Prescription Omega-3 Fatty Acids and Their Lipid Effects: Physiologic Mechanisms of Action and Clinical Implications

Harold E Bays; Ann P Tighe; Richard Sadovsky; Michael H Davidson


Expert Rev Cardiovasc Ther. 2008;6(3):391-409. 

In This Article

Omega-3 Fatty Acids: TG-lowering Mechanisms

As discussed above, omega-3 fatty acids are well-known to reduce TG blood levels. However, the mechanisms by which EPA and DHA reduce serum TGs are not well-known or completely understood. Simply put, preclinical and clinical studies provide compelling evidence that EPA and DHA can reduce hepatic VLDL-TG synthesis/secretion and enhances TG clearance from circulating VLDL particles (Figure 2).[97] Regarding hyperchylomicronemia, both EPA and DHA may equally accelerate chylomicron TG clearance by promoting increased lipoprotein lipase activity.[82]

Potential TG-lowering mechanisms of eicosapentaenoic acid and docosahexaenoic acid. Pathogenic adipose tissue, increased postprandial CHYL and increased VLDL particles may increase free FA delivery to the liver, and increase hepatic lipid content, which are substrates for TG synthesis and, thus, VLDL production. Most evidence supports that omega-3 fatty acids inhibit hepatic TG synthesis, decrease VLDL production/secretion and increase VLDL metabolism by: decreasing lipogenesis by decreasing the enzymatic conversion of acetyl CoA to FAs; increasing ß-oxidation of FA; inhibiting both PAP (an enzyme that catalyzes that reaction of converting PA to DAG) and DGAT (an enzyme that catalyzes the final step in TG synthesis); potentially increasing the degradation of apolipoprotein B; and increasing LPL activity, which is an enzyme that increases the conversion of VLDL particles to LDL particles. CHYL: Chylomicrons; DAG: diacylglycerol; DGAT: Diacylglycerol acyltransferase; FA: Fatty acid; LPL: Lipoprotein lipase; PA: Phosphatidic acid; PAP: phosphatidic acid phosphatase/phosphohydrolase; TG: Triglyceride; VLDL: Very low-density lipoprotein. Adapted from.[98]

Several mechanisms have been proposed as to how omega-3 fatty acids may reduce TG synthesis, reduce the incorporation of TG into VLDL particles, and ultimately reduce TG secretion. Omega-3 fatty acids may decrease hepatic lipogenesis, increase ß-oxidation of fatty acids, and increase degradation of apoB-100.[97,98]

Peroxisome proliferator-activated receptors (PPARs) and sterol regulatory element-binding proteins (SREBPs) are transcription factors that play a major role in regulating lipid metabolism. The nuclear receptors liver X receptor (LXR)α and retinoid X receptor (RXR)α typically form a heterodimer that regulates expression of the SREBP-1c gene by binding to the SREBP-1c promoter.[99] SREBPs regulate the expression of cholesterol-, fatty-acid-, and TG-synthesizing enzymes. Activation of the transcription factor SREBP-1c stimulates the synthesis of lipogenic enzymes such as acetyl-CoA carboxylase-1 (ACC1) and fatty-acid synthase (FAS).[100]

Fish-oil feeding in mice is associated with significant decreases in hepatic SREBP-1c mRNA expression and decreases in TG levels.[101] Fish oils may inhibit LXR/RXR heterodimer binding to the SREBP-1c gene promoter, thereby suppressing SREBP-1c mRNA expression[102] and, thus, decreasing lipogenic enzyme activity. DNA microarray analysis from rat livers indicates that SREBP-1 gene expression is decreased with a DHA-enriched diet compared with low fat, high fat, or low fat plus fenofibrate diets.[103] Data from HepG2 human hepatoma cells support the notion that EPA decreases TG synthesis by suppressing the expression of SREBP-1c mRNA and SREBP-1c protein.[104] However, not all evidence entirely supports this proposed mechanism of TG-lowering by omega-3 fatty acids, in that rat studies suggest that EPA-induced suppression of SREBP-1c may be independent of LXRα.[105]

