title: A novel cystine based antioxidant attenuates oxidative stress and hepatic steatosis in diet-induced obese mice.
abstract: Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver pathologies and is associated with obesity and the metabolic syndrome. Here, we investigated 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 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 (3 g/kg food) for 16 weeks. 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 with no change in serum albumin levels. High resolution light and electron microscopy revealed micro-and macro-vesicular steatosis in ApoE-/- mice fed on a HFD. HFD-induced obesity also led to increased lipogenesis, oxidative stress, activation of c-Jun-NH(2)-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK), perturbation of the BAX/BCL-2 rheostat, hepatocyte apoptosis, and activation of caspases 9 and 3. F1 fully prevented the adverse effects of HFD on serum triglyceride levels, body and liver weights, and hepatic steatosis and substantially attenuated HFD-induced increase in lipogenesis, oxidative stress, kinase activation, apoptotic signaling, and hepatocyte ultrastructural abnormalities. These results demonstrate that administration of F1, a glutathione precursor, ameliorates HFD-induced hepatic steatosis in ApoE-/- mice and emphasizes the role of oxidative stress in diet-induced obesity and hepatic steatosis.
authors.affiliation: Department of Internal Medicine, Charles R. Drew University, Los Angeles, CA, USA. indranisinhahikim@cdrewu.edu
authors.forename: Indrani
authors.initials: I
authors.lastname: Sinha-Hikim
authors.forename: Amiya P
authors.initials: AP
authors.lastname: Sinha-Hikim
authors.forename: Ruoqing
authors.initials: R
authors.lastname: Shen
authors.forename: Hyun Ju
authors.initials: HJ
authors.lastname: Kim
authors.forename: H
authors.initials: H
authors.lastname: Kim
authors.forename: Samuel W
authors.initials: SW
authors.lastname: French
authors.forename: Nosratola D
authors.initials: ND
authors.lastname: Vaziri
authors.forename: Nosratola D
authors.initials: ND
authors.lastname: Vaziri
authors.forename: Albert C
authors.initials: AC
authors.lastname: Crum
authors.forename: Albert
authors.initials: A
authors.lastname: Crum
authors.forename: Tripathi B
authors.initials: TB
authors.lastname: Rajavashisth
authors.forename: Keith C
authors.initials: KC
authors.lastname: Norris
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D004041:Dietary Fats / Q000009:adverse effects*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005234:Fatty Liver / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016166:Free Radical Scavengers / Q000494:pharmacology*; D022781:Hepatocytes; D050155:Lipogenesis / Q000187:drug effects; D048670:MAP Kinase Kinase 4 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease; D009765:Obesity / Q000150:complications / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012645:Selenomethionine / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; C494827:Bax protein, mouse; D004041:Dietary Fats; D016166:Free Radical Scavengers; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D012645:Selenomethionine; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D000111:Acetylcysteine