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

Abstract

BACKGROUND & AIMS:

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.

• Authors: Mohamed A Abdelmegeed, Atrayee Banerjee, Seong-Ho Yoo, Sehwan Jang, Frank J Gonzalez, Byoung-Joon Song
• Journal: Journal of hepatology (J Hepatol) Vol. 57 Issue 4 Pg. 860-6 (Oct 2012) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 22668639 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
• Copyright: Published by Elsevier B.V.

Chemical References

• Antigens, Differentiation
• Ccl2 protein, mouse
• Chemokine CCL2
• Glycation End Products, Advanced
• Receptor for Advanced Glycation End Products
• Receptors, Immunologic
• Tumor Necrosis Factor-alpha
• monocyte-macrophage differentiation antigen
• Osteopontin
• Cytochrome P-450 CYP2E1
• JNK Mitogen-Activated Protein Kinases

Topics

• Animals
• Antigens, Differentiation (metabolism)
• Body Weight
• Chemokine CCL2 (metabolism)
• Cytochrome P-450 CYP2E1 (genetics, metabolism)
• Diet, High-Fat (adverse effects)
• Fatty Liver (etiology, metabolism, pathology)
• Glucose Tolerance Test
• Glycation End Products, Advanced (metabolism)
• Inflammation (complications, metabolism)
• Insulin Resistance
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Lipid Peroxidation
• Male
• Mice
• Mice, Knockout
• Non-alcoholic Fatty Liver Disease
• Osteopontin (metabolism)
• Oxidative Stress
• Phosphorylation
• Protein Carbonylation
• Receptor for Advanced Glycation End Products
• Receptors, Immunologic (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)