A high‐fat diet generates alterations in nuclear receptor expression: Prevention by vitamin A and links with cyclooxygenase‐2 and β‐catenin

Abstract

Epidemiologic studies suggest that intake of high energy from fat, inducing overweight, increases the risk of cancer development and promotes colon carcinogenesis. It is therefore important to understand which parameters are affected early on by a high-fat diet in order to devise and improve protective nutritional strategies. We investigated the effect of high energy/fat intake on colon mucosa of male Wistar rats induced by a single 1,2-dimethylhydrazine (DMH) injection. Aberrant crypt foci (ACF) were numbered and modifications in cyclooxygenase-2 (COX-2) and b-catenin levels assessed. Peroxisome proliferator-and retinoic acid-activated receptors (PPAR and RAR, RXR) are key transcription factors regulating gene expression in response to nutrient-activated signals. A short-term study was designed to evaluate whether alterations in mRNA expression of nuclear receptors can be detected at the beginning of the weight gain phase induced by an appetizing hyperlipidic diet (HLD). HLD consumption induced early downregulation of PPARc (-33.1%) and RARb (-53.1%) mRNA expression concomitant with an increase in levels of COX-2 (145.5%) and b-catenin (184.56%) and in the number of ACF (191.56 6 88.60 vs. 21.14 6 11.64, p < 0.05). These findings suggest that HLD increases ACF occurrence, possibly through alterations in the mRNA expression profile of nuclear receptors. Moreover, the use HLD rich in retinyl esters or supplemented with all-trans retinoic acid led to a reduction in the number of ACF. Vitamin A also prevented HLD-induced alterations and the increase in levels of COX-2 and b-catenin. The present observations show a protective role for vitamin A against disturbances associated with HLD exposure in induced colon carcinogenesis. ' 2005 Wiley-Liss, Inc.Key words: colon carcinogenesis; nuclear receptor; high energy/fat intake; vitamin A The incidence of obesity and colon cancer is increasing in all industrialized countries. Colon carcinogenesis is a multifactorial disease, and diet is strongly involved in its etiology. A prospective cohort study has reported that increased body weight was associated with increased death rates form cancer.1 Thus, the high prevalence of obesity, explained by a lifestyle characterized by high energy/fat intake, led to increased risk of colon cancer development. These conclusions are reinforced by data suggesting that the number of preneoplastic colonic lesions 2-4 induced by a high-fat diet is reduced by restriction of energy intake 5 or by fiber-and vitamin-rich diets. 6,7 These data illustrate the potential of nutritional methods for reducing the deleterious consequences of high fat/energy intake on the risk of colon cancer.It is likely that diet affects cancer occurrence at the level of the cell signaling pathways rather than at the level of mutations. Nuclear receptors have a central role in the regulation of gene expression in response to diet. Thus, growing evidence points to the involvement of nuclear receptors in colon tumorigenesis. Indeed, they function as ligand-activated transcr...

CIN by WNT: Growth Pathways, Mitotic Control and Chromosomal Instability in Cancer

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Tumor-suppressive activity of retinoic acid receptor-β in cancer

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Celecoxib increases retinoid sensitivity in human colon cancer cell lines

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