Why Do Omega-3 Fish Oil Lower Triglycerides?
As you age, you are most afraid of high blood lipids, especially triglycerides. Triglycerides are an important predictor of cardiovascular disease and an important indicator of metabolic syndrome. The normal value reference range is 0.45~1.69mmol/L. Exceeding this level will raise atherosclerosis, and blood clots, and increase the risk of heart disease. Today, let’s analyze how fish oil lower triglycerides.
How does fish oil lower triglycerides?
Fish oil’s main mechanism for lowering triglycerides is its rich omega-3 unsaturated fatty acids, especially EPA and DHA.
Now, it has been found that omega-3 fatty acids are not effective in lowering triglycerides at ~130 mg/day, but at “pharmacologic” doses (>3 g/day EPA+DHA), the effect is significant. Clinical trials have shown that 3-4 grams/day of omega-3 fatty acids can reduce triglycerides by about 30%. Moreover, EPA and DHA are similarly effective in lowering triglycerides and are effective in a wide range of people with a variety of medical conditions.
At a drug dose of 3.4 g/day, plasma triglycerides were reduced by about 25-50% after one month of treatment, mainly due to the following reasons:
→ reduction of hepatic production of very low-density lipoprotein (VLDL)
The liver is the main production factory for triglycerides, and very low-density lipoproteins (VLDL) and celiac particles are the main triglyceride-containing lipoproteins.
Fish oil reduces the rate at which the liver makes triglycerides and reduces very low-density lipoprotein (VLDL) production, thereby lowering total triglyceride levels in the blood.
In this study, for example, researchers put five subjects with hypertriglyceridemia on a 4-week treatment of daily supplementation (15g) of fish oil and found that VLDL production was reduced by 65-68%.
→ Improved clearance: increased clearance of very low-density lipoprotein (VLDL)
The first point that needs to be made clear is that the concentration of plasma lipoproteins is determined by the balance between the rate of their appearance in the plasma (i.e., the rate of production) and their rate of removal from the plasma (i.e., the rate of clearance).
Elevated plasma triglycerides may be due to increased VLDL production, such as in familial hypercholesterolemia, and familial mixed hyperlipidemia, and, in patients undergoing hemodialysis, elevated triglycerides are also due to overproduction of VLDLapoB. Elevated triglycerides may also be due to decreased clearance, for example, in the presence of proteinuria (i.e., nephrotic syndrome).
Fish oil accelerates the removal of cholesterol particles and VLDL from the bloodstream. It’s like adding cleaner cars to the road, quickly clearing obstacles, and keeping traffic flowing.
One study showed that subjects taking 4 grams of EPA or DHA per day in the postprandial state had 60% higher binding of celiac-like particles to endothelial cells than those taking placebo.
Some researchers randomized healthy subjects (n=33) to supplement with 4 g/d of safflower oil (SAF), eicosapentaenoic acid (EPA), or docosahexaenoic acid (DHA) ethyl ester for 4 weeks.
The study showed that supplementation with Omega-3 fatty acids reduced postprandial triglyceride and apolipoprotein B (apoB)-48 and apoB-100 concentrations by 16%, 28%, and 24%, respectively. Reducing the particle size of celiac particles (mean diameter: 293+/-44 nm vs. 175+/-25 nm) increased heparin lipoprotein lipase activity in the fed state.
The subjects were insulin-sensitive, and the fish oil had no effect on fasting glucose or insulin. Although the subjects had normal triglycerides (84 mg/dL), triglycerides decreased by 36%, and fasting NEFA decreased by almost the same amount, 37%, an amount sufficient to reduce VLDL synthesis.
In yet another randomized controlled trial, severely hypertriglycemic subjects (N=40) were treated with 3.4 grams/day of omega-3 fatty acids for 6 weeks. The researchers found that NEFA dropped on average from 0.86 mmol/L to 0.66 mmol/L.
Compared to the placebo group (0.89 to 0.85 mmol/L), the comparison was significant, with a final observed reduction in plasma triglyceride levels of about 75%.
In addition, high NEFA in high triglycerides increases VLDLapoC-III, which is an inhibitor of lipoprotein lipase (LPL) and hepatic lipase catabolism, and fish oil blocks the accumulation of ApoC-III on VLDL and increases lipoprotein lipase lipolysis.
→ Anti-inflammation, activation of peroxisome proliferating factor activated PPAR-gamma
Inflammation is like a “fire alarm” in fat cells, and fish oil is like a “firefighter” to extinguish the flames in time and reduce the damage caused by the “fire”. A variety of transcription factors are involved in the regulation of fatty acid metabolism, and fish oils work by influencing these transcription factors.
For example, it inhibits the binding of liver X receptor-alpha (LXRα)/retinoic acid X receptor-alpha (RXRα) to the promoter region of the SREBP-1c gene and reduces the expression of SREBP-1c.
Omega-3 fatty acids in fish oil are natural ligands for PPARs (Peroxisome Proliferator-Activated Receptors), which are able to regulate lipid metabolism and inflammatory responses, regulate fatty acid oxidation-related gene expression, and promote fatty acid oxidation through the activation of PPARs, thereby lowering the level of triglycerides.
→ Production of N-acetyl taurine (NAT)
A new study from 2021, which used mouse models and human plasma samples, found that omega-3 fatty acid-derived N-acyl taurine (NAT) accumulates in large amounts in bile and plasma after omega-3 supplementation.
One of the NATs containing DHA (C22:6NAT) inhibits intestinal triglyceride hydrolysis and lipid absorption, thereby reducing plasma triglyceride levels.
Role of omega-3 in different tissues
→ Liver
Fish oil can inhibit the assembly and secretion of VLDL and ApoB, reduce triglyceride synthesis, up-regulate β-oxidation in hepatocytes, reduce triglyceride accumulation in the liver, and improve non-alcoholic fatty liver disease (NAFLD).
→ Adipose tissue
Fish oil reduces fat mass through increased mitochondrial biosynthesis and β-oxidation, while fish oil reduces nonesterified fatty acid output by decreasing hormone-sensitive lipase (HSL)-mediated intracellular lipolysis, decreasing fatty acid supply to the liver.
→ Heart and Skeletal Muscle
Heart and skeletal muscle are the main sites of fatty acid utilization. Fish oil enhances lipoprotein lipase activity, promotes triglyceride clearance, regulates the expression of genes involved in β-oxidation, and raises plasma lipocalin levels, thereby promoting triglyceride hydrolysis, fatty acid uptake, and β-oxidation, thus reducing plasma triglycerides.
The results showed that supplementation with Omega-3 fatty acids accelerated celiac triglyceride clearance by increasing lipoprotein lipolytic enzyme activity and that EPA and DHA had the same effect.
→ Inhibition of adipocyte catabolism and reduction of fat supply
There are three sources of fatty acids used in hepatic triglyceride synthesis: dietary (i.e., celiac/residue); adipogenesis from the head; and non-esterified fatty acids (NEFA).
Non-esterified fatty acids (NEFA) are the raw material for triglyceride production in the liver, and the omega-3 fatty acids in fish oil reduce triglyceride synthesis in the liver by inhibiting lipolysis in adipocytes, which reduces the supply of NEFA.
The effect of fish oil on NEFA was studied, for example, in a randomized controlled trial that had 20 healthy medical students include a large amount of fish oil in their diets (30 g/day) for 7 days.