Importance of peroxisome proliferator-activated receptor-gamma in hepatic ischemia/reperfusion injury in mice.
OBJECTIVE
Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a transcriptional factor belonging to the nuclear receptor superfamily. Recent studies have suggested that PPARgamma regulates inflammatory responses and PPARgamma specific agonists have beneficial effects on several disease conditions in the various organs. However, the precise role of PPARgamma in acute liver injury remains unknown.


METHODS
We investigated the pathophysiological role of PPARgamma and the effect of the selective PPARgamma agonist, pioglitazone, on the hepatic ischemia/reperfusion (I/R) injury.


RESULTS
PPARgamma expression in the liver was upregulated after reperfusion following ischemia. Pioglitazone treatment significantly inhibited hepatic I/R injury as determined by serological and histological analyses. The protective effect was associated with downregulation of the local expression of several potent proinflammatory cytokines, chemokines and adhesion molecules after reperfusion. The neutrophil accumulation was also inhibited by the treatment. Furthermore, the treatment inhibited the induction of apoptosis on hepatocytes. Finally, pioglitazone significantly improved the mouse survival in a lethal model of hepatic I/R injury.


CONCLUSIONS
PPARgamma plays an inhibitory role in hepatic I/R injury and the stimulation by selective agonist has a significant beneficial effect. Thus, PPARgamma may be a new therapeutic target for the protection of the liver against acute injury.
Akahori
Takahiro
T
Department of Surgery, Nara Medical University, Nara, Japan.
Sho
Masayuki
M
Hamada
Kaoru
K
Suzaki
Yasue
Y
Kuzumoto
Yukiyasu
Y
Nomi
Takeo
T
Nakamura
Shinji
S
Enomoto
Koji
K
Kanehiro
Hiromichi
H
Nakajima
Yoshiyuki
Y
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016207:Cytokines / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000473:pathology; D007249:Inflammation / Q000276:immunology; D008107:Liver Diseases / Q000188:drug therapy / Q000201:enzymology*; D051379:Mice; D009504:Neutrophils / Q000473:pathology; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D000077205:Pioglitazone; D015427:Reperfusion Injury / Q000188:drug therapy / Q000201:enzymology* / Q000517:prevention & control*; D015996:Survival Rate; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
D016207:Cytokines; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077205:Pioglitazone