Abstract:

Postnatal intestinal ontogenesis in an animal model of diabesity may recapitulate morphological and transduction features of diabesity-induced intestinal dysplasia and its amelioration by endogenous (n-3) polyunsaturated fatty acids (PUFA). Proliferation, differentiation, and transduction aspects of intestinal ontogenesis have been studied here in obese, insulin-resistant db/db mice, in fat-1 transgene coding for desaturation of (n-6) PUFA into (n-3) PUFA, in db/db crossed with fat-1 mice, and in control mice. Diabesity resulted in increased colonic proliferation and dedifferentiation of epithelial colonocytes and goblet cells, with increased colonic beta-catenin and hepatocyte nuclear factor (HNF)-4alpha transcriptional activities accompanied by enrichment in HNF-4alpha-bound (n-6) PUFA. In contrast, in fat-1 mice, colonic proliferation was restrained, accompanied by differentiation of crypt stem cells into epithelial colonocytes and goblet cells and by decrease in colonic beta-catenin and HNF-4alpha transcriptional activities, with concomitant enrichment in HNF-4alpha-bound (n-3) PUFA at the expense of (n-6) PUFA. Colonic proliferation and differentiation, the profile of beta-catenin and HNF-4alpha-responsive genes, and the composition of HNF-4alpha-bound PUFA of db/db mice reverted to wild-type by introducing the fat-1 gene into the db/db context. Suppression of intestinal HNF-4alpha activity by (n-3) PUFA may ameliorate diabesity-induced intestinal ontogenesis and offer an effective preventive modality for colorectal cancer.

Notes:

Algamas-Dimantov, Anna Davidovsky, Dana Ben-Ari, Julius Kang, Jing X Peri, Irena Hertz, Rachel Bar-Tana, Jacob Schwartz, Betty eng Research Support, Non-U.S. Gov't J Lipid Res. 2012 Jun;53(6):1056-70. doi: 10.1194/jlr.M021949. Epub 2012 Feb 22.