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

Lipid Atherosclerotic Risk Factors & Mechanisms of the Potential Atherogenicity of Hypertriglyceridemia

Hypertriglyceridemia is a risk factor for CHD, particularly in women,[53] although it is unclear if hypertriglyceridemia is always an independent risk factor.[54,55] What does seem clear is that when hypertriglyceridemia is combined with elevated total and LDL-C levels, then CHD risk is amplified.[56,57] The increased CHD risk with combined hyperlipidemia may be due to several mechanisms, many of which may or may not be independent of one another.

VLDL and its remnants carry cholesterol and, thus, constitute a component of non-HDL-C. Non-HDL-C is the sum of cholesterol carried by atherogenic lipoproteins (e.g., LDL, VLDL, IDL, lipoprotein (a) and lipoprotein remnants), and is thought to be a better predictor of CHD risk than LDL-C levels alone.[58,59,60] Mechanistically, an increase in atherogenic lipoprotein levels enhances cholesterol delivery to endothelial plaques, promotes atherosclerotic progression, and increases the risk of plaque rupture resulting in an increased risk of a CHD event.

Another marker that is thought to be a better predictor of CHD risk than LDL-C levels alone is a measurement of apoB-100.[58] Each LDL, VLDL and IDL particle contains one apoB-100 molecule. Thus, apoB-100 reflects the number of circulating atherogenic lipoproteins, and this may account for why this measurement is a strong predictor of CHD risk.[61] Increased TRL through increased VLDL particles and their remnants increases apoB-100 levels and, thus, may increase CHD risk.

Elevated TG levels are often associated with, and may contribute to, small, dense LDL particles. The generation of small, dense LDL particles often results from an interplay of various enzymes, including LPL, hepatic lipase and cholesteryl ester transfer protein.[62] Although all LDL particles are considered atherogenic, small, dense LDL particles may be more atherogenic than larger LDL particles. As with hypertriglyceridemia, not all analyses support that LDL particle size is an independent predictor of CHD.[63] However, if small, dense LDL particles are more atherogenic, then this is likely because they may be more able to penetrate arterial walls and have less resistance to oxidative stress. Small, dense LDL particles may also be associated with increased thrombosis, which may increase CHD events.

High TG levels are often associated with, and may contribute to, low HDL-C levels.[1] High HDL-C levels are generally associated with decreased CHD risk. Conversely, lower HDL-C levels may be associated with increased CHD risk.[1] Mechanistically, if lower HDL-C levels are directly associated with increased CHD risk, it is likely due to decreased flux of cholesterol from athero-sclerotic plaques, or possibly due to other effects, such as a reduced anti-inflammatory response otherwise attributable to HDL particles.

Postprandial hypertriglyceridemia may be an independent risk factor for CHD, which suggests that chylomicrons (even though they contain apoB-48, not apoB-100) and their remnants may be atherogenic.[64,65,66,67,68] If true, then an increase in atherogenicity through this mechanism may have practical consequences for clinicians and their patients. For example, patients may sometimes believe that as long as their fasting lipid levels are well-controlled with lipid-altering drug therapy (e.g., statins), then food choices and diet composition no longer affect their CHD risk. But if postprandial lipemia does contribute to atherosclerosis, then it is possible that even with lipid-altering drug administration, poor dietary habits may still increase CHD risk.

Similarly, preprandial increases in TRL remnants may also increase CHD risk, with some studies suggesting that VLDL remnants, or IDL, are strong and independent risk factors for atherosclerotic progression.[69] Animal studies have suggested that the generation of very large TRLs may not necessarily be atherogenic because they are unable to penetrate arterial endothelia.[70] However, when apoB-48-containing chylomicrons and apoB-100-containing VLDL particles undergo circulatory metabolism by lipoprotein lipase, then TRL remnants may be generated, resulting in smaller, more dense particles that are relatively depleted of TG, phospholipid and apoC, and enriched in cholesteryl esters and apoE.[32] TRL remnants may promote atherogenesis through impairment of endothelium-dependent vasorelaxation, enhancement of platelet aggregation and subendothelial macrophage uptake resulting in foam cell formation.

Elevated (postprandial) TG levels may unfavorably affect the coagulation system, increasing plasminogen activator inhibitor-1, an inhibitor of fibrolysis. Factor VII may also be increased, which may also increase the risk of thrombosis.[71] An increase in the risk of thrombosis increases the risk of CHD events.

ApoC-III, an apolipoprotein found on chylomicron, VLDL, IDL and HDL particles, inhibits LPL activity. An elevated apoC-III level may be associated with increased CHD risk.[72] This is most likely because it reflects the concentration of TRL. ApoC-III may also directly activate vascular endothelial cells, which promotes inflammatory cell adhesion and recruitment[73] and, thus, may directly contribute to the inflammatory process of atherosclerosis.


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