Journal of Molecular Medicine

, Volume 83, Issue 10, pp 774–785

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

  • Jeffrey M. Peters
  • Connie Cheung
  • Frank J. Gonzalez
Review

DOI: 10.1007/s00109-005-0678-9

Cite this article as:
Peters, J.M., Cheung, C. & Gonzalez, F.J. J Mol Med (2005) 83: 774. doi:10.1007/s00109-005-0678-9

Abstract

The peroxisome proliferator-activated receptor-α (PPARα), 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. PPARα 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 PPARα occurs across a number of mammalian species, thus demonstrating the essential role of this nuclear receptor in lipid homeostasis. In contrast, prolonged administration of PPARα agonists causes hepatocarcinogenesis, specifically in rats and mice, indicating that PPARα 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 PPARα. The cascade of molecular events leading to liver cancer in rodents involves hepatocyte proliferation and oxidative stress, but the PPARα target genes that mediate this response are unknown. This review focuses on the current understanding of the role of PPARα in hepatocarcinogenesis and identifies future research directions that should be taken to delineate the mechanisms underlying PPARα agonist-induced hepatocarcinogenesis.

Keywords

Peroxisome proliferator-activated receptor-α (PPARα)HepatocarcinogenesisFibratesHuman cancer

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Jeffrey M. Peters
    • 1
  • Connie Cheung
    • 2
  • Frank J. Gonzalez
    • 2
  1. 1.Department of Veterinary Science and Center for Molecular Toxicology and CarcinogenesisThe Pennsylvania State UniversityUniversity ParkUSA
  2. 2.The Laboratory of MetabolismNational Cancer InstituteBethesdaUSA