Global Deletion of Glutathione S-Transferase A4 Exacerbates Developmental Nonalcoholic Steatohepatitis

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 P 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 Gsta4 −/− and dKO groups ( P 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.