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: Mohamed A Abdelmegeed, Seong-Ho Yoo, Lauren E Henderson, Frank J Gonzalez, Kimberley J Woodcroft, Byoung-Joon Song
• Journal: The Journal of nutrition (J Nutr) Vol. 141 Issue 4 Pg. 603-10 (Apr 01 2011) ISSN: 1541-6100 [Electronic] United States
• PMID: 21346097 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Dietary Fats
• PPAR alpha
• Proteins
• Tumor Necrosis Factor-alpha
• Cytochrome P-450 CYP2E1
• Nitric Oxide Synthase Type II
• JNK Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases

Topics

• Animals
• Apoptosis
• Cytochrome P-450 CYP2E1 (analysis)
• Dietary Fats (administration & dosage)
• Fatty Liver (pathology, prevention & control)
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Lipid Peroxidation
• Liver (pathology)
• Male
• Mice
• Nitric Oxide Synthase Type II (analysis)
• Non-alcoholic Fatty Liver Disease
• Organ Size
• PPAR alpha (physiology)
• Proteins (metabolism)
• Tumor Necrosis Factor-alpha (analysis)
• p38 Mitogen-Activated Protein Kinases (metabolism)