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


METHODS
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 10 weeks. Liver histology and tissue homogenates were examined for various parameters of oxidative stress and inflammation.


RESULTS
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.


CONCLUSIONS
These data suggest that CYP2E1 is critically important in NASH development by promoting oxidative/nitrosative stress, protein modifications, inflammation, and insulin resistance.
Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892-9410, USA.
Mohamed A
MA
Abdelmegeed
Atrayee
A
Banerjee
Seong-Ho
SH
Yoo
Sehwan
S
Jang
Frank J
FJ
Gonzalez
Byoung-Joon
BJ
Song
D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D001835:Body Weight; D018932:Chemokine CCL2 / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects*; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D005951:Glucose Tolerance Test; D017127:Glycation End Products, Advanced / Q000378:metabolism; D007249:Inflammation / Q000150:complications / Q000378:metabolism; D007333:Insulin Resistance; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D015227:Lipid Peroxidation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease; D053495:Osteopontin / Q000378:metabolism; D018384:Oxidative Stress; D010766:Phosphorylation; D050050:Protein Carbonylation; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000943:Antigens, Differentiation; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha; C036763:monocyte-macrophage differentiation antigen; D053495:Osteopontin; D019392:Cytochrome P-450 CYP2E1; D048031:JNK Mitogen-Activated Protein Kinases