Peroxisome Proliferator-Activated Receptor γ (PPARγ) Suppresses Colonic Epithelial Cell Turnover and Colon Carcinogenesis Through Inhibition of the β-Catenin / T Cell Factor (TCF) Pathway

Abstract

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