title: The cytochrome P450 epoxygenase pathway regulates the hepatic inflammatory response in fatty liver disease.
abstract: Fatty liver disease is an emerging public health problem without effective therapies, and chronic hepatic inflammation is a key pathologic mediator in its progression. Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid to biologically active epoxyeicosatrienoic acids (EETs), which have potent anti-inflammatory effects. Although promoting the effects of EETs elicits anti-inflammatory and protective effects in the cardiovascular system, the contribution of CYP-derived EETs to the regulation of fatty liver disease-associated inflammation and injury is unknown. Using the atherogenic diet model of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH), our studies demonstrated that induction of fatty liver disease significantly and preferentially suppresses hepatic CYP epoxygenase expression and activity, and both hepatic and circulating levels of EETs in mice. Furthermore, mice with targeted disruption of Ephx2 (the gene encoding soluble epoxide hydrolase) exhibited restored hepatic and circulating EET levels and a significantly attenuated induction of hepatic inflammation and injury. Collectively, these data suggest that suppression of hepatic CYP-mediated EET biosynthesis is an important pathological consequence of fatty liver disease-associated inflammation, and that the CYP epoxygenase pathway is a central regulator of the hepatic inflammatory response in NAFLD/NASH. Future studies investigating the utility of therapeutic strategies that promote the effects of CYP-derived EETs in NAFLD/NASH are warranted.
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Schuck
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Weibin
authors.initials: W
authors.lastname: Zha
authors.affiliation: Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, United States of America.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Edin
authors.affiliation: Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, United States of America.
authors.forename: Artiom
authors.initials: A
authors.lastname: Gruzdev
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Kimberly C
authors.initials: KC
authors.lastname: Vendrov
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Tricia M
authors.initials: TM
authors.lastname: Miller
authors.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, United States of America.
authors.forename: Fred B
authors.initials: FB
authors.lastname: Lih
authors.affiliation: Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, United States of America.
authors.forename: Laura M
authors.initials: LM
authors.lastname: DeGraff
authors.affiliation: Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, United States of America.
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Tomer
authors.affiliation: Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: H Michael
authors.initials: HM
authors.lastname: Jones
authors.affiliation: Department of Nutrition, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Liza
authors.initials: L
authors.lastname: Makowski
authors.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Leaf
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Poloyac
authors.affiliation: Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, United States of America.
authors.forename: Darryl C
authors.initials: DC
authors.lastname: Zeldin
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Craig R
authors.initials: CR
authors.lastname: Lee
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D050197:Atherosclerosis; D015415:Biomarkers / Q000378:metabolism; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004032:Diet; D015777:Eicosanoids / Q000378:metabolism; D004851:Epoxide Hydrolases / Q000172:deficiency / Q000378:metabolism; D005234:Fatty Liver / Q000097:blood / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D005786:Gene Expression Regulation; D057446:Hydrodynamics; D007249:Inflammation / Q000097:blood / Q000235:genetics / Q000473:pathology*; D008055:Lipids / Q000097:blood; D008099:Liver / Q000201:enzymology* / Q000473:pathology*; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics; D008810:Mice, Inbred C57BL
chemical_list: D015415:Biomarkers; D015777:Eicosanoids; D008055:Lipids; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D000090762:Cytochrome P-450 CYP2J2; D004851:Epoxide Hydrolases; C518648:Ephx2 protein, mouse