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.

中文翻译：

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自噬抑制通过激活Nrf2-Keap1-ARE信号通路逆转酒精诱导的肝星状细胞激活

背景

许多文献表明自噬在酒精性肝纤维化（ALF）中起着至关重要的作用，但很少有论文报道其在肝星状细胞（HSC）激活中的功能。当前的研究旨在调查自噬在HSC激活中的调节作用，以进一步探索其所涉及的潜在机制。

方法

用乙醇，3-MA（自噬抑制剂）或雷帕霉素（自噬诱导剂）处理HSC-T6细胞，并用si-Nrf2或si-Keap1转染细胞。此外，建立了ALF动物模型并购买了Nrf-2 ^（-/-）和Keap1 ^（-/-）小鼠。在星状细胞和肝脏中评估自噬水平，α-SMA和CoL1A1的表达以及Nrf2抗氧化反应。

结果

培养细胞中的乙醇处理可增加自噬，氧化应激水平并促进HSC活化。自噬的抑制逆转了酒精诱导的HSCs活化并抑制了HSCs的氧化应激。Nrf2-Keap1-ARE通路参与自噬调节的HSC活化和氧化应激。此外，通过体内研究，我们发现抑制自噬可以减轻ALF模型小鼠的酒精性脂肪肝损伤，并且Nrf2信号传导参与自噬调节的HSC激活。

结论

这些数据暗示了自噬在调节HSC激活中的纤维化反应中的机制。