Epidemiological evidence suggests that the phenotype of glutathione S-transferase mu 1 (GSTM1), a hepatic high-expressed phase II detoxification enzyme, is closely associated with the incidence of alcohol-related liver disease (ALD). However, whether and how hepatic GSTM1 determines the development of ALD is largely unclear. This study was designed to elucidate the role and potential mechanism(s) of hepatic GSTM1 in the pathological process of ALD. GSTM1 was detected in the liver of various ALD mice models and cultured hepatocytes. Liver-specific GSTM1 or/and micro (miR)-743a-3p deficiency mice were generated by adenoassociated virus-8 delivered shRNA, respectively. The potential signal pathways involving in alcohol-regulated GSTM1 and GSTM1-associated ALD were explored via both genetic manipulation and pharmacological approaches. GSTM1 was significantly upregulated in both chronic alcohol-induced mice liver and ethanol-exposed murine primary hepatocytes. Alcohol-reduced miR-743a-3p directly contributed to the upregulation of GSTM1, since liver specific silencing miR-743a-3p enhanced GSTM1 and miR-743a-3p loss protected alcohol-induced liver dysfunctions, which was significantly blocked by GSTM1 knockdown. GSTM1 loss robustly aggravated alcohol-induced hepatic steatosis, oxidative stress, inflammation, and early fibrotic-like changes, which was associated with the activation of apoptosis signal-regulating kinase 1 (ASK1), c-Jun N-terminal kinase (JNK), and p38. GSTM1 antagonized ASK1 phosphorylation and its downstream JNK/p38 signaling pathway upon chronic alcohol consumption via binding with ASK1. ASK1 blockage significantly rescued hepatic GSTM1 loss-enhanced disorders in alcohol-fed mice liver. Chronic alcohol consumption-induced upregulation of GSTM1 in the liver provides a feedback protection against hepatic steatosis and liver injury by counteracting ASK1 activation. Down-regulation of miR-743a-3p improves alcohol intake-induced hepatic steatosis and liver injury via direct targeting on GSTM1. The miR-743a-3p–GSTM1 axis functions as an innate protective pathway to defend the early stage of ALD.

中文翻译：

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micro-743a-3p–GSTM1 通路是小鼠体内针对酒精相关肝病的内源性保护机制

流行病学证据表明，肝脏高表达的 II 期解毒酶谷胱甘肽 S-转移酶 mu 1 (GSTM1) 的表型与酒精相关性肝病 (ALD) 的发生密切相关。然而，肝脏 GSTM1 是否以及如何决定 ALD 的发展尚不清楚。本研究旨在阐明肝脏GSTM1在ALD病理过程中的作用和潜在机制。在各种 ALD 小鼠模型的肝脏和培养的肝细胞中检测到 GSTM1。肝脏特异性 GSTM1 或/和 micro (miR)-743a-3p 缺陷小鼠分别由腺相关病毒 8 递送的 shRNA 产生。通过基因操作和药理学方法探索了涉及酒精调节的 GSTM1 和 GSTM1 相关 ALD 的潜在信号通路。GSTM1 在慢性酒精诱导的小鼠肝脏和乙醇暴露的小鼠原代肝细胞中均显着上调。酒精减少的 miR-743a-3p 直接导致 GSTM1 的上调，因为肝脏特异性沉默 miR-743a-3p 增强了 GSTM1，而 miR-743a-3p 的丢失可以保护酒精诱导的肝功能障碍，而 GSTM1 敲低可显着阻断这种功能障碍。GSTM1 缺失会严重加剧酒精诱导的肝脂肪变性、氧化应激、炎症和早期纤维化样变化，这与凋亡信号调节激酶 1 (ASK1)、c-Jun N 末端激酶 (JNK) 的激活相关。和第38页。慢性饮酒时，GSTM1 通过与 ASK1 结合拮抗 ASK1 磷酸化及其下游 JNK/p38 信号通路。ASK1 阻断显着挽救了酒精喂养小鼠肝脏中 GSTM1 缺失增强的疾病。慢性饮酒引起的肝脏 GSTM1 上调通过抵消 ASK1 激活提供反馈保护，防止肝脂肪变性和肝损伤。miR-743a-3p 的下调通过直接靶向 GSTM1 改善酒精摄入诱导的肝脂肪变性和肝损伤。miR-743a-3p-GSTM1 轴作为先天保护途径来防御 ALD 的早期阶段。