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Metabolic diseases

The World Health Organization (WHO) predicts that in 15 years cardiovascular disease (CVD) will be the major killer worldwide, due to the accrual of several metabolic disorders, including obesity and diabetes (among others). Most would agree that diet is one of the most important factors in maintaining human health. Omega-3 fatty acids are described as pleiotropic molecules with a broad variety of biological actions, including hypotriglyceridemic, anti-aggregatory, anti-inflammatory, and anti-arrhythmic responses (Garg et al., 2006, Micallef & Garg, 2009). They have been shown to reduce the risk of CVD, coronary heart disease, type 2 diabetes, and insulin resistance, among other conditions (Woods & Fearon, 2009). These effects are mediated by alterations in circulating plasma lipids, eicosanoids, and cytokines, and physicochemical properties in the phospholipid membrane.

The anti-atherogenic properties of n-3 PUFAs are perhaps their ability to modify serum and tissue lipid alterations, while the most consistent finding is a reduction in fasting and postprandial serum triglycerides and free fatty acids (FFA) (Micallef & Garg, 2009). The displayed effects are decreased levels of very low density lipoprotein (VLDL) production by the liver, which occurs mostly through a reduction in the synthesis of triglycerides (Micallef & Garg, 2009), largely resulting from interference with most of the transcription factors that control the expression of enzymes responsible for both triglyceride assembly and FA oxidation. This leads to the decreased availability of FFAs released from adipose stores (Micallef & Garg, 2009). Omega-3 PUFAs have been shown to significantly reduce the expression of the sterol regulatory element-binding proteins (SREBP), which are transcription factors that regulate cholesterol, FA, and triglyceride-synthesizing enzymes (Micallef & Garg, 2009). This effect by EPA and DHA seems to induce inhibition of the liver X receptor a/retinoid X receptor a (LXRa/ RXRa) heterodimer by binding to the promoter of the SREBP-1cgen e (Micallef & Garg, 2009), and the activation of PPAR.

Long-chain EPA and DHA are potent anti-arrhythmic agents that help to improve the vascular endothelial function and to lower blood pressure, platelet sensitivity, and serum triglyceride levels. Dietary ALA consumed as flax seed oil was shown to raise serum n-3 PUFAs, such as EPA and DHA levels (Mantzioris et al., 1994; Cunnane et al., 1995). In a recent report, intake of flax seed oil and milled flax seed for 4 weeks resulted in significant increases in plasma ALA levels (Dupasquier et al., 2006; Austria et al., 2008) and aortic tissue. Flax seed supplementation was also reported to reduce the n-6 to n-3 PUFA ratio, primarily as a result of the elevated levels of circulating n-3 PUFAs (Dupasquier et al., 2006).

Supplementation of ALA from linseed oil/flax seed oil significantly decreased inflammatory markers, including C-reactive protein, serum amyloid A, IL-6, and soluble VCAM-1, in dysli-pidemic patients (Rallidis et al., 2003, 2004). Dupasquier et al. (2007) reported an antiatherogenic action by dietary flax seed. In their study, the authors revealed for the first time an antiproliferative and anti-inflammatory action of flax seed. Feeding flax seed to LDL receptor-deficient (LDLrKO) mice (which closely mimic the human condition) suppressed the expression of inflammatory markers such as IL-6, mac-3, and VCAM-1, and the proliferative marker PCNA by reducing the infiltration of macrophages into the sub-endothelial space, and reduced the inflammatory and proliferative state of atherosclerotic lesions. The authors attributed these effects to the omega-3 fatty acid content of flax seed.

Cancer

Several molecular mechanisms whereby omega-3 PUFAs potentially affect carcinogenesis have been proposed (Larsson et al., 2004). These mechanisms include the following:

1. Suppression of arachidonic acid (AA, 20:4n-6)-derived eicosanoid biosynthesis, which results in altered immune response to cancer cells, and modulation of inflammation, cell proliferation, apoptosis, metastasis, and angiogenesis.

2. Influences on transcription factor activity, gene expression, and signal transduction, which lead to changes in metabolism, cell growth, and differentiation.

3. Alteration of estrogen metabolism, which leads to reduced estrogen-stimulated cell growth.

4. Increased or decreased production of free radicals and reactive oxygen species.

5. Mechanisms involving insulin sensitivity and membrane fluidity (Larsson et al., 2004).

Linoleic acid (LA) and arachidonic acid (AA) activate protein kinase C (PKC) and induce mitosis, but EPA and DHA appear to reverse the protein kinase C activity changes associated with colon carcinogenesis (McCarty, 1996; Rose & Connolly, 1999a, 1999b). The AA products of cyclooxygenase (COX) and lipoxygenase (LOX) enzymes increase mitosis; EPA and DHA

FIGURE 58.4

Proposed mechanisms by which omega-6 and omega-3 polyunsaturated fatty acids may promote and suppress carcinogenesis. Adapted from Larsson et al. (2004).

FIGURE 58.4

Proposed mechanisms by which omega-6 and omega-3 polyunsaturated fatty acids may promote and suppress carcinogenesis. Adapted from Larsson et al. (2004).

decrease mitosis and inhibit growth of breast and colon cancers (Rose et al., 1995) (Figure 58.4). Flax seed oil was reported to reduce colon cancer (Williams et al., 2007) and mammary tumor growth at a late stage of carcinogenesis in rodents (Thompson et al., 1996a, 1996b); the authors attributed this effect to the high ALA content in the flax seed oil component, which was found to be more effective at the stage when tumors have already been established.

Further studies indicated a reduction in the growth and metastasis of human estrogen receptor negative (ER—) breast cancer in nude mice fed diets containing flax seed products (Wang et al., 2005). The authors concluded that the tumor inhibitory effect of flax seed products was due to its oil content, specifically ALA. Some of the actions proposed were a greater reduction of Ki-67 LI, decreased cell proliferation, and induction of apoptosis. Flax seed is high in phytochemicals, and includes many antioxidants. In addition to lignans, flax contains phenolic acids, cinnamic acids, flavonoids, and lignins (Lambert et al., 2005). Lignan metabolites from flax seed may decrease the risk of cancer by acting as antioxidants and free radical scavengers. Using human colonic cancer (SW480) cells, the lignan metabolites enterodiol and enterolactone were shown to inhibit cancer cell growth mediated by cytostatic and apoptotic mechanisms (Qu et al., 2005). Animal studies have shown that dietary flax seed oil rich in the omega-3 polyunsaturated fatty acid ALA can decrease natural killer (NK) cell activity (Thies et al., 2001). Many mechanisms seem to be operational in omega-3 fatty acid suppression of tumor growth. Most experimental studies have been conducted on primary cancers, but it seems reasonable that these same mechanisms might suppress the growth of metastatic cancer cells.

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