title: Amelioration of diabesity-induced colorectal ontogenesis by omega-3 fatty acids in mice.
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 β-catenin and hepatocyte nuclear factor (HNF)-4α transcriptional activities accompanied by enrichment in HNF-4α-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 β-catenin and HNF-4α transcriptional activities, with concomitant enrichment in HNF-4α-bound (n-3) PUFA at the expense of (n-6) PUFA. Colonic proliferation and differentiation, the profile of β-catenin and HNF-4α-responsive genes, and the composition of HNF-4α-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-4α activity by (n-3) PUFA may ameliorate diabesity-induced intestinal ontogenesis and offer an effective preventive modality for colorectal cancer.
authors.affiliation: Institute of Biochemistry, Food Science, and Nutrition and Interdepartmental Equipment Facility, Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Anna
authors.initials: A
authors.lastname: Algamas-Dimantov
authors.forename: Dana
authors.initials: D
authors.lastname: Davidovsky
authors.forename: Julius
authors.initials: J
authors.lastname: Ben-Ari
authors.forename: Jing X
authors.initials: JX
authors.lastname: Kang
authors.forename: Irena
authors.initials: I
authors.lastname: Peri
authors.forename: Rachel
authors.initials: R
authors.lastname: Hertz
authors.forename: Jacob
authors.initials: J
authors.lastname: Bar-Tana
authors.forename: Betty
authors.initials: B
authors.lastname: Schwartz
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D003106:Colon / Q000378:metabolism / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology*; D015525:Fatty Acids, Omega-3 / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000473:pathology*; D051379:Mice; D010641:Phenotype; D015398:Signal Transduction; D013045:Species Specificity
chemical_list: D015525:Fatty Acids, Omega-3