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

Journal of Molecular Medicine volume 83, pages 774–785 (2005)Cite this article

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.

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Acknowledgements

This study was supported in part by the National Institutes of Health grants CA89607 and CA97999 (J.M.P.).

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  1. Department of Veterinary Science and Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, 312 Life Sciences Building, University Park, PA, 16802, USA

    Jeffrey M. Peters

  2. The Laboratory of Metabolism, National Cancer Institute, Bethesda, MD, 20892, USA

    Connie Cheung & Frank J. Gonzalez

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  1. Jeffrey M. Peters
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  2. Connie Cheung
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  3. Frank J. Gonzalez
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Correspondence to Jeffrey M. Peters.

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Peters, J.M., Cheung, C. & Gonzalez, F.J. Peroxisome proliferator-activated receptor-α and liver cancer: where do we stand?. J Mol Med 83, 774–785 (2005). https://doi.org/10.1007/s00109-005-0678-9

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Keywords

  • Peroxisome proliferator-activated receptor-α (PPARα)
  • Hepatocarcinogenesis
  • Fibrates
  • Human cancer