Journal Article

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

Cheung, Connie, Gonzalez, Frank J, Peters, Jeffrey M

2005

Overview

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.

• Publisher: Springer Nature B.V
• Subject: Liver cancer