Peroxisome proliferator-activated receptor gamma (PPARgamma) suppresses colonic epithelial cell turnover and colon carcinogenesis through inhibition of the beta-catenin/T cell factor (TCF) pathway

Abstract

Peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear receptor superfamily member, plays a major role in lipid metabolism and insulin sensitivity. We investigated the role of PPARgamma in colonic epithelial cell turnover and carcinogenesis in colon because PPARgamma is strongly expressed in colonic epithelium. Administration of PPARgamma agonists suppressed epithelial cell turnover in mice. Expression level of beta-catenin protein, a key molecule in carcinogenesis, was increased in mouse colon treated with PPARgamma ligands. A direct interaction between beta-catenin and PPARgamma in cultured cell lines and colonic epithelium in mice was observed. Ligand-activated PPARgamma ligand directly interacts with beta-catenin, retaining it in the cytosol and reducing beta-catenin/T cell factor (TCF) transcriptional activity that is functionally important on aberrant crypt foci (ACF) formation. PPARgamma hetero-deficiency promoted the induction of ACF, but had no effect on the incidence of colonic polyps. These results indicate that PPARgamma regulates colonic epithelial cell turnover via direct interactions with beta-catenin, resulting in inhibition of beta-catenin-mediated transcriptional pathways that are involved in promoting cell proliferation. Our findings suggest that PPARgamma plays a role as a physiological regulator of colonic epithelial cell turnover and consequently predisposition to the development of colon cancer in early stage.