Beneficial effect of resveratrol on α‑naphthyl isothiocyanate‑induced cholestasis via regulation of the FXR pathway

Ding,Lili; Zhang,Binfeng; Li,Jinmei; Yang,Li; Wang,Zhengtao

doi:10.3892/mmr.2017.8051

Beneficial effect of resveratrol on α‑naphthyl isothiocyanate‑induced cholestasis via regulation of the FXR pathway

Authors:
- Lili Ding
- Binfeng Zhang
- Jinmei Li
- Li Yang
- Zhengtao Wang
View Affiliations

Affiliations: Shanghai Key Laboratory of Compound Chinese Medicines and The Ministry of Education Key Laboratory of Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
Published online on: November 14, 2017 https://doi.org/10.3892/mmr.2017.8051
Pages: 1863-1872

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Cholestasis is defined as a functional impairment of bile secretion which results in the accumulation of bile acids (BAs) and other toxic molecules in the blood and liver, however, there are very few effective therapies for cholestasis. The farnesoid X receptor (FXR), as a nuclear receptor for BAs, is important in the regulation of BA levels in enterohepatic circulation. It has previously been demonstrated that activation of the FXR pathway may be a useful strategy with which to treat cholestasis. Resveratrol, one of the important ingredients from grape skins and Chinese medicine Polygonum cuspidatum, resulted in FXR‑activated effects in vitro and exhibited a protective effect against α‑naphthylisothiocyanate (ANIT)‑induced cholestasis through FXR regulation in vivo. The underlying mechanisms of resveratrol against ANIT‑induced cholestasis may be due to the regulation of BA homeostasis, improvement of liver injury and attenuation of the inflammatory response, which were regulated in a FXR‑dependent manner and in turn contributed to overall cholestasis alleviation. Overall, resveratrol as a FXR agonist may act as a potential compound for the treatment of drug‑induced cholestasis.

