Submitted on April 25, 2003
Accepted on November 11, 2003
Peroxisome Proliferator-Activated Receptor-
(PPAR) Regulates Post-Ischemic Liver Injury
Tomohisa Okaya1 and Alex B. Lentsch1*
1 The Laboratory of Trauma, Sepsis & Inflammation Research, Department of Surgery, University of Cincinnati, Cincinnati, Ohio, USA
* To whom correspondence should be addressed. E-mail: alex.lentsch{at}uc.edu.
Peroxisome proliferator-activated receptor-
(PPAR) is a transcription factor that in some in
vitro systems has been linked with downregulation of proinflammatory mediators, thus
implicating a potential role for PPAR in the regulation of inflammatory processes. Hepatic
ischemia/reperfusion injury is characterized by an intense acute inflammatory response that is
dependent on a number of proinflammatory mediators. PPAR is abundantly expressed in
hepatic parenchymal cells, but not in Kupffer cells. This study examined whether PPAR is
involved in regulation of the hepatic inflammatory response to ischemia/reperfusion. Mice
nullizygous for PPAR had significantly greater liver injury than did their wild-type
counterparts. Consistent with these findings, C57BL/6 mice treated with the PPAR agonist,
WY-14643, had significantly less liver injury than mice receiving vehicle. PPAR-knockout
mice also had greatly augmented liver neutrophil accumulation and modest increases in
activation of the transcription factors, NF-
B and AP-1. However, these effects were not
associated with increased expression of proinflammatory cytokines or chemokines. In addition,
PPAR-knockout mice expressed far less inducible nitric oxide synthase in liver than did wild-type
mice after ischemia/reperfusion. Finally, treatment of cultured murine hepatocytes with
WY-14643, a specific agonist of PPAR, protected cells against oxidant-induced injury. The
data suggest that PPAR is an important regulator of the hepatic inflammatory response to
ischemia/reperfusion in a manner that is independent of proinflammatory cytokines.
