Single ethanol binge causes severe liver injury in mice fed Western diet.
Single ethanol binge causes severe liver injury in mice fed Western diet.
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DOI：
10.1097/hc9.0000000000000174
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发表时间：
2023-07-01
影响因子：
5.1
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中科院分区：
文献类型：
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酒精相关性肝脏疾病（ALD）和NAFLD通常在食用富含能量和含胆固醇的西方饮食的西方社会共存。在这些社会中，年轻人ALD死亡率的增加可能归因于酗酒。在西方饮食环境中，酗酒是如何导致肝损伤的，这在很大程度上是未知的。在这项研究中，我们发现，一个单一的乙醇狂欢（5克/公斤体重）诱导严重的肝损伤所示的2个转氨酶AST和ALT在C57 BL/6 J小鼠，已经喂了西方饮食3周的血清活性显着增加。西方饮食加酒精喂养的小鼠也表现出严重的脂滴沉积和高含量的甘油三酯和胆固醇在肝脏中，这与增加脂肪生成和减少脂肪酸氧化基因表达。这些动物具有最高的Cxcl 1 mRNA表达和肝脏中髓过氧化物酶（MPO）阳性中性粒细胞。他们的肝脏活性氧和脂质过氧化作用是最高的，但他们的线粒体氧化磷酸化蛋白的肝脏水平基本保持不变。在这些动物中，几种ER应激标志物的肝脏水平也最高，包括CHOP、ERO 1A、ERO 1B、BIM和BIP的mRNA，以及BIP/GRP 78和IRE-α的Xbp 1剪接和蛋白质。有趣的是，西方饮食喂养3周或酒精狂欢显着增加肝caspase 3切割，和两者的组合并没有进一步增加它。因此，我们成功地建立了一个小鼠模型的急性肝损伤模仿人类饮食和酗酒。这种简单的西方饮食加单一乙醇狂欢模型概括了ALD的主要肝脏表型，包括脂肪变性和脂肪性肝炎，其特征在于中性粒细胞浸润、氧化应激和ER应激。
Alcohol-associated liver disease (ALD) and NAFLD often coexist in Western societies that consume energy-rich and cholesterol-containing Western diets. Increased rates of ALD mortality in young people in these societies are likely attributable to binge drinking. It is largely unknown how alcohol binge causes liver damage in the setting of Western diets. In this study, we showed that a single ethanol binge (5 g/kg body weight) induced severe liver injury as shown by marked increases in serum activities of the 2 aminotransferases AST and ALT in C57BL/6J mice that have been fed a Western diet for 3 weeks. The Western diet plus binge ethanol-fed mice also displayed severe lipid droplet deposition and high contents of triglycerides and cholesterol in the liver, which were associated with increased lipogenic and reduced fatty acid oxidative gene expression. These animals had the highest Cxcl1 mRNA expression and myeloperoxidase (MPO)-positive neutrophils in the liver. Their hepatic ROS and lipid peroxidation were the highest, but their hepatic levels of mitochondrial oxidative phosphorylation proteins remained largely unaltered. Hepatic levels of several ER stress markers, including mRNAs for CHOP, ERO1A, ERO1B, BIM, and BIP, as well as Xbp1 splicing and proteins for BIP/GRP78 and IRE-α were also the highest in these animals. Interestingly, Western diet feeding for 3 weeks or ethanol binge dramatically increased hepatic caspase 3 cleavage, and the combination of the 2 did not further increase it. Thus, we successfully established a murine model of acute liver injury by mimicking human diets and binge drinking. This simple Western diet plus single ethanol binge model recapitulates major hepatic phenotypes of ALD, including steatosis and steatohepatitis characterized by neutrophil infiltration, oxidative stress, and ER stress.