Adenovirus-mediated peroxisome proliferator activated receptor gamma overexpression prevents nutritional fibrotic steatohepatitis in mice.
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.
Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, China. nanyuemin@163.com
Yue-Min
YM
Nan
Fang
F
Han
Ling-Bo
LB
Kong
Su-Xian
SX
Zhao
Rong-Qi
RQ
Wang
Wen-Juan
WJ
Wu
Jun
J
Yu
D000256:Adenoviridae / Q000235:genetics; D000813:Anilides / Q000008:administration & dosage; D000818:Animals; D002794:Choline; D004032:Diet; D005234:Fatty Liver / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D005822:Genetic Vectors / Q000008:administration & dosage*; D007249:Inflammation / Q000235:genetics / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D008106:Liver Cirrhosis, Experimental; D008297:Male; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000008:administration & dosage / Q000096:biosynthesis* / Q000235:genetics / Q000627:therapeutic use*; D011897:Random Allocation; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage; D014162:Transfection; D001616:beta-Galactosidase / Q000008:administration & dosage / Q000235:genetics
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D008715:Methionine; D001616:beta-Galactosidase; D002794:Choline