CYP2J2 overexpression attenuates nonalcoholic fatty liver disease induced by high-fat diet in mice.
Cytochrome P-450 epoxygenase-derived epoxyeicosatrienoic acids (EETs) exert diverse biological activities, which include potent vasodilatory, anti-inflammatory, antiapoptotic, and antioxidatant effects, and cardiovascular protection. Liver has abundant epoxygenase expression and high levels of EET production; however, the roles of epoxygenases in liver diseases remain to be elucidated. In this study, we investigated the protection against high-fat diet-induced nonalcoholic fatty liver disease (NAFLD) in mice with endothelial-specific CYP2J2 overexpression (Tie2-CYP2J2-Tr). After 24 wk of high-fat diet, Tie2-CYP2J2-Tr mice displayed attenuated NAFLD compared with controls. Tie2-CYP2J2-Tr mice showed significantly decreased plasma triglyceride levels and liver lipid accumulation, improved liver function, reduced inflammatory responses, and less increase in hepatic oxidative stress than wild-type control mice. These effects were associated with inhibition of NF-κB/JNK signaling pathway activation and enhancement of the antioxidant defense system in Tie2-CYP2J2-Tr mice in vivo. We also demonstrated that 14,15-EET treatment protected HepG2 cells against palmitic acid-induced inflammation and oxidative stress. 14,15-EET attenuated palmitic acid-induced changes in NF-κB/JNK signaling pathways, malondialdehyde generation, glutathione levels, reactive oxygen species production, and NADPH oxidase and antioxidant enzyme expression in HepG2 cells in vitro. Together, these results highlight a new role for CYP epoxygenase-derived EETs in lipotoxicity-related inflammation and oxidative stress and reveal a new molecular mechanism underlying EETs-mediated anti-inflammatory and antioxidant effects that could aid in the design of new therapies for the prevention and treatment of NAFLD.
Department of Internal Medicine and Gene Therapy Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China;
Guangzhi
G
Chen
Department of Medical Ultrasound, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China; and.
Renfan
R
Xu
Department of Internal Medicine and Gene Therapy Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China;
Shasha
S
Zhang
Department of Internal Medicine and Gene Therapy Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China;
Yinna
Y
Wang
Department of Internal Medicine and Gene Therapy Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China;
Peihua
P
Wang
Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina.
Matthew L
ML
Edin
Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina.
Darryl C
DC
Zeldin
Department of Internal Medicine and Gene Therapy Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China; dwwang@tjh.tjmu.edu.cn.
Dao Wen
DW
Wang
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002374:Catalase / Q000097:blood; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000097:blood; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005979:Glutathione Peroxidase / Q000097:blood; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology*; D019308:Palmitic Acid / Q000378:metabolism; D012313:RNA / Q000737:chemistry / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D013482:Superoxide Dismutase / Q000097:blood; D014280:Triglycerides / Q000097:blood
C000717350:CYP2J2 protein, human; D016207:Cytokines; D016328:NF-kappa B; D014280:Triglycerides; D019308:Palmitic Acid; D012313:RNA; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D003577:Cytochrome P-450 Enzyme System; D002374:Catalase; D005979:Glutathione Peroxidase; D000090762:Cytochrome P-450 CYP2J2; D013482:Superoxide Dismutase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D015126:8,11,14-Eicosatrienoic Acid
CYP2J2; EETs; inflammation; nonalcoholic fatty liver disease; oxidative stress; palmitic acid