Omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid and their mechanisms of action on apolipoprotein B-containing lipoproteins in humans: a review

Abstract

BackgroundEpidemiological and genetic studies suggest that elevated triglyceride (TG)-rich lipoprotein levels in the circulation increase the risk of cardiovascular disease. Prescription formulations of omega-3 fatty acids (OM3FAs), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), reduce plasma TG levels and are approved for the treatment of patients with severe hypertriglyceridemia. Many preclinical studies have investigated the TG-lowering mechanisms of action of OM3FAs, but less is known from clinical studies.MethodsWe conducted a review, using systematic methodology, of studies in humans assessing the mechanisms of action of EPA and DHA on apolipoprotein B-containing lipoproteins, including TG-rich lipoproteins and low-density lipoproteins (LDLs). A systematic search of PubMed retrieved 55 articles, of which 30 were used in the review; 35 additional arrticles were also included.ResultsIn humans, dietary DHA is retroconverted to EPA, while production of DHA from EPA is not observed. Dietary DHA is preferentially esterified into TGs, while EPA is more evenly esterified into TGs, cholesterol esters and phospholipids. The preferential esterification of DHA into TGs likely explains the higher turnover of DHA than EPA in plasma. The main effects of both EPA and DHA are decreased fasting and postprandial serum TG levels, through reduction of hepatic very-low-density lipoprotein (VLDL)-TG production. The exact mechanism for reduced VLDL production is not clear but does not include retention of lipids in the liver; rather, increased hepatic fatty acid oxidation is likely. The postprandial reduction in TG levels is caused by increased lipoprotein lipase activity and reduced serum VLDL-TG concentrations, resulting in enhanced chylomicron clearance. Overall, no clear differences between the effects of EPA and DHA on TG levels, or on turnover of TG-rich lipoproteins, have been observed. Effects on LDL are complex and may be influenced by genetics, such as APOE genotype.ConclusionsEPA and DHA diminish fasting circulating TG levels via reduced production of VLDL. The mechanism of reduced VLDL production does not involve hepatic retention of lipids. Lowered postprandial TG levels are also explained by increased chylomicron clearance. Little is known about the specific cellular and biochemical mechanisms underlying the TG-lowering effects of EPA and DHA in humans.

Effects of free omega-3 carboxylic acids and fenofibrate on liver fat content in patients with hypertriglyceridemia and non-alcoholic fatty liver disease: A double-blind, randomized, placebo-controlled study

“…3,5 Omega-3 fatty acids reduce serum TG levels by decreasing VLDL production rates, while VLDL clearance rates are less consistently affected. 12,13 A meta-analysis of human interventional studies showed that omega-3 fatty acids decrease liver fat content in the absence of weight loss. 14 Liver fat content is positively associated with VLDL production, 15 and therefore current knowledge suggests that omega-3 fatty acids may reduce VLDL production by lowering the liver lipid content.…”

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“…The main effects of both EPA and DHA are decreased fasting and postprandial serum TG levels, through reduction of hepatic Very Low Density Lipoproteins (VLDL) and TG production. The exact mechanism for reduced VLDL production is not clear but does not include retention of lipids in the liver; rather, increased hepatic fatty acid oxidation is likely [9]. It is important to notice that when compared to prescription fish oil products that contain specific amounts of EPA, over-the-counter unregulated fish oil supplements vary in concentration of EPA and DHA.…”

“…Hypertriglyceridemia is a common disorder and polygenic and lifestyle factors are its main etiologic factors; monogenic etiology is much rarer [9]. It can result from either increased TG production or reduced clearance.…”

“…It is important to exclude secondary causes of hypertriglyceridemia in all patients [8]. It is believed that moderate hypertriglyceridemia may enhance the risk of cardiovascular disease [9,14] while severe hypertriglyceridemia is strongly associated with an increased risk of acute pancreatitis [8,14,15]. Ideally, serum TG concentration should be less than 500 mg/dL to prevent pancreatitis.…”

Is Plant Sterols a Good Strategy to Lower Cholesterol?

“…However, no significant effect of PS on serum HDL-C was observed. Considering the mechanism behind TGs lowering, PS, EPA, and DHA inhibit hepatic TGs synthesis, decrease VLDL synthesis and secretion, and increase plasma lipoprotein lipase LPL activity 26 . The consumption of PS and EPA+DHA also have beneficial effects on lipoprotein metabolism as they significantly reduced non HDL-C concentrations, which could suppress the VLDL-C production.…”