Leclercq I A, Farrell G C, Field J, Bell D R, Gonzalez F J, Robertson G R
Storr Liver Unit, Department of Medicine and Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead NSW 2145, Australia.
J Clin Invest. 2000 Apr;105(8):1067-75. doi: 10.1172/JCI8814.
Nonalcoholic steatohepatitis (NASH) and alcoholic liver disease have similar pathological features. Because CYP2E1 plays a key role in alcoholic liver disease with its ability to stimulate lipid peroxidation, we tested the proposal that CYP2E1 could also be a factor in the development of NASH. In a dietary model - mice fed a methionine- and choline-deficient (MCD) diet - liver injury was associated with both induction of CYP2E1 and a 100-fold increase in hepatic content of lipid peroxides. Microsomal NADPH-dependent lipid oxidases contributed to the formation of these lipid peroxides, and in vitro inhibition studies demonstrated that CYP2E1 was the major catalyst. To further define the role of CYP2E1 as an initiator of oxidative stress in NASH, Cyp2e1(-/-)mice were administered the MCD diet. CYP2E1 deficiency neither prevented the development of NASH nor abrogated the increased microsomal NADPH-dependent lipid peroxidation, indicating the operation of a non-CYP2E1 peroxidase pathway. In Cyp2e1(-/-) mice with NASH (but not in wild-type mice), CYP4A10 and CYP4A14 were upregulated. Furthermore, hepatic microsomal lipid peroxidation was substantially inhibited by anti-mouse CYP4A10 antibody in vitro. These results show that experimental NASH is strongly associated with hepatic microsomal lipid peroxidation. CYP2E1, the main enzyme associated with that process in wild-type mice, is not unique among P450 proteins in catalyzing peroxidation of endogenous lipids. We have now identified CYP4A enzymes as alternative initiators of oxidative stress in the liver.
非酒精性脂肪性肝炎(NASH)和酒精性肝病具有相似的病理特征。由于细胞色素P450 2E1(CYP2E1)通过刺激脂质过氧化作用在酒精性肝病中起关键作用,我们测试了CYP2E1也可能是NASH发病因素的这一假说。在一种饮食模型中——给小鼠喂食蛋氨酸和胆碱缺乏(MCD)饮食——肝损伤与CYP2E1的诱导以及肝脂质过氧化物含量增加100倍有关。微粒体NADPH依赖性脂质氧化酶促成了这些脂质过氧化物的形成,体外抑制研究表明CYP2E1是主要催化剂。为了进一步明确CYP2E1作为NASH氧化应激引发剂的作用,给Cyp2e1基因敲除(Cyp2e1(-/-))小鼠喂食MCD饮食。CYP2E1缺乏既不能预防NASH的发生,也不能消除微粒体NADPH依赖性脂质过氧化增加的现象,这表明存在一条非CYP2E1过氧化物酶途径。在患有NASH的Cyp2e1(-/-)小鼠中(但野生型小鼠中没有),细胞色素P450 4A10(CYP4A10)和细胞色素P450 4A14(CYP4A14)上调。此外,体外抗小鼠CYP4A10抗体可显著抑制肝微粒体脂质过氧化。这些结果表明,实验性NASH与肝微粒体脂质过氧化密切相关。在野生型小鼠中与该过程相关的主要酶CYP2E1,在催化内源性脂质过氧化方面并非P450蛋白中的唯一酶。我们现已确定CYP4A酶是肝脏氧化应激的替代引发剂。