title: Global Deletion of Glutathione S-Transferase A4 Exacerbates Developmental Nonalcoholic Steatohepatitis.
abstract: We established a mouse model of developmental nonalcoholic steatohepatitis (NASH) by feeding a high polyunsaturated fat liquid diet to female glutathione-S-transferase 4-4 (Gsta4-/-)/peroxisome proliferator activated receptor α (Ppara-/-) double knockout 129/SvJ mice for 12 weeks from weaning. We used it to probe the importance of lipid peroxidation in progression of NASH beyond simple steatosis. Feeding Gsta4-/-/Ppara-/-double-knockout (dKO) mice liquid diets containing corn oil resulted in a percentage fat-dependent increase in steatosis and necroinflammatory injury (P < 0.05). Increasing fat to 70% from 35% resulted in increases in formation of 4-hydroxynonenal protein adducts accompanied by evidence of stellate cell activation, matrix remodeling, and fibrosis (P < 0.05). Comparison of dKO mice with wild-type (Wt) and single knockout mice revealed additive effects of Gsta4-/-and Ppara-/-silencing on steatosis, 4-hydroxynonenal adduct formation, oxidative stress, serum alanine amino transferase, expression of tumor necrosis factor alpha, Il6, interferon mRNA, and liver pathology (P < 0.05). Induction of Cyp2e1 protein by high-fat diet was suppressed in Gsta4-/-and dKO groups (P < 0.05). The dKO mice had similar levels of markers of stellate cell activation and matrix remodeling as Ppara-/-single KO mice. These data suggest that lipid peroxidation products play a role in progression of liver injury to steatohepatitis in NASH produced by high-fat feeding during development but appear less important in development of fibrosis.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center-New Orleans, New Orleans, Louisiana. Electronic address: mronis@lsuhsc.edu.
authors.forename: Martin
authors.initials: M
authors.lastname: Ronis
authors.affiliation: Arkansas Children's Nutrition Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas; Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Electronic address: kmercer@uams.edu.
authors.forename: Kelly
authors.initials: K
authors.lastname: Mercer
authors.affiliation: Department of Laboratory Animal Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Bridgette
authors.initials: B
authors.lastname: Engi
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center-New Orleans, New Orleans, Louisiana.
authors.forename: Casey
authors.initials: C
authors.lastname: Pulliam
authors.affiliation: Department of Pharmacology and Toxicology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Piotr
authors.initials: P
authors.lastname: Zimniak
authors.affiliation: Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Leah
authors.initials: L
authors.lastname: Hennings
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Colin
authors.initials: C
authors.lastname: Shearn
authors.affiliation: Arkansas Children's Nutrition Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas; Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Thomas
authors.initials: T
authors.lastname: Badger
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Dennis
authors.initials: D
authors.lastname: Petersen
mesh_terms: D000818:Animals; D015153:Blotting, Western; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005260:Female; D005982:Glutathione Transferase / Q000172:deficiency*; D015227:Lipid Peroxidation / Q000502:physiology*; D008099:Liver / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000201:enzymology* / Q000473:pathology*; D047493:PPAR alpha / Q000172:deficiency; D016133:Polymerase Chain Reaction; D059467:Transcriptome
chemical_list: D047493:PPAR alpha; C529117:GSTA4-4 protein, mouse; D005982:Glutathione Transferase