Although the beneficial effects of omega-3 fatty acid in reducing the risk of various of human diseases, such as hypertriglyceridemia and nonalcoholic fatty liver disease, have been demonstrated in clinical and pre-clinical studies, the mechanism of its action is poorly understood. several studies has been reported that Dietary supplementation with fish oil induces many changes in plasma TG profile. N-3 fatty acid found in fish oil has been reported that reduce plasma TG and VLDL lev- els. Intercellular lipid droplets is the key regulator of plasma fatty acids and lipoproteins level. Here we show that n-3 fatty acid supplementation triggers intercellular lipid droplets degradation independent from known fatty acid mobilization pathways namely lipophagy and lipolysis . ATGL and HSL are consider as two major lipolysis enzymes.SiRNA study of these two lipolysis enzymes did not attenuate lipid droplets degradation. Lipophagy has been reported as a selective mechanism for degradation of lipid droplets during the starvation condition. Knock down of autophagy (macroautophagy) related pro- teins, could not block degradation of intercellular lipids by EPA. Degradation of lipid droplets is lysosomes dependent and requires lysosomal motility machinery. Lysosomes are interacting directly with lipid droplets during the process that is similar to kiss and run pattern. The morphological examination of this process by electron microscopy indicated its re- semblance to microautophagy like structure. Importantly, (over expression) Arl8b which has been shown that play a role in peripheral distribution of lysosomes along with FYCO1, specifically accelerates the effect of EPA on degradation of intercellular lipid droplets independent from its role in engagement of lysosomal plus end distribution. in particular, Arl8b recruited HOPS protein complex in EPA dependent fashion and si- lencing of HOPS complex interfered with normal lysosomal degradation of lipid droplets. Thus, this finding reveals new mechanism for intercellular lipid mobilization and offer an explanation for the therapeutic benefits of omega-3 fatty acids.

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The impact of the source of n-3 fatty acids on cardiovascular disease has not been fully investigated. This study was carried out to investigate cardiovascular benefits of diets with a low ratio (2:1) of n-6:n-3 fatty acids from different sources, either fish or flaxseed oil, in C57BL/6 mice. Twenty-one mice were divided into 3 groups (n=7) and fed an atherogenic diet supplemented with either a fish or flaxseed oil-based ‘designer oil’ with low n-6:n-3 fatty acid ratio (treated groups) or safflower oil-based formulation with a high ratio (control group) for 16 weeks. Plasma cholesterol levels declined significantly in both treated groups, by greater than 30%, compared to those in control. The ratio of n-6:n-3 fatty acids in liver was significantly lower in fish and flax groups as compared to control. Our data suggest that lowering dietary ratio of n-6:n-3 fatty acids may significantly reduce cardiovascular risks regardless of the source of n-3 fatty acids. / October 2008

The impact of the source of n-3 fatty acids on cardiovascular disease has not been fully investigated. This study was carried out to investigate cardiovascular benefits of diets with a low ratio (2:1) of n-6:n-3 fatty acids from different sources, either fish or flaxseed oil, in C57BL/6 mice. Twenty-one mice were divided into 3 groups (n=7) and fed an atherogenic diet supplemented with either a fish or flaxseed oil-based ‘designer oil’ with low n-6:n-3 fatty acid ratio (treated groups) or safflower oil-based formulation with a high ratio (control group) for 16 weeks. Plasma cholesterol levels declined significantly in both treated groups, by greater than 30%, compared to those in control. The ratio of n-6:n-3 fatty acids in liver was significantly lower in fish and flax groups as compared to control. Our data suggest that lowering dietary ratio of n-6:n-3 fatty acids may significantly reduce cardiovascular risks regardless of the source of n-3 fatty acids.

The impact of the source of n-3 fatty acids on cardiovascular disease has not been fully investigated. This study was carried out to investigate cardiovascular benefits of diets with a low ratio (2:1) of n-6:n-3 fatty acids from different sources, either fish or flaxseed oil, in C57BL/6 mice. Twenty-one mice were divided into 3 groups (n=7) and fed an atherogenic diet supplemented with either a fish or flaxseed oil-based ‘designer oil’ with low n-6:n-3 fatty acid ratio (treated groups) or safflower oil-based formulation with a high ratio (control group) for 16 weeks. Plasma cholesterol levels declined significantly in both treated groups, by greater than 30%, compared to those in control. The ratio of n-6:n-3 fatty acids in liver was significantly lower in fish and flax groups as compared to control. Our data suggest that lowering dietary ratio of n-6:n-3 fatty acids may significantly reduce cardiovascular risks regardless of the source of n-3 fatty acids.

