Li X, Liu R, Yang J et al.
Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, Jiangsu, China.
Hepatology (Baltimore, Md.). Mar 2017.
The multi-drug resistance 2 knockout (Mdr2(-/-) ) mouse is a well-established model of cholestatic cholangiopathies. Female Mdr2(-/-) mice develop more severe hepatobiliary damage than male Mdr2(-/-) mice, which is correlated with a higher proportion of taurocholate (TCA) in bile. Although estrogen has been identified as an important player in intrahepatic cholestasis, the underlying molecular mechanisms of gender-based disparity of cholestatic injury remain unclear. The long non-coding RNA H19 is an imprinted, maternally expressed and estrogen-targeted gene, which is significantly induced in human fibrotic/cirrhotic liver and bile duct ligated mouse liver. However, whether aberrant expression of H19 accounts for gender-based disparity of cholestatic injury in Mdr2(-/-) mice remains unknown. The current study demonstrated that H19 was markedly induced (∼200-fold) in the livers of female Mdr2(-/-) mice at advanced stages of cholestasis (100-day-old), but not in aged-matched male Mdr2(-/-) mice. During the early stages of cholestasis, H19 expression was minimal. We further determined that the hepatic H19 was mainly expressed in cholangiocytes, not hepatocytes. Both TCA and estrogen significantly activated the ERK1/2 signaling pathway and induced H19 expression in cholangiocytes. Knocking down H19 not only significantly reduced TCA/estrogen-induced expression of fibrotic genes and sphingosine 1-phosphate receptor 2 (S1PR2) in cholangiocytes, but also markedly reduced cholestatic injury in female Mdr2(-/-) mice. Furthermore, the expression of small heterodimer partner was substantially inhibited at advanced stages of liver fibrosis, which was reversed by H19 shRNA in female Mdr2(-/-) mice. Similar findings were obtained in human PSC liver samples.H19 plays a critical role in the disease progression of cholestasis and represents a key factor that causes the gender disparity of cholestatic liver injury in Mdr2(-/-) mice. This article is protected by copyright. All rights reserved.