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The activation of hepatic stellate cells (HSCs) plays a central role in liver fibrosis, however non-alcoholic fatty liver disease (NAFLD) associated liver fibrogenesis have been poorly understood. We aimed to determine the significance of mineralocorticoid receptor (MR)/osteopontin (OPN)/high-mobility group box-1 (HMGB1) axis in this setting. Liver specimens were collected from NAFLD patients and murine NAFLD models established with 12-week high fat diet (HFD) for analysis of both upstream signals of MR and intrahepatic MR/OPN/HMGB1 axis. The in vitro cell model of NAFLD-associated liver fibrogenesis was established by treating LX-2 (a cell line of human HSCs) with free fatty acids (FFA). The effects of MR signaling were evaluated using with ALD (MR activator) or eplerenone (Ep, MR antagonist). Moreover, the in vitro loss- and gain- of function approaches were applied to confirm the upstream and downstream relationships of mediators contained in the intracellular MR/OPN/HMGB1 axis of LX-2. In NAFLD condition, both human and mouse liver tissue samples demonstrated a significant up-regulation of MR/OPN/HMGB1 axis simultaneously with enhanced expression of pro-fibrogenic markers, including ACTA2, TIMP1, TGFB1 and COL1A1. Besides, enhanced production of serum aldosterone (ALD) was also observed in mouse NAFLD models. Moreover, the in vitro data demonstrated MR play an essential role in FFA-induced HSCs fibrogenesis. Meanwhile, MR acts as the upstream effector mediator of OPN and shares downstream HMGB1 with OPN. The MR/OPN/HMGB1 axis could be therapeutically targeted to treat NAFLD associated hepatic fibrogenesis. Copyright © 2020. Published by Elsevier Inc.


Min Tang, Haoyu Jia, Shuai Chen, Bo Yang, Bhuvanesh Kinish Patpur, Weiping Song, Yizhong Chang, Jing Li, Changqing Yang. Significance of MR/OPN/HMGB1 axis in NAFLD-associated hepatic fibrogenesis. Life sciences. 2021 Jan 01;264:118619

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PMID: 33091447

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