title: PPARalpha expression protects male mice from high fat-induced nonalcoholic fatty liver.
abstract: Emerging evidence suggests that the lack of PPARα enhances hepatic steatosis and inflammation in Ppara-null mice when fed a high-fat diet (HFD). Thus, the aim of this study was to determine whether Ppara-null mice are more susceptible to nonalcoholic steatohepatitis (NASH) than their wild-type (WT) counterparts following short-term feeding with a HFD. Age-matched male WT and Ppara-null mice were randomly assigned to consume ad libitum a standard Lieber-DeCarli liquid diet (STD) (35% energy from fat) or a HFD (71% energy from fat) for 3 wk. Liver histology, plasma transaminase levels, and indicators of oxidative/nitrosative stress and inflammatory cytokines were evaluated in all groups. Levels of lobular inflammation and the NASH activity score were greater in HFD-exposed Ppara-null mice than in the other 3 groups. Biochemical analysis revealed elevated levels of ethanol-inducible cytochrome P450 2E1 and TNFα accompanied by increased levels of malondialdehyde as well as oxidized and nitrated proteins in Ppara-null mice. Elevated oxidative stress and inflammation were associated with activation of c-Jun-N-terminal kinase and p38 kinase, resulting in increased hepatocyte apoptosis in Ppara-null mice fed a HFD. These results, with increased steatosis, oxidative stress, and inflammation observed in Ppara-null mice fed a HFD, demonstrate that inhibition of PPARα functions may increase susceptibility to high fat-induced NASH.
authors.affiliation: Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA..
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Abdelmegeed
authors.forename: Seong-Ho
authors.initials: SH
authors.lastname: Yoo
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Henderson
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Kimberley J
authors.initials: KJ
authors.lastname: Woodcroft
authors.forename: Byoung-Joon
authors.initials: BJ
authors.lastname: Song
mesh_terms: D000818:Animals; D017209:Apoptosis; D019392:Cytochrome P-450 CYP2E1 / Q000032:analysis; D004041:Dietary Fats / Q000008:administration & dosage*; D005234:Fatty Liver / Q000473:pathology / Q000517:prevention & control; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D015227:Lipid Peroxidation; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D052247:Nitric Oxide Synthase Type II / Q000032:analysis; D065626:Non-alcoholic Fatty Liver Disease; D009929:Organ Size; D047493:PPAR alpha / Q000502:physiology*; D011506:Proteins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D004041:Dietary Fats; D047493:PPAR alpha; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; D019392:Cytochrome P-450 CYP2E1; D052247:Nitric Oxide Synthase Type II; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases