title: Cytochrome P450-2E1 promotes aging-related hepatic steatosis, apoptosis and fibrosis through increased nitroxidative stress.
abstract: The role of ethanol-inducible cytochrome P450-2E1 (CYP2E1) in promoting aging-dependent hepatic disease is unknown and thus was investigated in this study. Young (7 weeks) and aged female (16 months old) wild-type (WT) and Cyp2e1-null mice were used in this study to evaluate age-dependent changes in liver histology, steatosis, apoptosis, fibrosis and many nitroxidative stress parameters. Liver histology showed that aged WT mice exhibited markedly elevated hepatocyte vacuolation, ballooning degeneration, and inflammatory cell infiltration compared to all other groups. These changes were accompanied with significantly higher hepatic triglyceride and serum cholesterol in aged WT mice although serum ALT and insulin resistance were not significantly altered. Aged WT mice showed the highest rates of hepatocyte apoptosis and hepatic fibrosis. Further, the highest levels of hepatic hydrogen peroxide, lipid peroxidation, protein carbonylation, nitration, and oxidative DNA damage were observed in aged WT mice. These increases in the aged WT mice were accompanied by increased levels of mitochondrial nitroxidative stress and alteration of mitochondrial complex III and IV proteins in aged WT mice, although hepatic ATP levels seems to be unchanged. In contrast, the aging-related nitroxidative changes were very low in aged Cyp2e1-null mice. These results suggest that CYP2E1 is important in causing aging-dependent hepatic steatosis, apoptosis and fibrosis possibly through increasing nitroxidative stress and that CYP2E1 could be a potential target for translational research in preventing aging-related liver disease.
authors.affiliation: Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Abdelmegeed
authors.affiliation: Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.
authors.forename: Youngshim
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.
authors.forename: Seung-Kwon
authors.initials: SK
authors.lastname: Ha
authors.affiliation: Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA. Electronic address: bj.song@nih.gov.
authors.forename: Byoung-Joon
authors.initials: BJ
authors.lastname: Song
mesh_terms: D000375:Aging; D000818:Animals; D017209:Apoptosis; D019392:Cytochrome P-450 CYP2E1 / Q000502:physiology*; D005234:Fatty Liver / Q000201:enzymology* / Q000473:pathology; D005260:Female; D022781:Hepatocytes / Q000502:physiology; D015227:Lipid Peroxidation; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D018384:Oxidative Stress; D050050:Protein Carbonylation
chemical_list: D019392:Cytochrome P-450 CYP2E1
keywords: Aging; Apoptosis; CYP2E1; Fibrosis; Liver; Nitroxidative stress; Steatohepatitis