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Background: Numerous documents have indicated a critical role of autophagy in alcoholic liver fibrosis (ALF), but few papers have reported its function in hepatic stellate cells (HSCs) activation. The current study aimed to investigate the regulation effect of autophagy in HSCs activation, in further to explore the underlying mechanism involved., Methods: HSC-T6 cells were treated with ethanol, 3-MA (autophagy inhibitor) or rapamycin (autophagy inducer), and cells were also transfected with si-Nrf2 or si-Keap1. Moreover, ALF animal model was established and Nrf-2 (-/-) , Keap1 (-/-) mice were purchased. The level of autophagy, the expression of α-SMA and CoL1A1, and Nrf2 antioxidant response were evaluated in stellate cells and livers., Results: Ethanol treatment in cultured cells increased autophagy, oxidative stress level and promoted HSCs activation. Inhibition of autophagy reversed alcohol-induced HSCs activation and suppressed HSCs oxidative stress. Nrf2-Keap1-ARE pathway was involved in HSCs activation and oxidative stress regulated by autophagy. In addition, through in vivo study, we found that inhibition of autophagy could alleviate alcoholic fatty liver injury in ALF model mice and Nrf2 signaling was involved in autophagy regulated HSCs activation., Conclusion: These data implicated mechanisms underlying autophagy in regulating the fibrogenic response in HSCs activation., (Copyright © 2018 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Activation of hepatic stellate cells (HSCs) is a prominent driver of liver fibrogenesis, including alcoholic liver fibrosis (ALF). Furthermore, autophagy contributes to HSCs activation. This study aims to investigate the role and the mechanisms of long noncoding RNA XIST in regulating HSCs autophagy and activation. Human HSC cells (LX‐2) were treated with 100 mmol/L ethanol to mimic HSCs activation. The HSCs activation was evaluated by determining cell viability and protein levels of fibrosis markers α‐smooth muscle actin (α‐SMA) and collagen type 1 α1 (CoL1A1). The autophagy was evaluated by measuring autophagy markers Beclin‐1 and LC3‐II. The interaction among XIST, miR‐29b, and high‐mobility group box‐1 (HMGB1) were analyzed using luciferase reporter assay, qRT‐PCR, and western blot. Lentiviruses targeting sh‐XIST (LV‐sh‐XIST) were injected into ALF model mice via tail vein to elucidate the in vivo role of XIST in ALF injury. XIST was upregulated in ethanol‐activated LX‐2 cells. Furthermore, XIST served as a competitive endogenous RNA of miR‐29b to facilitate HMGB1 expression, and thus enhanced ethanol‐induced HSCs autophagy and activation. Further in vivo assay showed that downregulation of XIST by LV‐sh‐XIST alleviated ALF injury in ALF model mice. Collectively, XIST enhances ethanol‐induced HSCs autophagy and activation via miR‐29b/HMGB1 axis. [ABSTRACT FROM AUTHOR]