Zheng-Yuan Xie1, Zhi-Hua Xiao2, Fen-Fen Wang2. 1. Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China. Electronic address: xzyxzy1230@163.com. 2. Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China.
Abstract
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.
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.
Authors: Ana Blas-García; Nadezda Apostolova; Federico Lucantoni; Ana M Benedicto; Aleksandra Gruevska; Ángela B Moragrega; Isabel Fuster-Martínez; Juan V Esplugues Journal: Cell Death Dis Date: 2022-04-20 Impact factor: 9.685
Authors: Lozan Sheriff; Reenam S Khan; Raquel Saborano; Richard Wilkin; Nguyet-Thin Luu; Ulrich L Gunther; Stefan G Hubscher; Philip N Newsome; Patricia F Lalor Journal: Dis Model Mech Date: 2020-12-29 Impact factor: 5.758