Consumption of alcohol in immoderate quantity induces endoplasmic reticulum (ER) stress response (alcohol-induced ER stress). Mesencephalic astrocyte-derived neurotrophic factor (MANF), an ER stress-inducible protein, works as an evolutionarily conserved regulator of systemic and liver metabolic homeostasis. In this study, the effects of MANF on alcohol-induced liver injury were explored by using hepatocyte-specific MANF-knockout mice (MANF^ΔHep) in a chronic-plus-binge alcohol feeding model. We found that alcohol feeding upregulated MANF expression and MANF^ΔHep mice exhibited more severe liver injury with extra activated ER stress after alcohol feeding. In addition, we found that MANF deficiency activated iNOS and p65 and increased the production of NO and anti-inflammatory cytokines, which was further enhanced after alcohol treatment. Meanwhile, MANF deletion upregulated the levels of CYP2E1, 4-HNE, and MDA and downregulated the levels of GSH and SOD. These results indicate that MANF has potential protection on alcohol-induced liver injury, and the underlying mechanisms may be associated with meliorating the overactivated ER stress triggered by inflammation and oxidative stress via inhibiting and reducing NO/NF-κB and CYP2E1/ROS, respectively. Therefore, MANF might be a negative regulator in alcohol-induced ER stress and participate in the crosstalk between the NF-κB pathway and oxidative stress in the liver. Conclusions. This study identifies a specific role of MANF in alcohol-induced liver injury, which may provide a new approach for the treatment of ALI.

中文翻译：

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中脑星形胶质细胞源性神经营养因子在酒精引起的肝损伤中的作用。

适量饮酒会引起内质网（ER）应激反应（酒精引起的ER应激）。中脑星形胶质细胞源性神经营养因子（MANF），一种内质网应激诱导蛋白，可作为系统和肝脏代谢稳态的进化保守调节剂。在这项研究中，MANF的对酒精诱导的肝损伤的影响通过使用肝细胞特异性MANF敲除小鼠（MANF探索^Δ的Hep在慢性加无节制醇馈送模型）。我们发现，酒精供给上调MANF表达和MANF ^Δ的Hep饮酒后，小鼠表现出更严重的肝损伤，并伴有额外的内质网应激。另外，我们发现MANF缺乏激活了iNOS和p65，并增加了NO和抗炎细胞因子的产生，酒精处理后这种作用进一步增强。同时，MANF缺失上调CYP2E1、4-HNE和MDA的水平，而下调GSH和SOD的水平。这些结果表明，MANF对酒精性肝损伤的潜在的保护，和潜在的机制可经由抑制和减少NO / NF-meliorating由炎症和氧化应激触发的过度激活ER应激相关联κ B和CYP2E1 / ROS， 。因此，MANF可能是酒精诱导的内质网应激的负调节剂，并参与了NF-肝脏中的κB通路和氧化应激。结论。这项研究确定MANF在酒精引起的肝损伤中的特定作用，这可能为ALI的治疗提供新的方法。