Eicosapentaenoic acid (EPA), one representative of n-3 unsaturated fatty acids (n-3 PUFAs), is clinically used for its lipid-lowering effects (1). n-3 PUFAs were shown to exert various physiological functions such as antiplatelet actions (by antagonizing effects of arachidonic acid) and plaque stabilization (2,3). Several epidemiological studies have explored antiatherogenic and cardioprotective effects of n-3 PUFA that are abundantly contained in fish oil (4). Dyslipidemia accompanying the metabolic syndrome is often associated with elevated levels of remnant lipoprotein particles and small dense LDL (sdLDL), which are newly recognized risk factors for cardiovascular disease (CVD) (5). It was reported that fish oil improved lipoprotein subclass profiles in subjects with an atherogenic lipoprotein phenotype (6). Besides EPA, docosahexaenoic acid and cholesterol are present in fish oil (7), but it is not clear whether purified EPA independently affects lipoprotein subclass profiles. Therefore, we used purified EPA ethyl ester and examined effects of EPA on atherogenic sdLDL particles and remnant lipoprotein particles in the metabolic syndrome, a precursor of CVD. Furthermore, sdLDL has been reported to synergistically interact with inflammation in pathophysiologic processes leading to CVD (8). Therefore, we simultaneously measured effects of EPA on C-reactive protein (CRP), a marker of inflammation, and examined how alteration of lipoprotein profiles by EPA affects systemic inflammation.

Conclusions
This study is the first to demonstrate that EPA significantly reduces serum sdLDL and CRP in the metabolic syndrome. Reduction of sdLDL by EPA treatment in this study is believed to be due to a suppression of triglycerides production in the liver by EPA. In addition, since CETP is an important enzyme in cholesterol metabolism—responsible for the transfer of cholesteryl esters from HDL to LDLs (11)—degradation of CETP activity by EPA treatment may also have contributed to the decrease in the generation of remnants and sdLDL. Furthermore, we detected that reductions in RLP cholesterol and sdLDL also correlated with a decrease in CRP by EPA, which was consistent with a previous report (8) showing that LDL particle size had a strong inverse association with CRP. Atherogenic sdLDL particles are susceptible to oxidative modifications; then, oxidized LDL is easily taken into macrophages through damaged endothelial cells, thereby inducing inflammation and early atherosclerotic lesions (5,15). On the other hand, CRP has also been shown to accelerate LDL modifications during inflammatory processes (8). These findings suggest that EPA may be capable of preventing the progression of atherosclerosis in the metabolic syndrome by suppressing reciprocal interactions of atherogenic lipoproteins and inflammation. There are several reports demonstrating that n-3 PUFA does not decrease CETP protein mass and CRP (16,17). This may be caused by the differences outlined in the research designs and methods of each report.
Recently, the Japan EPA Lipid Intervention Study reported that EPA provided further benefits in preventing major coronary events without changing reductions in LDL cholesterol levels (18). Considering the improvements in lipoprotein profiles by EPA in this study, EPA may exert cardioprotective effects not by changing the quantity but by improving the quality of LDL cholesterol.
Collectively, the present study is the first to demonstrate that purified EPA reduces sdLDL, remnants, and CRP, thereby potentially leading to the reduction in development of atherosclerosis and CVD in the metabolic syndrome.

PMID: 17192349

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