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Published on: August 7, 2012
Peroxisome proliferator-activated receptor-gamma protects against hepatic ischemia/reperfusion injury in mice
Satoshi Kuboki1, Thomas Shin, Nadine Huber
1Laboratory of Trauma, Sepsis & Inflammation Research, Department of Surgery, University of Cincinnati, Cincinnati, OH 45267-0558, USA.
Unlabelled:
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.
Conclusion:
These data suggest that PPARgamma is an important endogenous regulator of, and potential therapeutic target for, ischemic liver injury.
Insights
Peroxisome proliferator-activated receptor-gamma (PPARgamma) plays a protective role in liver injury. Activating PPARgamma reduced liver damage during ischemia/reperfusion, suggesting it as a therapeutic target.
Area of Science:
- Hepatology
- Molecular Biology
- Immunology
Background:
- The role of peroxisome proliferator-activated receptor-gamma (PPARgamma) in hepatic inflammation and injury remains unclear.
- Investigating PPARgamma's function in hepatic ischemia/reperfusion (I/R) injury is crucial for understanding liver disease mechanisms.
Purpose of the Study:
- To determine the role of PPARgamma in hepatic ischemia/reperfusion injury in mice.
- To evaluate the potential of PPARgamma as a therapeutic target for ischemic liver injury.
Main Methods:
- Male mice underwent 90 minutes of partial hepatic ischemia followed by 8 hours of reperfusion.
- PPARgamma activation, protein expression, and ligand levels were assessed.
- Mice were treated with PPARgamma agonists (rosiglitazone, connecting peptide) or were PPARgamma-deficient.
Main Results:
- Hepatic PPARgamma activation decreased significantly during ischemia and reperfusion.
- Reduced PPARgamma activation correlated with decreased natural ligand expression and coactivator interaction.
- PPARgamma agonist treatment reduced liver injury, while PPARgamma-deficient mice showed increased injury.
Conclusions:
- PPARgamma is an endogenous regulator of hepatic ischemia/reperfusion injury.
- Activating PPARgamma demonstrates hepatoprotective effects.
- PPARgamma represents a potential therapeutic target for ischemic liver injury.
