Peroxisome proliferator-activated receptor-α and liver cancer:: where do we stand?

The peroxisome proliferator-activated receptor-alpha (PPAR alpha), first identified in 1990 as a member of the nuclear receptor superfamily, has a central role in the regulation of numerous target genes encoding proteins that modulate fatty acid transport and catabolism. PPAR alpha is the molecular target for the widely prescribed lipid-lowering fibrate drugs and the diverse class of chemicals collectively referred to as peroxisome proliferators. The lipid-lowering function of PPAR alpha occurs across a number of mammalian species, thus demonstrating the essential role of this nuclear receptor in lipid homeostasis. In contrast, prolonged administration of PPAR alpha agonists causes hepatocarcinogenesis, specifically in rats and mice, indicating that PPAR alpha also mediates this effect. There is no strong evidence that the low-affinity fibrate ligands are associated with cancer in humans, but it still remains a possibility that chronic activation with high-affinity ligands could be carcinogenic in humans. It is now established that the species difference between rodents and humans in response to peroxisome proliferators is due in part to PPAR alpha. The cascade of molecular events leading to liver cancer in rodents involves hepatocyte proliferation and oxidative stress, but the PPAR alpha target genes that mediate this response are unknown. This review focuses on the current understanding of the role of PPAR alpha in hepatocarcinogenesis and identifies future research directions that should be taken to delineate the mechanisms underlying PPAR alpha agonist-induced hepatocarcinogenesis.