Fatty acids, which are substrates for TG synthesis, are degraded by the ß-oxidation pathway. An increased rate of hepatic fatty acid oxidation can decrease the amount of fatty acids available for TG synthesis and decrease the amount of TG available for incorporation into VLDL particles. Rat studies show that EPA and/or DHA increase free fatty acid ß-oxidation in peroxisomes and mitochondria,[98] leaving less substrate available for TG and VLDL synthesis. Evaluation of healthy human subjects taking 9 g of omega-3 fatty acids containing 5.4 g EPA and 3.6 g DHA per day[106] also supports a faster rate of hepatic fatty acid oxidation. EPA binds to all PPAR subtypes (PPAR-α, -ß and -γ),[75] and PPAR-α may be involved in omega-3 fatty acid modulation of fatty acid ß-oxidation. But, as before, not all evidence is supportive of this mechanism, in that other studies in rats[98,103] and monkeys[107] have shown that EPA and/or DHA had no significant effect on ß-oxidation.

Phosphatidic acid phosphatase/phosphohydrolase (PAP) is an enzyme that catalyzes the conversion of phosphatidic acid to diacylglycerol. Diacylglycerol acyltransferase (DGAT) is an enzyme that catalyzes the final step in TG synthesis. Both are key enzymes involved in TG synthesis in the liver. Results from preclinical studies are divided with regard to the effect of EPA and DHA on PAP and DGAT activity. Some studies show that EPA and DHA inhibit the activity of PAP and DGAT in rat liver microsomes; other studies show no such effect.[98] Thus, the extent to which the TG-lowering effects of EPA and DHA depend on the inhibition of PAP and/or DGAT activity is unclear.

Omega-3 fatty acids may increase TG removal from circulating VLDL and chylomicron particles, through increased hydrolysis by LPL. Specifically, EPA and DHA may increase LPL activity, and, thus, increase LPL-mediated clearance of TRL.[82,108] EPA increases PPAR-γ mRNA in cultured adipocytes,[109] and PPAR-γ mRNA levels in adipose tissue of obese subjects may be positively correlated with plasma EPA concentrations.[109] Agonism of the transcription factor PPAR-γ may increase LPL activity in adipose tissue.[110] Therefore, it is plausible that an increased LPL activity associated with EPA and DHA treatment may be due, in part, to increased activity of PPAR-γ.

Additionally, DHA may be a ligand for the farnesoid X receptor (FXR),[111] which is a nuclear receptor found in the liver and intestine, and for which bile acids are a natural ligand. FXR may also play a role in lipid homeostasis. ApoC-III resides on the surface of VLDL and LDL particles and inhibits the activity of LPL, thereby slowing the clearance of TG-rich lipoproteins.[112] Conversely, apoC-II activates LPL.[113] FXR suppresses apoC-III gene expression[114] and induces apoC-II[115] and VLDL-receptor gene expression,[116] all of which may contribute to the TG-lowering action of FXR agonists. Although speculative, FXR-induced changes in the expression of apoC-II, apoC-III, and/or VLDL-receptor gene may also play a role in LPL activity and the TG-lowering effect of DHA. Irrespective of the mechanism, omega-3 fatty acids increase TRL clearance, and decrease their circulating half-life.[82]

Coadministration of P-OM3 with statins improves the lipid profile in patients with hypertriglyceridemia to a greater extent than statin treatment alone.[117,118,119,120] Statins inhibit hydroxymethylglutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol biosynthesis. Inhibition of cholesterol synthesis leads to reduced hepatic cholesterol content, which in turn increases LDL receptor expression and activity and, thus, clears more LDL-C from the circulation. LDL-C levels are reduced. Upregulated LDL receptors may also increase clearance of other TG-containing lipoproteins, at least partially accounting for the modest TG-lowering effects of statins. The degree of TG lowering with P-OM3 is generally similar in statin-treated patients compared with nonstatin-treated patients because the mechanisms of actions of P-OM3 differ from that of statins.[118] Specifically, P-OM3 decreases the rate of VLDL secretion and increases the conversion of VLDL to IDL and LDL (Figure 3), while statins decrease apoB-containing lipo-proteins, such as VLDL, IDL and LDL.[118]

Effects of statins, fish oils and their combination on lipoprotein secretion rate (not lipid levels) and conversion. P-OM3 and atorvastatin lower triglyceride levels by different mechanisms. (A) Percentage change in the secretion rate of apoB-containing lipoproteins into the plasma. (B) Percentage change in the interconversion of apoB-containing lipoproteins. P-OM3, alone or in combination with atorvastatin, increased conversion of TG-rich lipoproteins to LDL. *p < 0.01 compared with placebo group. IDL: Intermediate-density lipoprotein; P-OM3: Prescription omega-3-acid ethyl esters; VLDL: Very-low-density lipoprotein. Reproduced from.[118] © 2002 American Diabetes Association.

