Amelioration of diabesity-induced colorectal ontogenesis by omega-3 fatty acids in mice

Abstract

This article is available online at http://www.jlr.org stationary, pluripotent stem cells at the base of the crypt give rise to rapidly proliferating cells that differentiate into postmitotic columnar absorptive colonocytes, mucinsecreting goblet cells, and enteroendocrine cells as they migrate from the crypt base to the surface, followed fi nally by their shedding into the intestinal lumen (reviewed in Ref. 1 ). Several signaling pathways, notably ␤ -catenin/Tcf and hepatocyte nuclear factor (HNF)-4 ␣ , modulate and control the proliferation and differentiation of adult colonocytes, whereas their perturbation via mutation or epigenetic modifi cation may ultimately result in colorectal cancer (CRC). Moreover, cell dedifferentiation correlates with key tumor features, such as tumor progression rates, invasiveness, drug resistance, and metastatic potential ( 2 ). Hence, perturbation of programming commitment during ontogenesis may mimic primary features of intestinal oncogenesis. In contrast to humans, major intestinal maturation processes of rodents take place only following birth ( 3 ), allowing for searching intestinal ontogenesis as a function of variable conditions reported to promote or suppress CRC.The metabolic syndrome (MetS) and its individual diseases (upper-body obesity, type 2 diabetes, dyslipidemia, and hypertension) are associated with an increased risk for CRC, and CRC incidence seems to be associated with the number of MetS components present at baseline (reviewed in Refs. 4, 5 ). Thus, the relative risk (RR) of CRC increases 2-fold with increase in waist circumference of MetS subjects ( 6 ), whereas the age-and sex-adjusted RR of CRC for an hemoglobin (Hb)A1c у 7% amounts to 2.94, compared with 1. Manuscript received 29 October 2011 and in revised form 20 February 2012. Published, JLR Papers in Press, February 22, 2012 DOI 10.1194 Amelioration of diabesity-induced colorectal ontogenesis by omega-3 fatty acids in mice Abbreviations: CRC, colorectal cancer; EPA, eicosapentaenoic acid; HE, hematoxylin and eosin; HNF-4 ␣ , hepatocyte nuclear factor 4 ␣ ; LA, linoleic acid; LBD, ligand binding domain; LCFA, long-chain fatty acid; MetS, metabolic syndrome; PCNA, proliferating cell nuclear antigen; RR, relative risk.

Endogenously synthesized n-3 fatty acids in fat-1 transgenic mice prevent melanoma progression by increasing E-cadherin expression and inhibiting β-catenin signaling

“…This suggests that the reverse EMT process, known as mesenchymal-epithelial transition, may have occurred in fat-1 tumor tissues. Consistent with these results, recent studies have demonstrated that breast and colorectal cancer tissues from fat-1 mice display increased levels of E-cadherin expression, which indicates that its expression may be modulated by endogenous n-3 PUFAs (37,38). However, in the present study, the formation of metastases in the lungs or other organ sites in fat-1 and WT mice was not observed (data not shown).…”

Mechanisms linking obesity, inflammation and altered metabolism to colon carcinogenesis

“…As noted earlier, we have recently demonstrated that obesity‐associated diabetes leads to distorted colonic morphology and colonic dysplasia (65). Proliferation, differentiation and transduction aspects of intestinal ontogenesis are disturbed in the diabetes‐obese murine model (db/db mice) but are prone to significant amelioration by endogenous n‐3 PUFA provided by crossing db/db mice with fat‐1 mice.…”

“…We have recently demonstrated severe alterations in postnatal intestinal ontogenesis of the large intestine in an animal model of hyperinsulinemia‐associated obesity (db/db mice) (65). We demonstrated, in this mouse model, distorted colonic morphology and associated transduction features, all of which might affect colonic dysplasia.…”

“…Indeed, in an examination of the putative role played by HNF‐4α in CRC in which we evaluated the effect of HNF‐4α antagonists and HNF‐4α siRNA on CRC growth and proliferation in cultured CRC cells and xenotransplanted nude mice in vivo , we found that both HNF‐4α ligand antagonists and siRNA inhibit growth and proliferation of HT29 and Caco2 CRC cells; this was accompanied by an increase in the subG1 cell population, and increased apoptotic death (74). In a subsequent study, we offered a molecular rationale for the reported increase in CRC prevalence in obese diabetic subjects and its putative amelioration by n‐3 PUFA (65). The intestinal ontogenic programme of obesity‐associated diabetes and the transformation sequence of CRC are both characterized by increased epithelial cell proliferation and de‐differentiation.…”

Consumption of a high-fat diet abrogates inhibitory effects of methylseleninic acid on spontaneous metastasis of Lewis lung carcinoma in mice

“…This diet was low (0.5% of dietary energy) in α-linolenic acid (18:3n3), which comprises 1% of fatty acids in corn oil (25). It is possible that this fatty acid imbalance (47) may have contributed to the effects observed for the high-fat diet, as α-linolenic acid has been suggested to be anticarcinogenic (48,49). This possibility warrants further investigation.…”