期刊
BIOLOGY-BASEL
卷 9, 期 12, 页码 -出版社
MDPI
DOI: 10.3390/biology9120419
关键词
CYP2E1; E3 ubiquitin ligase; gp78/AMFR; CHIP; ubiquitin-dependent proteasomal degradation (UPD); NAFLD/NASH
类别
资金
- NIH-NIGMS [GM44037]
- NIDDK [P30DK26743]
Simple Summary Cytochrome P450 CYP2E1 is an enzyme engaged in the breakdown of various compounds (drugs, carcinogens, dietary nutrients and toxins) as well as endogenous compounds (steroids and fatty acids), resulting in both detoxification and elimination of these agents. Often, it can also convert these agents, i.e., Acetaminophen, into more toxic products. Elevated liver CYP2E1 content is implicated in various metabolic diseases including alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), diabetes and obesity. While liver CYP2E1 elevation is considered essential to the pathogenesis of these liver diseases, our findings of elevated liver CYP2E1 content in two genetic mouse models with impaired degradation and thus a disrupted disposal of CYP2E1 when fed a regular lab chow diet, argue that it is not sufficient for triggering NAFLD/NASH. Thus, despite comparable hepatic CYP2E1 elevation and functional stabilization in these two models, NAFLD/NASH was only observed in the mouse livers that exhibited concurrently enhanced liver fat production. These findings reinforce the notion that in addition to elevated liver CYP2E1 content, CYP2E1-mediated NAFLD/NASH requires liver fat accumulation derived from either enhanced liver fat-production or ingestion of a high fat/high carbohydrate diet. Hepatic cytochrome P450 CYP2E1 is an enzyme engaged in the metabolic biotransformation of various xenobiotics and endobiotics, resulting in both detoxification and/or metabolic activation of its substrates to more therapeutic or toxic products. Elevated hepatic CYP2E1 content is implicated in various metabolic diseases including alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), diabetes and obesity. While hepatic CYP2E1 elevation is considered essential to the pathogenesis of these liver diseases, our findings in two mouse models of E3 ubiquitin ligase genetic ablation fed a regular lab chow diet, argue that it is not sufficient for triggering NAFLD/NASH. Thus, albeit comparable hepatic CYP2E1 elevation and functional stabilization in these two models upon E3 ubiquitin ligase genetic ablation and consequent disruption of its ubiquitin-dependent proteasomal degradation, NAFLD/NASH was only observed in the mouse livers that exhibited concurrent SREBP1c-transcriptional upregulation of hepatic lipogenesis. These findings reinforce the critical complicity of an associated prolipogenic scenario induced by either an inherently upregulated hepatic lipogenesis or a high fat/high carbohydrate diet in CYP2E1-mediated NAFLD/NASH.
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