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Differential expression, distribution, and function of PPAR- in the proximal and distal colon

¹ Department of Cancer Biology, Mayo Clinic College of Medicine, Jacksonville, Florida
² Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas

Suppression of colon carcinogenesis by peroxisome proliferator-activated receptor (PPAR)- is likely due to some effect of PPAR- on normal colonic epithelial cells. However, our understanding of the effects of PPAR- in such cells is limited. We analyzed the abundance, distribution, and function of PPAR- in epithelial cells isolated from the murine proximal and distal colon. Marked differences in PPAR- abundance and distribution were observed, suggesting tissue-specific responses. Analysis of PPAR- effects on DNA synthesis, formation of preneoplastic lesions, and activation of MAPK signaling in proximal and distal colonic epithelial cells in vivo indicates that PPAR- regulates both tissue-specific and common responses within the proximal and distal colon. Three major functional cohorts of PPAR- target genes were identified by genomic profiling of isolated colonic epithelial cells: genes that are involved in metabolism, in signaling, and in cellular adhesion and motility. Two subsets of PPAR- target genes were differentially expressed in the proximal and distal epithelium. Proximal target genes were primarily involved in metabolic activities, whereas signal transduction, adhesion, and motility targets were more pronounced in the distal colon. Remarkably, those target genes that are differentially expressed in the proximal colon were all induced on activation of PPAR-, whereas all target genes that are preferentially expressed in the distal colon were repressed. Our data indicate that PPAR- exerts both common and tissue-specific effects in the colon and challenge the general conclusions that PPAR- is induced on differentiation of colonic epithelial cells and that this receptor stimulates differentiated function in epithelial cells throughout the colon.

nuclear receptors; microarrays; colon cancer; gastrointestinal epithelium

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