Peroxisome proliferator-activated receptor-gamma protects against hepatic ischemia/reperfusion injury in mice.
The function of peroxisome proliferator-activated receptor-gamma (PPARgamma) in hepatic inflammation and injury is unclear. In this study, we sought to determine the role of PPARgamma in hepatic ischemia/reperfusion injury in mice. Male mice were subjected to 90 minutes of partial hepatic ischemia followed by up to 8 hours of reperfusion. PPARgamma was found to be constitutively activated in hepatocytes but not in nonparenchymal cells. Upon induction of ischemia, hepatic PPARgamma activation rapidly decreased and remained suppressed throughout the 8-hour reperfusion period. This reduced activation was not a result of decreased protein availability as hepatic nuclear PPARgamma, retinoid X receptor-alpha (RXRalpha), and PPARgamma/RXRalpha heterodimer expression was maintained. Accompanying the decrease in PPARgamma activation was a decrease in the expression of the natural ligand 15-deoxy-Delta(12,14)-prostaglandin J(2). This was associated with reduced interaction of PPARgamma and the coactivator, p300. To determine whether PPARgamma activation is hepatoprotective during hepatic ischemia/reperfusion injury, mice were treated with the PPARgamma agonists, rosiglitazone and connecting peptide. These treatments increased PPARgamma activation and reduced liver injury compared to untreated mice. Furthermore, PPARgamma-deficient mice had more liver injury after ischemia/reperfusion than their wild-type counterparts.


CONCLUSIONS
These data suggest that PPARgamma is an important endogenous regulator of, and potential therapeutic target for, ischemic liver injury.
Kuboki
Satoshi
S
Laboratory of Trauma, Sepsis & Inflammation Research, Department of Surgery, University of Cincinnati, Cincinnati, OH 45267-0558, USA.
Shin
Thomas
T
Huber
Nadine
N
Eismann
Thorsten
T
Galloway
Elizabeth
E
Schuster
Rebecca
R
Blanchard
John
J
Zingarelli
Basilia
B
Lentsch
Alex B
AB
D000818:Animals; D002096:C-Peptide / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008107:Liver Diseases / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism*; D047490:Retinoid X Receptor alpha / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology
C477819:15-deoxyprostaglandin J2; D002096:C-Peptide; D047495:PPAR gamma; D047490:Retinoid X Receptor alpha; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse; D015230:Prostaglandin D2