We have previously shown that dietary fish oil and fiber, particularly the highly-fermentable pectin, are protective against colon cancer in a rat model of carcinogenesis. Therefore, based upon the current body of literature and our previous experimental findings, we hypothesized that one mechanism by which dietary fish oil+pectin suppress the promotion stage of colon cancer is through butyrate, the fermentation product of fiber, targeting (in particular) the p21Waf1/Cip1 gene and, via targeted histone hyperacetylation, inducing its expression. We found that dietary butyrate supplementation increased the concentration of fecal butyrate (mole %) in the distal colon, and that this increase corresponded to an increase in histone H4 acetylation. Similarly, diets supplemented with butyrate increased p21Waf1/Cip1 expression despite azoxymethane (AOM) treatment, which was not seen in non-butyrate supplemented diets. Furthermore, fish oil+butyrate diets resulted in the highest levels of apoptosis and the lowest levels of ACF, while corn oil+butyrate diets resulted in the lowest levels of apoptosis and the highest levels of ACF. Thus, it appears that the protective effect of fish oil+butyrate is due to the unique properties of fish oil, providing an environment in which butyrate’s enhancement of histone acetylation and p21 expression are pro-apoptotic, thereby diminishing pre-neoplastic ACF development.

We have previously shown that dietary fish oil and the fiber pectin protect against colon cancer in rats by increasing apoptosis induced by reactive oxygen species (ROS) at the initiation stage of tumorigenesis. We hypothesized that fish oil would incorporate into the cardiolipin of colonic mitochondrial membranes, creating an environment in which butyrate, a fermentation product of pectin, would also increase ROS and lead to apoptosis, as evidenced by decreased mitochondrial membrane potential (MMP), enhanced caspase-3 activity and cytochrome c translocation from the mitochondria, thus protecting against colon cancer by removing DNA damaged cells at the promotion stage of carcinogenesis. Sixty rats were provided a diet containing 15% corn or fish oil for 11 wk and injected with azoxymethane (AOM) or saline at wk 3 and 4. At wk 11, colonocytes were exposed to +/- butyrate ex vivo for 30 or 60 min. ROS and MMP were measured using fluorescence microscopy, and cytochrome c concentration and caspase-3 activity were measured using ELISA assays. Cardiolipin fatty acid enrichment was measured via TLC and GC. Butyrate increased ROS (p<0.0001) regardless of diet or treatment group. In colonic crypts from fish oilconsuming rats, butyrate reduced MMP (p=0.05). However, butyrate had no effect on MMP if the rats were consuming corn oil. In colonocytes from rats consuming fish oil, butyrate decreased mitochondrial cytochrome c (11%; p=0.02) concomitant with an increase in caspase-3 activity (17%; p=0.04) in the distal colon. In fish oil-fed animals, the n-3 fatty acids DHA and EPA were incorporated into cardiolipin at the expense of n-6 fatty acids. Regression analysis revealed a positive relationship between DHA (R=0.49, p=0.03) and EPA (R=0.59, p=0.02) and cytosolic cytochrome c content. As the percentage of DHA and EPA in the cardiolipin increased, the level of cytochrome c in the cytosol increased. These relationships were not seen in rats consuming corn oil and suggest that these results, induced only by the combination of butyrate with fish oil, may lead to increased apoptosis at the promotion stage of colon carcinogenesis via a mitochondria-mediated mechanism.

We have previously shown that dietary fish oil and fiber, particularly the highly-fermentable pectin, are protective against colon cancer in a rat model of carcinogenesis. Therefore, based upon the current body of literature and our previous experimental findings, we hypothesized that one mechanism by which dietary fish oil+pectin suppress the promotion stage of colon cancer is through butyrate, the fermentation product of fiber, targeting (in particular) the p21Waf1/Cip1 gene and, via targeted histone hyperacetylation, inducing its expression. We found that dietary butyrate supplementation increased the concentration of fecal butyrate (mole %) in the distal colon, and that this increase corresponded to an increase in histone H4 acetylation. Similarly, diets supplemented with butyrate increased p21Waf1/Cip1 expression despite azoxymethane (AOM) treatment, which was not seen in non-butyrate supplemented diets. Furthermore, fish oil+butyrate diets resulted in the highest levels of apoptosis and the lowest levels of ACF, while corn oil+butyrate diets resulted in the lowest levels of apoptosis and the highest levels of ACF. Thus, it appears that the protective effect of fish oil+butyrate is due to the unique properties of fish oil, providing an environment in which butyrate’s enhancement of histone acetylation and p21 expression are pro-apoptotic, thereby diminishing pre-neoplastic ACF development.

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