Mrp2 and Bsep expressions. Pediatr Res 2016; 79: 589-595
• 27 Chen P, Li J, Fan X. et al. Oleanolic acid attenuates obstructive cholestasis in bile duct-ligated mice, possibly via activation of NRF2-MRPs and FXR antagonism. Eur J Pharmacol 2015; 765: 131-139
• 28 Wagner M, Zollner G, Fickert P. et al. Hepatobiliary transporter expression in intercellular adhesion molecule 1 knockout and Fas receptor-deficient mice after common bile duct ligation is independent of the degree of inflammation and oxidative stress. Drug Metab Dispos 2007; 35: 1694-1699
• 29 Chen WD, Wang YD, Zhang L. et al. Farnesoid X receptor alleviates age-related proliferation defects in regenerating mouse livers by activating forkhead box m1b transcription. Hepatology 2010; 51: 953-962
• 30 Liu B, Li Y, Ji H. et al. Glutamine attenuates obstructive cholestasis in rats via farnesoid X receptor-mediated regulation of Bsep and Mrp2. Can J Physiol Pharmacol 2017; 95: 215-223