Peroxisome proliferator-activated receptor-γ protects against hepatic ischemia/reperfusion injury in mice

Abstract

The function of peroxisome proliferator-activated receptor-␥ (PPAR␥) in hepatic inflammation and injury is unclear. In this study, we sought to determine the role of PPAR␥ 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. PPAR␥ was found to be constitutively activated in hepatocytes but not in nonparenchymal cells. Upon induction of ischemia, hepatic PPAR␥ 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 PPAR␥, retinoid X receptor-␣ (RXR␣), and PPAR␥/RXR␣ heterodimer expression was maintained. Accompanying the decrease in PPAR␥ 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 PPAR␥ and the coactivator, p300. To determine whether PPAR␥ activation is hepatoprotective during hepatic ischemia/reperfusion injury, mice were treated with the PPAR␥ agonists, rosiglitazone and connecting peptide. These treatments increased PPAR␥ activation and reduced liver injury compared to untreated mice. Furthermore, PPAR␥-deficient mice had more liver injury after ischemia/reperfusion than their wildtype counterparts. Conclusion: These data suggest that PPAR␥ is an important endogenous regulator of, and potential therapeutic target for, ischemic liver injury. I schemia and reperfusion of the liver is a primary complication of liver resection surgery, transplantation, and trauma. 1 This insult can lead to hepatocellular damage and organ dysfunction through the initiation of a biphasic inflammatory response. 2 The initial phase of this response is characterized by activation of Kupffer cells and their subsequent production and release of reactive oxygen species. This causes mild injury to the hepatic parenchyma, but the oxidative stress activates redox-sensitive transcription factors, such as nuclear factor B and activator protein-1, that regulate the expression of many proinflammatory mediators. [3][4][5] Proximal cytokines, such as interleukin-12 (IL-12), tumor necrosis factor-␣ (TNF␣), and IL-1 are critically involved in promoting the second phase of liver injury by inducing the hepatic expression of neutrophil-attracting CXC chemokines and endothelial cell adhesion molecules. 6-11 CD4 T lymphocytes are also recruited to the liver early during reperfusion, and these cells facilitate the subsequent recruitment of neutrophils by modulating chemokine expression. 12,13 The cooperative effects of CXC chemokines and adhesion molecules result in adherence of neutrophils in the hepatic microcirculation and their subsequent transmigration into the hepatic parenchyma. Accumulated neutrophils release oxidants and proteases that directly injure hepatocytes and vascular endothelial cells. 14

Activation of Peroxisome Proliferator-Activated Receptor-γ During Hepatic Ischemia Is Age-Dependent

“…Of these, we and others have recently shown that PPARγ is an important regulator of post-ischemic liver injury (7,8). We found that activation of PPARγ was suppressed during the ischemic period and that treatment with a synthetic PPARγ ligand restored activation and reduced injury (7). In the present study, we examined whether PPARγ activation in the liver during ischemia was agedependent.…”

“…Our previous study (7) showed that activation of PPARγ reduced injury without affecting the inflammatory response. Furthermore, that study showed that the majority of PPARγ-DNA-binding activity in the liver was found in hepatocytes.…”

“…Methods for extracting samples for tissue ELISA are described elsewhere (7). The measurement of liver fatty acid composition was performed by gas chromatography at the Mouse Metabolic Phenotyping Center at the University of Cincinnati.…”

Liver apoptosis is age dependent and is reduced by activation of peroxisome proliferator-activated receptor-γ in hemorrhagic shock

“…In this regard, natural (cyclopentenone prostaglandins) and synthetic PPAR␥ ligands (thiazolidinediones) have been reported to exert beneficial effects in hemorrhagic shock in young experimental animals (1,5). We have also demonstrated that pharmacological activation of PPAR␥ reduces the systemic inflammatory response and lung injury secondary to severe hemorrhage (4,39) and preserves organ structure and function in hepatic ischemia and reperfusion injury in young rats (19). To further support the role of PPAR␥ in inflammation, several studies including ours have reported that its expression and function may be altered by cytotoxic mediators.…”

Intestinal Glucose Uptake Protects Liver from Lipopolysaccharide and d-Galactosamine, Acetaminophen, and Alpha-Amanitin in Mice

“…10 Cells were cultured for 18 hours in William's E medium, or in medium with high glucose concentration (10 g/L ϭ 5ϫ standard concentration), and then incubated for 24 hours with APAP (10 mmol/L). Cytotoxicity was measured by the release of lactate dehydrogenase (LDH) into the culture medium.…”