Role of Mesencephalic Astrocyte-Derived Neurotrophic Factor in Alcohol-Induced Liver Injury
Role of Mesencephalic Astrocyte-Derived Neurotrophic Factor in Alcohol-Induced Liver Injury
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DOI：
10.1155/2020/9034864
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发表时间：
2020-07-07
影响因子：
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通讯作者：
Shen, Yuxian
中科院分区：
文献类型：
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作者：
Chhetri, Goma;Liang, Yanyan;Shen, Yuxian
过量饮酒诱导内质网应激反应（酒精诱导内质网应激）。中脑星形胶质细胞衍生神经营养因子（MANF）是一种内质网应激诱导蛋白，是一种进化保守的全身和肝脏代谢稳态调节因子。在这项研究中，通过在慢性加暴酒精喂养模型中使用肝细胞特异性MANF敲除小鼠（MANF(Delta Hep)）来探索MANF对酒精诱导的肝损伤的影响。我们发现酒精喂养上调了MANF的表达，并且酒精喂养后，MANF（Delta Hep）小鼠表现出更严重的肝损伤和额外激活的ER应激。此外，我们发现MANF缺乏激活iNOS和p65，增加NO和抗炎细胞因子的产生，酒精处理后进一步增强。同时，MANF缺失上调CYP2E1、4-HNE、MDA水平，下调GSH、SOD水平。这些结果表明，MANF对酒精性肝损伤具有潜在的保护作用，其潜在机制可能与通过抑制和减少NO/NF-kappa B和CYP2E1/ROS分别改善炎症和氧化应激引发的过度激活内质网应激有关。因此，MANF可能是酒精诱导内质网应激的负调节因子，并参与肝脏nf - κ B通路与氧化应激之间的串扰。本研究确定了MANF在酒精性肝损伤中的特定作用，这可能为ALI的治疗提供新的途径。
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(Delta Hep)) in a chronic-plus-binge alcohol feeding model. We found that alcohol feeding upregulated MANF expression and MANF(Delta Hep)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-kappa B and CYP2E1/ROS, respectively. Therefore, MANF might be a negative regulator in alcohol-induced ER stress and participate in the crosstalk between the NF-kappa B 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.