Diabetes and Obesity Drug Discovery & Therapy
(Track)
A novel cystine based antioxidant attenuates high fat diet-induced oxidative stress and hepatic steatosis in apolipoprotein E knockout mice
Keith Curtis Norris
Charles R. Drew University of Medicine and Science, UCLA, UC Irvine, Harbor-UCLA Medical Center, California and Proimmune, Rhinebeck,USA
Abstract:
Nonalcoholic fatty liver disease (NAFLD) is a common liver disorder and is associated with obesity and metabolic syndrome. We examined the molecular mechanisms by which a novel cystine based glutathione precursor with added selenomethionine (F1) prevents hepatic steatosis in a moderate high fat dietary model of NAFLD. Adult (8 weeks old), male apolipoprotein E (ApoE)-/- mice were fed for 16 weeks with a normal diet (ND) or high fat diet (HFD), consisting of 21% fat and 0.21% cholesterol, with or without dietary supplementation of F1 (3g/kg food). Compared with ApoE-/- mice fed with ND with or without F1, ApoE-/- mice fed with HFD exhibited significant weight gain, hepatomegaly, and increased serum cholesterol and triglycerides levels. There was no change in serum albumin levels. High-resolution light and electron microscopy revealed micro-and macro-vesicular steatosis in HFD ApoE-/- mice. HFD led to increased lipogenesis, oxidative stress, and hepatocyte apoptosis; activation of caspases 9 and 3, c-Jun-NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK); and perturbation of the BAX/BCL-2 rheostat. F1 attenuated HFD-induced oxidative stress as well as lipogenesis, kinase activation, apoptotic signaling, hypertriglyceridemia, increased body and liver weights, hepatic steatosis, and hepatocyte ultrastructural abnormalities. These results demonstrate that administration of F1, a glutathione precursor leveraging the pleiotropic nature of L-cystine/L-cysteine, ameliorates HFD-induced hepatic steatosis in ApoE-/- mice and emphasizes the role of oxidative stress in diet-induced obesity and hepatic steatosis.
