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Activators of the nuclear receptor PPARγ enhance colon polyp formation

Nature Medicine volume 4, pages 1058–1061 (1998)Cite this article

Abstract

A high-fat diet increases the risk of colon, breast and prostate cancer. The molecular mechanism by which dietary lipids promote tumorigenesis is unknown. Their effects may be mediated at least in part by the peroxisome proliferator-activated receptors (PPARs). These ligand-activated nuclear receptors modulate gene expression in response to fatty acids, lipid-derived metabolites and antidiabetic drugs. To explore the role of the PPARs in diet-induced carcinogenesis, we treated mice predisposed to intestinal neoplasia with a synthetic PPARγ ligand. Reflecting the pattern of expression of PPARγ in the gastrointestinal tract, treated mice developed a considerably greater number of polyps in the colon but not in the small intestine, indicating that PPARγ activation may provide a molecular link between a high-fat diet and increased risk of colorectal cancer.

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Figure 1: Expression of PPARγ mRNA in the gastrointestinal tracts of wild-type and ApcMin mice.
Figure 2: Troglitazone enhances polyp formation in the colon but not small intestine of ApcMin mice.
Figure 3: Histology of tumors from control (a–d) and troglitazone-treated (e–h) ApcMin mice.
Figure 4: Expression of PPARγ protein in normal colonic mucosa and polyps from ApcMin mice.

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Acknowledgements

Troglitazone was a gift from Sankyo Co.LTD. We thank R. Boland, R. Kucherlapati, R. Kolodner, G. Wahl, R. Heyman and J. Auwerx for discussions, and B. Gilpin for statistical analysis. R.M.E. is an Investigator of the Howard Hughes Medical Institute at the Salk Institute for Biological Studies. E.S. is a fellow of the Susan G. Komen Breast Cancer Foundation.

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Authors and Affiliations

  1. The Salk Institute for Biological Studies, Howard Hughes Medical Institute, La Jolla, 92037 , California, USA

    Enrique Saez, Peter Tontonoz, Michael C. Nelson, Jacqueline G.A. Alvarez, Tze Ming U & Ronald M. Evans

  2. Department of Pathology, University of California, San Diego, 92093, California, USA

    Peter Tontonoz & Stephen M. Baird

  3. Pathology and Laboratory Medicine, VA Medical Center , San Diego, 92161, CA, USA

    Stephen M. Baird

  4. Departments of Pathology and Integrative Biology, University of Texas at Houston Medical School, Houston, 77225, Texas, USA

    Vilmos A. Thomazy

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  1. Enrique Saez
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Correspondence to Ronald M. Evans.

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Saez, E., Tontonoz, P., Nelson, M. et al. Activators of the nuclear receptor PPARγ enhance colon polyp formation. Nat Med 4, 1058–1061 (1998). https://doi.org/10.1038/2042

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