![]() If the response to therapy indeed depends on the baseline omega-3 index, it would suggest that omega-3 intervention studies should stratify for baseline omega-3 levels, or better, subjects should be titrated to an optimal omega-3 index instead of using a single dosing regimen. No studies to date have examined whether the magnitude of TG-reduction is a function of the baseline omega-3 index. In fact, the endogenous level of EPA and DHA ( e.g., red blood cells EPA+DHA, or the omega-3 index ) is itself a biomarker for cardiovascular disease risk. EPA and DHA appear to be equally potent in lowering plasma TG and are effective in multiple settings including type II diabetes (T2D), metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), HIV-dyslipidemida, nephrotic syndrome and hemodialysis populations.ĮPA and DHA belong to a unique group of nutri-pharmaceutical agents that are already present in tissues prior to use. ![]() The effect is dose dependent with the minimal effective dose being > 2 g/day. ![]() The TG-lowering effect of EPA+DHA has been demonstrated in numerous trials and 3-4 g/day of omega-3 FAs decrease plasma TG by about 30% (range 16-45%). ![]() The pharmaceutical preparation of omega-3 acid FAs (Lovaza, GlaxoSmithKine) provides EPA and DHA as acid ethyl esters, and the approved dose is 4, 1-g capsules per day which provides 1,860 mg of EPA and 1,500 mg of DHA for a total of 3.4 g omega-3 FAs/day. This is similar to another dietary component, niacin (vitamin B3), that is also lipid-lowering at supra-nutritional intakes. Although the TG-lowering effects of FO are not evident at intakes typical of Western diets (about 130 mg/day) they manifest at “pharmacologic” doses ( i.e., >3 g/day of EPA+DHA). Omega-3 FAs have long been known to lower plasma TG along with variety of other drugs such as fibrates, statins, thiazolidinediones, niacin, and metformin. FO could activate transcription factors which control metabolic pathways in a tissue specific manner regulating nutrient traffic and reducing plasma TG. In addition, FO increases extracellular lipolysis by lipoprotein lipase (LpL) in adipose, heart and skeletal muscle and enhances hepatic and skeletal muscle β-oxidation which contributes to reduced FA delivery to the liver. FO counteracts intracellular lipolysis in adipocytes by suppressing adipose tissue inflammation. The key regulator of plasma NEFA is intracellular adipocyte lipolysis via hormone sensitive lipase (HSL), which increases as insulin sensitivity worsens. Thus reducing NEFA delivery to the liver would be a likely locus of action for fish oils (FO). Of these, NEFAs contribute the largest fraction to VLDL-TG production in both normotriglyceridemic subjects and hypertriglyceridemic, insulin resistant patients. The liver derives FAs from three sources: diet (delivered via chylomicron remnants), de novo lipogenesis, and circulating non-esterified FAs (NEFAs). Numerous mechanisms have been shown to contribute to the TG overproduction, but a key component is an increase in the availability of FAs in the liver. At the pharmaceutical dose, 3.4 g/day, they reduce plasma TG by about 25-50% after one month of treatment, resulting primarily from the decline in hepatic very low density lipoprotein (VLDL-TG) production, and secondarily from the increase in VLDL clearance. Long chain omega-3 fatty acids (FAs) are effective for reducing plasma triglyceride (TG) levels.
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