In patients with persistent hypertriglyceridemia after achieving LDL-C treatment goals, as might occur after statin administration in combined hyperlipidemic patients, it is then recommended that non-HDL-C (total cholesterol minus HDL-C) levels be reduced to values less than 30 mg/dl added to the LDL-C treatment goal. Thus, it is relevant that in a study of statin-treated patients with persistent hypertriglyceridemia, P-OM3 added to ongoing simvastatin therapy produced significant additional improvements in reducing non-HDL-C levels and other lipid and lipoprotein parameters to a greater extent than simvastatin alone (Figure 3 & Table 4 ).[120] Thus mechanistically, in patients treated with statins and P-OM3, LDL-C levels may be reduced as a result of the statin-induced increase in hepatic LDL receptor activity. IDL and VLDL remnants may be reduced by P-OM3 impairment of VLDL synthesis and secretion. VLDL may also have enhanced clearance through enhanced LPL activity (by P-OM3) and upregulation of LDL receptor (by statins). This is an illustrative example of complementary mechanisms of actions by these two lipid-altering drugs, which may be of benefit in patients with combined hyperlipidemia.

With regard to other lipid parameters, EPA and DHA administration is sometimes associated with a modest increase in HDL-C levels. LDL-C levels may be variably increased. As with fibrates, the degree of LDL-C elevations observed with P-OM3 treatment is generally related to the pretreatment TG levels. P-OM3 increases LDL-C levels the most in patients with the highest pretreatment TG levels ( Table 3 ). The reason for the increased LDL-C levels with omega-3 fatty acids is related to the increased conversion of VLDL particles to LDL particles (Figure 4 and Figure 5). For example, weight loss in overweight subjects with hypertriglyceridemia has been shown to raise LDL-C, and this effect has been attributed to a reduction in the fractional catabolic rate of LDL.[121] As reviewed earlier, owing to their complementary mechanisms of action, concurrent treatment with statins may mitigate the rise in LDL-C in patients with hypertriglyceridemia treated with P-OM3.[120]

Effect of P-OM3 on non-HDL-C in patients with triglycerides of 500 mg/dl. Non-HDL-C is reduced in many P-OM3 trials, concomitantly with an apparent paradoxical increase in LDL-C levels. This can be explained by P-OM3's increased conversion of VLDL to LDL particles. Thus, in this case, P-OM3 resulted in a decrease in VLDL-C levels and decrease in VLDL particle size, and an increase in LDL-C levels and increase in LDL particle size, with a net decrease in the total cholesterol carried by atherogenic lipoproteins, as represented by non-HDL-C. HDL-C: HDL cholesterol; LDL-C: LDL cholesterol; P-OM3: Prescription omega-3-acid ethyl esters; VLDL: Very-low-density lipoprotein. Reproduced from.[92]

Revealing the underlying atherogenic potential of hypertriglyceridemia. Many patients with hypertriglyceridemia have increased cholesterol carried by atherogenic particles, which is best assessed by measuring non-HDL-C levels. VLDL particles are considered to be atherogenic. Omega-3 fatty acid therapy decreases the cholesterol carried by VLDL particles, and is a cholesterol effect not typically measured in clinical practice. Omega-3 fatty acids may also decrease VLDL particle size. Conversely, omega-3 fatty acids may increase LDL-C levels, which is a lipid parameter that is often measured in clinical practice. This is thought to be due to the increased conversion of VLDL particles to LDL particles. Finally, omega-3 fatty acids may increase LDL particle size, which may render them less atherogenic. Overall, despite a potential increase in LDL-C levels, many studies have reported that P-OM3 reduces non-HDL-C, which may be a better predictor of atherosclerotic coronary heart disease risk than LDL-C alone. HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; P-OM3: Prescription omega-3-acid ethyl esters; VLDL: Very-low-density lipoprotein.


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