title: Cytochrome P450-2E1 promotes fast food-mediated hepatic fibrosis.
abstract: Cytochrome P450-2E1 (CYP2E1) increases oxidative stress. High hepatic cholesterol causes non-alcoholic steatohepatitis (NASH) and fibrosis. Thus, we aimed to study the role of CYP2E1 in promoting liver fibrosis by high cholesterol-containing fast-food (FF). Male wild-type (WT) and Cyp2e1-null mice were fed standard chow or FF for 2, 12, and 24 weeks. Various parameters of liver fibrosis and potential mechanisms such as oxidative and endoplasmic reticulum (ER) stress, inflammation, and insulin resistance (IR) were studied. Indirect calorimetry was also used to determine metabolic parameters. Liver histology showed that only WT fed FF (WT-FF) developed NASH and fibrosis. Hepatic levels of fibrosis protein markers were significantly increased in WT-FF. The nitroxidative stress marker iNOS, but not CYP2E1, was significantly elevated only in FF-fed WT. Serum endotoxin, TLR-4 levels, and inflammatory markers were highest in WT-FF. FAS, PPAR-α, PPAR-γ, and CB1-R were markedly altered in WT-FF. Electron microscopy and immunoblot analyses showed significantly higher levels of ER stress in FF-fed WT. Indirect calorimetry showed that Cyp2e1-null-mice fed FF exhibited consistently higher total energy expenditure (TEE) than their corresponding WT. These results demonstrate that CYP2E1 is important in fast food-mediated liver fibrosis by promoting nitroxidative and ER stress, endotoxemia, inflammation, IR, and low TEE.
authors.affiliation: Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, 20892, 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, 20892, USA.
authors.forename: Youngshim
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20982, USA.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Godlewski
authors.affiliation: Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, 20892, 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, 20892, USA.
authors.forename: Atrayee
authors.initials: A
authors.lastname: Banerjee
authors.affiliation: Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, 20892, USA.
authors.forename: Sehwan
authors.initials: S
authors.lastname: Jang
authors.affiliation: Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, 20892, USA.
authors.forename: Byoung-Joon
authors.initials: BJ
authors.lastname: Song
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D004734:Energy Metabolism; D057140:Fast Foods; D005355:Fibrosis; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D018836:Inflammation Mediators / Q000097:blood; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism*; D018384:Oxidative Stress
chemical_list: D018836:Inflammation Mediators; D002784:Cholesterol; D019392:Cytochrome P-450 CYP2E1