Toxicological consequences of altered peroxisome proliferator-activated receptor γ (PPARγ) expression in the liver: insights from models of obesity and type 2 diabetes

Abstract

The pivotal role of peroxisome proliferator-activated receptor γ (PPARγ) in the liver, although important for the regulation of genes involved in glucose and lipid metabolism, has generally not been fully appreciated. This may be due to the fact that PPARγ, in contrast to PPARα or PPARδ, is not abundantly expressed in liver under normal conditions. However, recent findings have revealed that in several murine models of obesity and type 2 diabetes mellitus (T2DM), PPARγ mRNA and receptor protein are highly up-regulated in the liver, and that the receptor causes increased transcriptional activity as demonstrated by the activation of PPARγ-responsive genes in the liver. Prolonged treatment of obese and diabetic mice, but not of lean control mice, with the selective PPARγ ligands and activators, thiazolidinediones (TZDs), including troglitazone, rosiglitazone, or pioglitazone, has resulted in the development of severe hepatic centrilobular steatosis. In contrast to these effects in hepatocytes, TZD-mediated effects on Kupffer cells (down-regulation of proinflammatory cytokines) seem to be PPARγ-independent. In view of the findings that sustained hepatic steatosis can lead to steatohepatitis and/or fibrosis and that troglitazone (but not the other TZDs) has been associated with rare but serious hepatotoxicity in patients, further insight into PPARγ-mediated versus non-PPARγ-mediated effects of TZDs is desirable. It is concluded that liver-specific effects associated with TZD antidiabetics may become relevant under conditions of selective PPARγ up-regulation in the liver. Therefore, receptor expression in human liver tissue of obese and T2DM patients should deserve increased consideration in the future.