CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis
CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis
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DOI：
10.1172/jci8814
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发表时间：
2000-04-01
影响因子：
15.9
通讯作者：
Robertson, GR
中科院分区：
文献类型：
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作者：
Leclercq, IA;Farrell, GC;Robertson, GR
非酒精性脂肪性肝炎（NASH）与酒精性肝病具有相似的病理特征。由于CYP 2 E1在酒精性肝病中起着关键作用，其能够刺激脂质过氧化，因此我们测试了CYP 2 E1也可能是NASH发展的一个因素的建议。在饮食模型中-喂食蛋氨酸和胆碱缺乏（MCD）饮食的小鼠-肝损伤与CYP 2 E1诱导和肝脏脂质过氧化物含量增加100倍相关。微粒体NADPH依赖性脂质氧化酶有助于这些脂质过氧化物的形成，体外抑制研究表明：CYP 2 E1是主要催化剂。为进一步确定CYP 2 E1作为NASH中氧化应激引发剂的作用，对Cyp 2 e1（-/-）小鼠给予MCD饲料。CYP 2 E1缺乏既不能阻止NASH的发展，也不能消除微粒体NADPH依赖性脂质过氧化作用的增加，表明非CYP 2 E1过氧化物酶途径的作用。在患有NASH的Cyp 2 e1（-/-）小鼠中（而非野生型小鼠），CYP 4A 10和CYP 4A 14上调。此外，抗小鼠CYP 4A 10抗体在体外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。CYP 2 E1是野生型小鼠中与该过程相关的主要酶，在催化内源性脂质过氧化的P450蛋白中并不是唯一的。我们现在已经确定CYP 4A酶作为肝脏氧化应激的替代引发剂。
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 wildtype 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.