Role of CYP2E1 in Mitochondrial Dysfunction and Hepatic Injury by Alcohol and Non-Alcoholic Substances.
Alcoholic fatty liver disease (AFLD) and non-alcoholic fatty liver disease (NAFLD) are two pathological conditions that are spreading worldwide. Both conditions are remarkably similar with regard to the pathophysiological mechanism and progression despite different causes. Oxidative stressinduced mitochondrial dysfunction through post-translational protein modifications and/or mitochondrial DNA damage has been a major risk factor in both AFLD and NAFLD development and progression. Cytochrome P450-2E1 (CYP2E1), a known important inducer of oxidative radicals in the cells, has been reported to remarkably increase in both AFLD and NAFLD. Interestingly, CYP2E1 isoforms expressed in both endoplasmic reticulum (ER) and mitochondria, likely lead to the deleterious consequences in response to alcohol or in conditions of NAFLD after exposure to high fat diet (HFD) and in obesity and diabetes. Whether CYP2E1 in both ER and mitochondria work simultaneously or sequentially in various conditions and whether mitochondrial CYP2E1 may exert more pronounced effects on mitochondrial dysfunction in AFLD and NAFLD are unclear. The aims of this review are to briefly describe the role of CYP2E1 and resultant oxidative stress in promoting mitochondrial dysfunction and the development or progression of AFLD and NAFLD, to shed a light on the function of the mitochondrial CYP2E1 as compared with the ER-associated CYP2E1. We finally discuss translational research opportunities related to this field.
Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, 9000 Rockville Pike, Bethesda, MD 20892. United States.
Mohamed A
MA
Abdelmegeed
Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane, Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD. United States.
Seung-Kwon
SK
Ha
Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane, Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD. United States.
Youngshim
Y
Choi
Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane, Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD. United States.
Mohammed
M
Akbar
Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane, Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD. United States.
Byoung-Joon
BJ
Song
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology* / Q000473:pathology; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D006801:Humans; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000473:pathology; D018384:Oxidative Stress; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction
D019392:Cytochrome P-450 CYP2E1
Alcoholic fatty liver disease; CYP2E1; lipid peroxidation; mitochondria; mitochondrial dysfunction; non-alcoholic fatty liver disease; oxidative stress; post-translational protein modification