Adenovirus-mediated peroxisome proliferator activated receptor gamma overexpression prevents nutritional fibrotic steatohepatitis in mice.

Abstract

OBJECTIVE:

The pathogenesis of non-alcoholic steatohepatitis is still unclear. We have demonstrated previously that peroxisome proliferator activated receptor gamma (PPARγ) ligand protects against inflammation and fibrogenesis in experimental non-alcoholic steatohepatitis. We aim to elucidate the effect and the mechanism of PPARγ itself on nutritional fibrotic steatohepatitis in mice.

METHODS:

C57BL/6J mice were fed with methionine-choline deficient (MCD) diet for 8 weeks to induce fibrotic steatohepatitis. Mice fed the MCD diet were treated with adenovirus carrying PPARγ (Ad-PPARγ), Ad-PPARγ plus PPARγ agonist rosiglitazone, or PPARγ antagonist 2-chloro-5-nitrobenzaniliden (GW9662), respectively. The effects of up-regulation of PPARγ in the presence or absence of its agonist/or antagonist were assessed by comparing the severity of hepatic injury, activation of hepatic stellate cells and the expression of adiponectin, heme oxygenase-1, and fibrogenic related genes.

RESULTS:

Mice fed with MCD diet for 8 weeks showed severe hepatic injury including hepatic steatosis, inflammatory infiltration, and fibrosis. Administration of Ad-PPARγ significantly lowered serum alanine aminotransferase level and ameliorated hepatic steatosis, necroinflammation, and fibrosis. These effects were associated with enhanced expression of PPARγ, up-regulated expression of adiponectin and heme oxygenase-1, and down-regulated expression of tumor necrosis factor alpha, interleukin-6, α-smooth muscle actin, transforming growth factor beta 1, matrix metallopeptidase-2, and -9. Administration of GW9662 promoted the severity of liver histology.

CONCLUSIONS:

The present study provided evidences for the protective role of overexpressing PPARγ in ameliorating hepatic fibrosing steatohepatitis in mice. Modulation of PPARγ expression might serve as a therapeutic approach for fibrotic steatohepatitis.

• Authors: Yue-Min Nan, Fang Han, Ling-Bo Kong, Su-Xian Zhao, Rong-Qi Wang, Wen-Juan Wu, Jun Yu
• Journal: Scandinavian journal of gastroenterology (Scand J Gastroenterol) Vol. 46 Issue 3 Pg. 358-69 (Mar 2011) ISSN: 1502-7708 [Electronic] England
• PMID: 20969493 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-chloro-5-nitrobenzanilide
• Anilides
• PPAR gamma
• Thiazolidinediones
• Rosiglitazone
• Methionine
• beta-Galactosidase
• Choline

Topics

• Adenoviridae (genetics)
• Anilides (administration & dosage)
• Animals
• Choline
• Diet
• Fatty Liver (etiology, genetics, metabolism, prevention & control)
• Genetic Vectors (administration & dosage)
• Inflammation (genetics, physiopathology)
• Liver Cirrhosis (etiology, genetics, metabolism, prevention & control)
• Liver Cirrhosis, Experimental
• Male
• Methionine (deficiency)
• Mice
• Mice, Inbred C57BL
• PPAR gamma (administration & dosage, biosynthesis, genetics, therapeutic use)
• Random Allocation
• Rosiglitazone
• Thiazolidinediones (administration & dosage)
• Transfection
• beta-Galactosidase (administration & dosage, genetics)