Mechanisms by which docosahexaenoic acid and related fatty acids reduce colon cancer risk and inflammatory disorders of the intestine

Abstract

A growing body of epidemiological, clinical, and experimental evidence has underscored both the pharmacological potential and the nutritional value of dietary fish oil enriched in very long chain n-3 PUFAs such as docosahexaenoic acid (DHA, 22:6, n-3) and eicosapentaenoic acid (EPA, 20:5, n-3). The broad health benefits of very long chain n-3 PUFAs and the pleiotropic effects of dietary fish oil and DHA have been proposed to involve alterations in membrane structure and function, eicosanoid metabolism, gene expression and the formation of lipid peroxidation products, although a comprehensive understanding of the mechanisms of action has yet to be elucidated. In this review, we present data demonstrating that DHA selectively modulates the subcellular localization of lipidated signaling proteins depending on their transport pathway, which may be universally applied to other lipidated protein trafficking. An interesting possibility raised by the current observations is that lipidated proteins may exhibit different subcellular distribution profiles in various tissues, which contain a distinct membrane lipid composition. In addition, the current findings clearly indicate that subcellular localization of proteins with a certain trafficking pathway can be subjected to selective regulation by dietary manipulation. This form of regulated plasma membrane targeting of a select subset of upstream signaling proteins may provide cells with the flexibility to coordinate the arrangement of signaling translators on the cell surface. Ultimately, this may allow organ systems such as the colon to optimally decode, respond, and adapt to the vagaries of an ever-changing extracellular environment.

Figure 1. Induction of apoptosis in fatty acid and butyrate-treated colonocytes

Cultures contained 5 mM butyrate and 50 µM DHA, LA or no fatty acid treatment. Apoptosis was measured by DNA fragmentation ELISA. Data represent mean absorbance at 405 nm ± SE divided by the total number of adherent cells per dish, n=4–6 separate wells from 1 of 4 representative experiments. Values not sharing the same letters are significantly different (P < 0.05). Adapted from Ng et al (2005).

Figure 2. Proposed molecular model of DHA and butyrate-induced apoptosis

We have previously demonstrated that butyrate induces colonocyte apoptosis via a non-mitochondrial, Fas-mediated, extrinsic pathway which is antagonized by activated Ras [Fan, 1999]. DHA and butyrate work coordinately in the colon to initiate a distinct intrinsic proapoptotic cycle involving the activation of store-operated channels (SOC), leading to rapid entry of Ca²⁺ through the plasma membrane and mitochondrial Ca²⁺ loading. This directly or indirectly increases mitochondrial phospholipid hydroperoxides (PLOOH) and triggers the opening of the permeability transition pore (PTP) and release of pro-apoptotic molecules like cytochrome C. These effects culminate in the induction of apoptosis.

Figure 3. Modulation of protein-membrane localization by dietary DHA

Potential effects of dietary PUFA on post translational lipidation (fatty acylation and/or prenylation) and membrane composition. These effects may culminate in a shift in the localization of intracellular proteins.

Figure 4

DHA-induced modulation of vesicular protein transport