title: Characterization of the Cytochrome P450 epoxyeicosanoid pathway in non-alcoholic steatohepatitis.
abstract: Non-alcoholic steatohepatitis (NASH) is an emerging public health problem without effective therapies. Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid into bioactive epoxyeicosatrienoic acids (EETs), which have potent anti-inflammatory and protective effects. However, the functional relevance of the CYP epoxyeicosanoid metabolism pathway in the pathogenesis of NASH remains poorly understood. Our studies demonstrate that both mice with methionine-choline deficient (MCD) diet-induced NASH and humans with biopsy-confirmed NASH exhibited significantly higher free EET concentrations compared to healthy controls. Targeted disruption of Ephx2 (the gene encoding for soluble epoxide hydrolase) in mice further increased EET levels and significantly attenuated MCD diet-induced hepatic steatosis, inflammation and injury, as well as high fat diet-induced adipose tissue inflammation, systemic glucose intolerance and hepatic steatosis. Collectively, these findings suggest that dysregulation of the CYP epoxyeicosanoid pathway is a key pathological consequence of NASH in vivo, and promoting the anti-inflammatory and protective effects of EETs warrants further investigation as a novel therapeutic strategy for NASH.
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Wells
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
authors.forename: Kimberly C
authors.initials: KC
authors.lastname: Vendrov
authors.affiliation: Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, United States.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Edin
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Ferslew
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
authors.forename: Weibin
authors.initials: W
authors.lastname: Zha
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
authors.forename: Bobbie K H
authors.initials: BK
authors.lastname: Nguyen
authors.affiliation: University of North Carolina Institute for Drug Safety Sciences, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Church
authors.affiliation: Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, United States.
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, NC, United States.
authors.forename: Laura M
authors.initials: LM
authors.lastname: DeGraff
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
authors.forename: Kim L R
authors.initials: KL
authors.lastname: Brouwer
authors.affiliation: Division of Gastroenterology and Hepatology, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
authors.forename: A Sidney
authors.initials: AS
authors.lastname: Barritt
authors.affiliation: Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, United States.
authors.forename: Darryl C
authors.initials: DC
authors.lastname: Zeldin
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. Electronic address: craig_lee@unc.edu.
authors.forename: Craig R
authors.initials: CR
authors.lastname: Lee
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000378:metabolism; D000328:Adult; D000818:Animals; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004032:Diet / Q000009:adverse effects; D018450:Disease Progression; D004851:Epoxide Hydrolases / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006801:Humans; D006868:Hydrolysis; D008099:Liver / Q000201:enzymology; D008297:Male; D024821:Metabolic Syndrome / Q000150:complications; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications / Q000201:enzymology* / Q000378:metabolism; D012995:Solubility
chemical_list: D003577:Cytochrome P-450 Enzyme System; D000090762:Cytochrome P-450 CYP2J2; D004851:Epoxide Hydrolases; D015126:8,11,14-Eicosatrienoic Acid
keywords: CYP2C; CYP2J; Epoxyeicosatrienoic acids; Humans; Mice; Non-alcoholic fatty liver disease; Soluble epoxide hydrolase