Insulin resistance enhances binge ethanol-induced liver injury through promoting oxidative stress and up-regulation CYP2E1
Insulin resistance enhances binge ethanol-induced liver injury through promoting oxidative stress and up-regulation CYP2E1
复制标题
胰岛素抵抗通过促进氧化应激和上调 CYP2E1 来增强酗酒引起的肝损伤
DOI：
10.1016/j.lfs.2022.120681
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发表时间：
2022
期刊：
影响因子：
6.1
通讯作者：
Xin Wang
中科院分区：
文献类型：
--
作者：
Jiangzheng Liu;Deqin Kong;Duo Ai;Anqi Xu;Weihua Yu;Zhengwu Peng;Jie Peng;Zhao Wang;Zhao Wang;Rui Liu;Wenli Li;Chunxu Hai;Xiaodi Zhang;Xin Wang
酒精性肝病（ALD）对酒精滥用人群的公共和个人健康造成了严重的负担。胰岛素抵抗（IR）对ALD的影响及其机制尚不清楚。在本研究中，我们研究了乙醇与IR暴露小鼠肝脏损伤、炎症、凋亡、线粒体功能障碍和CYP2E1的变化。我们发现IR增加了乙醇暴露小鼠肝损伤的敏感性，表现为血清AST和ALT活性升高，甘油三酯积累，肝脏病理恶化，炎症因子增加。IR还加重了乙醇暴露小鼠肝脏的细胞凋亡和线粒体功能障碍。IR对乙醇肝损伤的增敏作用可能与氧化应激的增加和抗氧化防御能力的降低有关，其机制可能与MDA水平的升高和GSH/GSSG水平的下降有关，并通过抑制Nrf-2通路使抗氧化酶SOD、GR失活有关。CYP2E1的激活也可能参与了IR对乙醇诱导小鼠肝损伤的致敏作用。这些结果表明IR对酒精性肝损伤具有显著的促氧化和促凋亡作用。我们的研究帮助我们更好地理解IR对ALD的敏感作用，并提示酒精摄入可能对IR患者更有害。•胰岛素抵抗（IR）增加了ALD患者肝损伤和炎症的敏感性。IR加重乙醇小鼠肝脏线粒体功能障碍和细胞凋亡。•IR对ALD的增敏作用可能与氧化应激的增加和抗氧化防御能力的降低有关。•CYP2E1的激活可能参与了IR对ALD的增敏作用。
Alcoholic liver disease (ALD) has caused a serious burden on public and personal health in crowd with ethanol abuse. The effects of insulin resistance (IR) on ALD and the mechanisms underlying these responses are still not well understood. In this study, we investigated the changes of liver injury, inflammation, apoptosis, mitochondrial dysfunction and CYP2E1 changes in liver of mice exposed to ethanol with IR or not. We found IR increased the sensitivity of liver injury in mice exposed to ethanol, manifested as the increase serum activities of AST and ALT, the accumulation of triglycerides, the deterioration of liver pathology and increase of inflammatory factors. IR also exacerbated apoptosis and mitochondrial dysfunction in liver of mice exposed to ethanol. The increase of oxidative stress and the decrease of antioxidant defense ability might be responsible for the sensitizing effects of IR on ethanol-induced liver injury, supported by the increase of MDA levels and the decline of GSH/GSSG, the inactivation of antioxidant enzymes SOD, GR through the inhibition of Nrf-2 pathway. The activation of CYP2E1 might be also involved in the sensitizing effects of IR on ethanol induced liver injury in mice. These results demonstrated that IR exhibited a significant pro-oxidative and pro-apoptosis effects to aggravate alcoholic liver injury. Our study helped us to better understand the sensitive role of IR on ALD and suggested that alcohol intake may be more harmful for people with IR. • Insulin resistance (IR) increased the sensitivity of liver injury and inflammation in ALD. • IR exacerbated mitochondrial dysfunction and apoptosis in liver of mice exposed to ethanol. • The increase of oxidative stress and the decrease of antioxidant defense ability might be responsible for the sensitizing effects of IR on ALD. • The activation of CYP2E1 might be involved in the sensitizing effects of IR on ALD.