Cytochrome P450 2E1 contributes to ethanol-induced fatty liver in mice
Cytochrome P450 2E1 contributes to ethanol-induced fatty liver in mice
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DOI：
10.1002/hep.22222
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发表时间：
2008-05-01
期刊：
影响因子：
13.5
通讯作者：
Cederbaum, Arthur I.
中科院分区：
文献类型：
--
作者：
Lu, Yongke;Zhuge, Jian;Cederbaum, Arthur I.
细胞色素P450 2E1被认为在酒精性肝病中发挥作用，包括酒精性脂肪肝、酒精性肝炎和酒精性肝硬变。在这项研究中，我们研究了在口服酒精喂养的实验性酒精性脂肪肝模型中，CYP2E1是否起到了作用。乙醇喂养4周后，野生型小鼠肝脏可见大泡状脂肪蓄积和甘油三酯蓄积，而CYP2E1基因敲除小鼠未见蓄积。相反，在CYP2E1基因敲除的小鼠中，游离脂肪酸(FFAs)增加，而在野生型小鼠中则没有。野生型小鼠用乙醇诱导的氧化应激高于野生型小鼠。脂肪酸氧化调节因子--过氧化物酶体增殖物激活受体α(PPARα)在摄入乙醇的CYP2E1基因敲除小鼠中上调，而在野生型小鼠中则不表达。在野生型小鼠中，PPARα靶基因酰基辅酶A氧化酶被乙醇降低，而在CYP2E1基因敲除的小鼠中则没有。野生型小鼠摄入乙醇后，细胞色素P450酶抑制剂氯甲唑降低了大泡脂肪堆积，抑制了氧化应激，并上调了PPARα蛋白水平。通过腺病毒将细胞色素P450_2E_1基因敲除的小鼠导入细胞色素P450_2E_1基因，恢复了大泡脂肪的蓄积。这些结果表明，在该模型中，CYP2E1参与了实验性酒精性脂肪肝的形成，并提示该氧化应激可能通过阻止乙醇上调PPARα而抑制脂肪酸的氧化，从而导致脂肪肝。
Cytochrome P450 2E1 (CYP2E1) is suggested to play a role in alcoholic liver disease, which includes alcoholic fatty liver, alcoholic hepatitis, and alcoholic cirrhosis. In this study, we investigated whether CYP2E1 plays a role in experimental alcoholic fatty liver in an oral ethanol-feeding model. After 4 weeks of ethanol feeding, macrovesicular fat accumulation and accumulation of triglyceride in liver were observed in wild-type mice but not in CYP2E1-knockout mice. In contrast, free fatty acids (FFAs) were increased in CYP2E1-knockout mice but not in wild-type mice. CYP2E1 was induced by ethanol in wild-type mice, and oxidative stress induced by ethanol was higher in wild-type mice than in Cyp2E1 knockout mice. Peroxisome proliferator-activated receptor alpha (PPAR alpha), a regulator of fatty acid oxidation, was up-regulated in CYP2E1-knockout mice fed ethanol but not in wild-type mice. A PPAR alpha target gene, acyl CoA oxidase, was decreased by ethanol in wild-type but not in CYP2E1-knockout mice. Chlormethiazole, an inhibitor of CYP2E1, lowered macrovesicular fat accumulation, inhibited oxidative stress, and up-regulated PPAR alpha protein level in wild-type mice fed ethanol. The introduction of CYP2E1 to CYP2E1-knockout mice via an adenovirus restored macrovesicular fat accumulation. These results indicate that CYP2E1 contributes to experimental alcoholic fatty liver in this model and suggest that CYP2E1-derived oxidative stress may inhibit oxidation of fatty acids by preventing up-regulation of PPAR alpha by ethanol, resulting in fatty liver.