View Figures

View References

1	Plaa GL and Priestly BG: Intrahepatic cholestasis induced by drugs and chemicals. Pharmacol Rev. 28:207–273. 1976.
2	Zimmerman HJ: Drug-induced liver disease. Drugs. 16:25–45. 1978. View Article : Google Scholar
3	Kossor DC, Meunier PC, Handler JA, Sozio RS and Goldstein RS: Temporal relationship of changes in hepatobiliary function and morphology in rats following alpha-naphthylisothiocyanate (ANIT) administration. Toxicol Appl Pharmacol. 119:108–114. 1993. View Article : Google Scholar
4	Roth RA and Dahm LJ: Neutrophil- and glutathione-mediated hepatotoxicity of alpha-naphthylisothiocyanate. Drug Metab Rev. 29:153–165. 1997. View Article : Google Scholar
5	Yoshidome H, Miyazaki M, Shimizu H, Ito H, Nakagawa K, Ambiru S, Nakajima N, Edwards MJ and Lentsch AB: Obstructive jaundice impairs hepatic sinusoidal endothelial cell function and renders liver susceptible to hepatic ischemia/reperfusion. J Hepatol. 33:59–67. 2000. View Article : Google Scholar
6	Tekin R, Yolbas I, Dal T, Demirpençe Ö, Kaya S, Bozkurt F, Deveci Ö, Çelen MK and Tekin A: Evaluation of adults with acute viral hepatitis a and review of the literature. Clin Ter. 164:537–541. 2013.
7	Flora KD and Benner KG: Liver disease in cystic fibrosis. Clin Liver Dis. 2:51–61. 1998. View Article : Google Scholar
8	Eaton JE, Talwalkar JA, Lazaridis KN, Gores GJ and Lindor KD: Pathogenesis of primary sclerosing cholangitis and advances in diagnosis and management. Gastroenterology. 145:521–536. 2013. View Article : Google Scholar
9	Hirschfield GM, Chapman RW, Karlsen TH, Lammert F, Lazaridis KN and Mason AL: The genetics of complex cholestatic disorders. Gastroenterology. 144:1357–1374. 2013. View Article : Google Scholar :
10	Fickert P, Pollheimer MJ, Silbert D, Moustafa T, Halilbasic E, Krones E, Durchschein F, Thüringer A, Zollner G, Denk H and Trauner M: Differential effects of norUDCA and UDCA in obstructive cholestasis in mice. J Hepatol. 58:1201–1208. 2013. View Article : Google Scholar :
11	Makishima M, Okamoto AY, Repa JJ, Tu H, Learned RM, Luk A, Hull MV, Lustig KD, Mangelsdorf DJ and Shan B: Identification of a nuclear receptor for bile acids. Science. 284:1362–1365. 1999. View Article : Google Scholar
12	Parks DJ, Blanchard SG, Bledsoe RK, Chandra G, Consler TG, Kliewer SA, Stimmel JB, Willson TM, Zavacki AM, Moore DD and Lehmann JM: Bile acids: Natural ligands for an orphan nuclear receptor. Science. 284:1365–1368. 1999. View Article : Google Scholar
13	Wang H, Chen J, Hollister K, Sowers LC and Forman BM: Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell. 3:543–553. 1999. View Article : Google Scholar
14	Huber RM, Murphy K, Miao B, Link JR, Cunningham MR, Rupar MJ, Gunyuzlu PL, Haws TF, Kassam A, Powell F, et al: Generation of multiple farnesoid-X-receptor isoforms through the use of alternative promoters. Gene. 290:35–43. 2002. View Article : Google Scholar
15	Goodwin B, Jones SA, Price RR, Watson MA, McKee DD, Moore LB, Galardi C, Wilson JG, Lewis MC, Roth ME, et al: A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell. 6:517–526. 2000. View Article : Google Scholar
16	Xie MH, Holcomb I, Deuel B, Dowd P, Huang A, Vagts A, Foster J, Liang J, Brush J, Gu Q, et al: FGF-19, a novel fibroblast growth factor with unique specificity for FGFR4. Cytokine. 11:729–735. 1999. View Article : Google Scholar
17	Kong B, Wang L, Chiang JY, Zhang Y, Klaassen CD and Guo GL: Mechanism of tissue-specific farnesoid X receptor in suppressing the expression of genes in bile-acid synthesis in mice. Hepatology. 56:1034–1043. 2012. View Article : Google Scholar :
18	Meng Q, Chen XL, Wang CY, Liu Q, Sun HJ, Sun PY, Huo XK, Liu ZH, Yao JH and Liu KX: Alisol B 23-acetate protects against ANIT-induced hepatotoxity and cholestasis, due to FXR-mediated regulation of transporters and enzymes involved in bile acid homeostasis. Toxicol Appl Pharmacol. 283:178–186. 2015. View Article : Google Scholar
19	Chen H, Huang X, Min J, Li W, Zhang R, Zhao W, Liu C, Yi L, Mi S, Wang N, et al: Geniposidic acid protected against ANIT-induced hepatotoxity and acute intrahepatic cholestasis, due to Fxr-mediated regulation of Bsep and Mrp2. J Ethnopharmacol. 179:197–207. 2016. View Article : Google Scholar
20	Severgnini M, Sherman J, Sehgal A, Jayaprakash NK, Aubin J, Wang G, Zhang L, Peng CG, Yucius K, Butler J and Fitzgerald K: A rapid two-step method for isolation of functional primary mouse hepatocytes: Cell characterization and asialoglycoprotein receptor based assay development. Cytotechnology. 64:187–195. 2012. View Article : Google Scholar
21	Li T and Chiang JY: Bile acid signaling in metabolic disease and drug therapy. Pharmacol Rev. 66:948–983. 2014. View Article : Google Scholar :
22	Schuetz EG, Strom S, Yasuda K, Lecureur V, Assem M, Brimer C, Lamba J, Kim RB, Ramachandran V, Komoroski BJ, et al: Disrupted bile acid homeostasis reveals an unexpected interaction among nuclear hormone receptors, transporters, and cytochrome P450. J Biol Chem. 276:39411–39418. 2001. View Article : Google Scholar
23	Tanaka Y, Aleksunes LM, Cui YJ and Klaassen CD: ANIT-induced intrahepatic cholestasis alters hepatobiliary transporter expression via Nrf2-dependent and independent signaling. Toxicol Sci. 108:247–257. 2009. View Article : Google Scholar :
24	Wang T, Zhou ZX, Sun LX, Li X, Xu ZM, Chen M, Zhao GL, Jiang ZZ and Zhang LY: Resveratrol effectively attenuates α-naphthyl-isothiocyanate-induced acute cholestasis and liver injurythrough choleretic and anti-inflammatory mechanisms. Acta Pharmacol Sin. 35:1527–1536. 2014. View Article : Google Scholar :
25	Ding L, Yang L, Wang Z and Huang W: Bile acid nuclear receptor FXR and digestive system diseases. Acta Pharm Sin B. 5:135–144. 2015. View Article : Google Scholar :
26	Matsubara T, Li F and Gonzalez FJ: FXR signaling in the enterohepatic system. Mol Cell Endocrinol. 368:17–29. 2013. View Article : Google Scholar
27	Greve JW, Gouma DJ and Buurman WA: Bile acids inhibit endotoxin-induced release of tumor necrosis factor by monocytes: An in vitro study. Hepatology. 10:454–458. 1989. View Article : Google Scholar
28	Gu X, Ke S, Liu D, Sheng T, Thomas PE, Rabson AB, Gallo MA, Xie W and Tian Y: Role of NF-kappaB in regulation of PXR-mediated gene expression: A mechanism for the suppression of cytochrome P-450 3A4 by proinflammatory agents. J Biol Chem. 281:17882–17889. 2006. View Article : Google Scholar
29	Wang YD, Chen WD, Wang M, Yu D, Forman BM and Huang W: Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response. Hepatology. 48:1632–1643. 2008. View Article : Google Scholar :