In a series of seminal preclinical studies, we have demonstrated that the pleiotropic bioactive components generated by fish oil (containing DHA) and fermentable fiber act coordinately to protect against colon cancer, in part, by enhancing apoptosis at the base of the crypt throughout all stages of colon tumorigenesis. This is significant because the induction of apoptosis represents a potent cellular mechanism against cancer. With respect to a mechanism of action, pectin is metabolized by microbes in the lumen of the gut to butyrate and other short chain fatty acids. We have recently shown that DHA and butyrate synergize to enhance a p53-independent, oxidation sensitive, mitochondrial Ca2+-dependent (intrinsic) apoptotic pathway in the colon. These data indicate that highly fermentable fiber, which generates butyrate in the colon, has enhanced chemotherapeutic value when n-3 PUFA is the lipid source.
Butyrate (a fiber fermentation product) is (i) the preferred energy source for colonocytes, (ii) contributes to acetyl CoA production where it serves as an essential cofactor for Histone Acetyl Transferases, and (iii) is a Histone Deacetylase inhibitor known to alter transcriptional regulation by remodeling chromatin structure. Consequently, we also investigated the epigenetic therapeutic potential of chemoprotective dietary treatment (combined fish oil and pectin) in rats and mice exposed to carcinogen (AOM). Specifically, we determined how diet modulates colonic chromatin structure, microRNAs and their target genes following exposure to AOM. Oncogenic PTK2B, PDE4B and TCF4, targeted by miR-19b, miR-26b and miR-203, respectively, were suppressed by the chemoprotective (fish oil and pectin) combination diet compared to a control diet at both the mRNA and protein levels.
The interaction of total dietary fat and fiber on colorectal cancer (CRC) risk has been assessed and found to be null among postmenopausal women. However, the evaluation of specific sub-types of dietary fiber and fatty acids, in combination, with respect to risk of CRC in a large prospective cohort has yet to be undertaken. This is an important evaluation considering the varied biologic, biochemical and metabolic roles of dietary fat and fiber subtypes. Collectively, these critical observations emphasize the need to examine the specific chemical characteristics of lipids and fibers in the diet as opposed to simply focusing on the overall lipid and fiber content of diets. The failure to address an interaction between types of fat and fiber may explain why the chemoprotective effects of n-3 PUFA are obscured in prospective cohort studies.
Citation Format: Robert S. Chapkin, Laurie A. Davidson, Johanna W. Lampe, Nancy D. Turner, Yang-Yi Fan, Joanne R. Lupton. Fat-fiber combination: The missing ingredient? [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr CN02-03.