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

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• 作者：Martin Ronis^&lowast ; ; ^{mronis@lsuhsc.edu} ; Kelly Mercer^&dagger ; ; ^&Dagger ; ; ^{kmercer@uams.edu} ; Bridgette Engi^§ ; ; Casey Pulliam^&lowast ; ; Piotr Zimniak^¶ ; ; Leah Hennings^‖ ; Colin Shearn^&lowast ; &lowast ; ; Thomas Badger^&dagger ; ; ^&Dagger ; ; Dennis Petersen^&lowast ; &lowast ;
• 刊名：The American Journal of Pathology
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：187
• 期：2
• 页码：418-430
• 全文大小：2849 K
• 卷排序：187

文摘

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.