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首页> 外文期刊>European journal of gastroenterology and hepatology >Overexpression of liver-specific cytochrome P4502E1 impairs hepatic insulin signaling in a transgenic mouse model of nonalcoholic fatty liver disease.
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Overexpression of liver-specific cytochrome P4502E1 impairs hepatic insulin signaling in a transgenic mouse model of nonalcoholic fatty liver disease.

机译：在非酒精性脂肪肝疾病的转基因小鼠模型中，肝特异性细胞色素P4502E1的过表达损害肝胰岛素信号传导。

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OBJECTIVE: Cytochrome P4502E1 (CYP2E1) expression in the liver is increased in nonalcoholic fatty liver disease. The aim of this study was to determine whether CYP2E1 overexpression in the liver interferes with insulin signaling pathways in a mouse model of nonalcoholic fatty liver disease. METHODS: Male mice containing the human CYP2E1 transgene under control of the mouse albumin enhancer-promoter (Tg) and control, nontransgenic mice were fed a diet containing 20% calories from fat for 8 months ad libitum. MEASUREMENTS: Liver injury was measured by histology and alanine aminotransferase. Malondialdehyde and protein carbonyls were measured as markers of oxidative stress. Total and phosphorylated proteins involved in the insulin signaling cascade were measured by western blotting. RESULTS: Tg mice had higher fasting insulin, and greater hepatic fat accumulation and histological liver injury. Malondialdehyde and protein carbonyls were increased in Tg mice liver indicating increased oxidative stress. Tyrosine phosphorylation of insulin receptor substrates 1 and 2, and serine phosphorylation of PKB/Akt, were significantly decreased in Tg mice. Serine phosphorylation of glycogen synthase kinase 3alpha was decreased in Tg mice and liver glycogen content was decreased correspondingly. Serine phosphorylation of the transcription factor Fox01a was decreased, and expression of the enzyme phosphoenolcarboxykinase was increased in Tg mice. CONCLUSION: Hepatocyte-specific overexpression of CYP2E1 increased hepatic oxidative stress in the liver, fasting insulin, and histological liver damage. CYP2E1 overexpression reduced hepatic insulin signaling and reduced glycogen storage and increased glucose synthesis. Overall, this study suggests an association of hepatic CYP2E1 with increased oxidative stress, increased systemic insulin resistance, decreased insulin signaling in the liver and increased hepatic fat accumulation.
机译：目的：非酒精性脂肪肝患者肝脏中细胞色素P4502E1（CYP2E1）的表达增加。这项研究的目的是确定在非酒精性脂肪肝疾病的小鼠模型中，肝脏中CYP2E1的过表达是否干扰胰岛素信号通路。方法：在小鼠白蛋白增强剂（Tg）和对照的控制下，将含有人CYP2E1转基因的雄性小鼠随意喂食含20％卡路里的脂肪的饮食，持续8个月。测量：通过组织学和丙氨酸转氨酶测量肝损伤。丙二醛和蛋白质羰基被测量为氧化应激的标志。通过蛋白质印迹法测量参与胰岛素信号传导级联的总蛋白和磷酸化蛋白。结果：Tg小鼠空腹胰岛素水平较高，肝脏脂肪堆积和组织学肝损伤也较高。 Tg小鼠肝脏中丙二醛和蛋白质羰基的含量增加，表明氧化应激增加。在Tg小鼠中，胰岛素受体底物1和2的酪氨酸磷酸化以及PKB / Akt的丝氨酸磷酸化显着降低。 Tg小鼠糖原合酶激酶3alpha的丝氨酸磷酸化降低，肝糖原含量相应降低。在Tg小鼠中，转录因子Fox01a的丝氨酸磷酸化降低，而磷酸烯醇羧激酶的表达增加。结论：CYP2E1的肝细胞特异性过表达增加了肝脏的肝氧化应激，空腹胰岛素和肝组织学损害。 CYP2E1的过表达减少了肝胰岛素的信号传导，减少了糖原的存储并增加了葡萄糖的合成。总的来说，这项研究表明肝CYP2E1与氧化应激增加，全身胰岛素抵抗增加，肝中胰岛素信号传导减少和肝脂肪积累增加有关。

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