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Title: Global deletion of glutathione S-Transferase A4 exacerbates developmental nonalcoholic steatohepatitis

item RONIS, MARTIN - Louisiana State University
item MERCER, KELLY - Arkansas Children'S Nutrition Research Center (ACNC)
item ENGI, BRIDGETTE - University Arkansas For Medical Sciences (UAMS)
item PULLIAM, CASEY - Louisiana State University
item ZIMNIAK, PIOTR - University Arkansas For Medical Sciences (UAMS)
item HENNINGS, LEAH - University Arkansas For Medical Sciences (UAMS)
item SHEARM, COLIN - University Of Colorado
item Badger, Thomas
item PETERSEN, DENNIS - University Of Colorado

Submitted to: American Journal of Pathology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/17/2016
Publication Date: 2/1/2017
Citation: Ronis, M.J., Mercer, K.E., Engi, B., Pulliam, C., Zimniak, P., Hennings, L., Shearn, C.T., Badger, T.M., Petersen, D.R. 2017. Global deletion of glutathione S-Transferase A4 exacerbates developmental nonalcoholic steatohepatitis. American Journal of Pathology. 187(2):418-430.

Interpretive Summary: Childhood obesity is an early risk factor for many chronic diseases seen in adults, including cardiovascular disease, type 2 diabetes, and cancer. Many obese children at risk for these adult diseases have fatty liver disease, in which the liver accumulates excessive fat that in turn impairs liver function. In the liver, chronic overeating coupled to inadequate exercise results in an increase in fat accumulation, i.e. the name fatty liver, which increases oxidative stress and inflammation, which can damage the liver. To study the potential ways fatty liver develops in obese children in order to consider interventions to prevent this condition, we developed a mouse model of pediatric liver disease. In this study, we focused on liver oxidative stress. Mice that are sensitive to liver oxidative stress (called GSTA4 knockout mice) were fed a high fat diet at weaning and continued the diet for 12 weeks into early adulthood. In these mice, we observed a larger oxidative stress response that promoted the accumulation of lipids in the liver. There was also increased inflammation in a second set of mice that were sensitive to both oxidative stress and inflammatory response (GSTA4-/-/PPARa-/- double knockout mice). However, we did not see an increase in markers of fibrosis, a marker for more progressive liver disease. The results suggest that increased lipid oxidative stress and inflammation in the liver increases the progression of liver injury in mice, but is less important in the development of fibrosis, at least in early adulthood. This highlights the need to test whether that dietary or other interventions that limit oxidative stress and inflammation early in life ameliorates at least some of the negative effects of early-life obesity on liver health.

Technical 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 a (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 fatedependent 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.