Article

Critical role of cytochrome P450 2E1 (CYP2E1) in the development of high fat-induced non-alcoholic steatohepatitis

Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.
Journal of Hepatology (Impact Factor: 11.34). 06/2012; 57(4):860-6. DOI: 10.1016/j.jhep.2012.05.019
Source: PubMed

ABSTRACT

Ethanol-inducible cytochrome P450 2E1 (CYP2E1) activity contributes to oxidative stress. However, CYP2E1 may have an important role in the pathogenesis of high-fat mediated non-alcoholic steatohepatitis (NASH). Thus, the role of CYP2E1 in high-fat mediated NASH development was evaluated.
Male wild type (WT) and Cyp2e1-null mice were fed a low-fat diet (LFD, 10% energy-derived) or a high-fat diet (HFD, 60% energy-derived) for 10weeks. Liver histology and tissue homogenates were examined for various parameters of oxidative stress and inflammation.
Liver histology showed that only WT mice fed a HFD developed NASH despite the presence of increased steatosis in both WT and Cyp2e1-null mice fed HFD. Markers of oxidative stress such as elevated CYP2E1 activity and protein amounts, lipid peroxidation, protein carbonylation, nitration, and glycation with increased phospho-JNK were all markedly elevated only in the livers of HFD-fed WT mice. Furthermore, while the levels of inflammation markers osteopontin and F4/80 were higher in HFD-fed WT mice, TNFα and MCP-1 levels were lower compared to the corresponding LFD-fed WT. Finally, only HFD-fed WT mice exhibited increased insulin resistance and impaired glucose tolerance.
These data suggest that CYP2E1 is critically important in NASH development by promoting oxidative/nitrosative stress, protein modifications, inflammation, and insulin resistance.

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    • "On the other hand, other studies indicate that metabolic oxidative stress, autophagy, and inflammation are hallmarks of NASH progression. In this sense, CYP2E1, the principal isoform of the CYP450 enzyme, seems to be critically important in NASH development by promoting oxidative/nitrosative stress, protein modifications, inflammation, and IR.211,212 Moreover, Das et al suggest that purinergic receptor X7 (P2X7), upregulated by CYP2E1, might have a key role in autophagy induced by metabolic oxidative stress in NASH.213 "
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    • "In humans and animal models of diabetes and NAFLD, the increase in circulating levels of ketone bodies and fatty acids may directly interact with CYP2E1 not only as substrates but also as inducers. Indeed, this isoform is induced in the presence of obesity , fatty liver and NASH in both humans and rodents, and its increase appears to correlate well with the severity of NAFLD (Sindhu et al., 2006; Abdelmegeed et al., 2012). Hence, it is very likely that in our model, CYP2E1 induction is due to both transcript and protein stabilization, similar to what occurs in the case of diabetes (Song et al., 1987). "
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