Nonalcoholic fatty liver disease is characterized by dysregulated hepatic oxidative metabolism which may progress to a state of elevated inflammation and fibrosis (NASH). The lipophilic antioxidant vitamin E (VitE) has shown promise as an effective strategy for treating NASH in some clinical trials. Here we tested whether dietary VitE supplementation is sufficient to prevent NASH development and mitigate aberrant glucose and oxidative liver metabolism during overnutrition. Hyperphagic, melanocortin-4-receptor deficient mice (MC4R-/-) were fed a chow, western diet (WD) or WD+VitE (500IU/kg diet) ad lib starting at 8 or 20 weeks of age. All mice were studied at 28 weeks of age; thus, 5, 28 week-old MC4R-/- groups were investigated: chow, WD or WD+VitE for 20 weeks, and WD or WD+VitE for 8 weeks. This design allowed us to test whether VitE limits NASH pathogenesis after an intermediate or long exposure to WD. Mice (n=8-11, per group) underwent jugular vein and carotid artery catheterization for 13C/2H isotope-based metabolic flux analysis to calculate in vivo liver glucose and citric acid cycle fluxes. Body weight and fat mass were unaffected by WD or WD+VitE feeding for 8 weeks. 20 weeks of WD or WD+VitE, however, increased these parameters relative to chow. Glucose production, gluconeogenesis, and pyruvate cycle fluxes were also elevated by 20 weeks of WD or WD+VitE feeding. Unlike mice fed WD for 8 weeks, WD+VitE for 8 weeks also accelerated gluconeogenesis. All mice fed a WD or WD+VitE had increased hepatocellular steatosis, ballooning, lobular inflammation and activity compared to chow; fibrosis was more extensive in mice fed a WD or WD+VitE for 20 weeks. Thus, the provision of VitE during hyperphagia and WD failed to limit NASH pathogenesis. In fact, shorter term VitE supplementation accelerated WD-mediated changes in glucose production, indicating VitE may actually exacerbate the dysregulation of liver metabolism that occurs in response to chronic overnutrition.


C. Hasenour: None. J. Young: None.

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