Fish-Derived Omega-3 Fatty Acids: Guardians of High-Density Lipoprotein?

See article vol. 30: 884-906

Accumulated epidemiological evidence has demonstrated that the consumption of fish is associated with reduced risk of atherosclerotic cardiovascular disease (ASCVD) ¹⁾ . The mechanism underlying the suppression of ASCVD by fish consumption is assumed to depend on the cardioprotective effect of omega-3 fatty acids. The effect of long-term use of eicosapentaenoic acid (EPA), one of the omega-3 fatty acids, on the prevention of major coronary events in patients with hypercholesterolaemia was demonstrated in Japan EPA Lipid Intervention Study (JELIS) ²⁾ . Recently, reduction of cardiovascular events with icosapent ethyl-intervention trial (REDUCE-IT) has also proven the cardiovascular effect of EPA in strong-statin era ³⁾ . Beyond their triglyceride-lowering effects, fish-derived omega-3 fatty acids appear to have diverse effects including anti-inflammatory properties. Previously, the INTERLIPID study, which compared lipid profiles and multiple dietary factors in the Japanese and the Japanese–Americans with similar genetic backgrounds, demonstrated a positive association between fish-derived omega-3 fatty acid intake and circulating high-density lipoprotein cholesterol (HDL-C) levels ⁴⁾ . In this issue, Okami Y. et al have revealed that the intake of fish-derived omega-3 fatty acids was also associated with HDL subclass distribution using comprehensive lipid profile data in the INTERLIPID study provided by nuclear magnetic resonance (NMR) spectroscopy ⁵⁾ . The present findings could provide a new explanation for the atheroprotective effects of fish-derived omega-3 fatty acids.

Over the years, numerous epidemiological evidence has demonstrated that low levels of circulating HDL-C are associated with an increased risk for atherosclerotic cardiovascular disease (ASCVD). On the contrary, in the Framingham Offspring Study, low HDL-C was not an ASCVD risk factor when levels of low-density lipoprotein cholesterol and triglycerides were not elevated ⁶⁾ . Recently, a large contemporary biracial cohort has proven that low HDL-C was associated with increased ASCVD risk in White but not Black adults ⁷⁾ . Moreover, several studies have revealed that very high HDL-C levels are paradoxically associated with high ASCVD mortality ⁸⁾ . Under these circumstances, establishment of novel measures for HDL evaluation has garnered a lot of interest.

Until now, enough evidence suggests that HDL particle concentration can be superior to HDL-C as a predictor of ASCVD incidence ⁹⁾ . On the contrary, the data regarding the relationship between HDL subclasses and ASCVD risk are conflicting ( Fig.1 ) . HDLs are heterogeneous particles that differ in size, density, and charge; they are formed as small, dense, lipid-poor discoid particles, which can be classified as HDL3. After interaction with lecithin:cholesterol acyltransferase (LCAT), which generates hydrophobic core of cholesteryl esters, discoid HDL becomes large, light, lipid-rich spherical particles, HDL2 ¹⁰⁾ . Most of the previous reports found that greater concentration of blood HDL2 subfracion has inverse association with the ASCVD risk, while that of HDL3 subfraction appears to be associated with increased risk ¹¹⁾ . A plausible reason for the association of lower HDL2 to increased ASCVD risk can be cholesterol efflux capacity of larger HDL ¹¹⁾ . HDL biogenesis and maturation is coordinated by ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1), and scavenger receptor class B type I (SR-BI); ABCA1 initially mediates the export of cellular cholesterol and phospholipids to nascent HDL and ABCG1 and SR-BI subsequently provide additional cholesterol to larger HDL ¹²⁾ . The Chicago Healthy Aging study revealed that HDL particle size was significantly associated with HDL efflux capacity ¹³⁾ . In the hypertriglyceridemia state, a reduction in the number of large HDL particles, and concomitant impairment of SR-BI-dependent efflux was observed ¹⁴⁾ . Large HDL2 also decreased in patients with insulin resistance and type 2 diabetes ¹⁵⁾ suggesting that impairment of HDL maturation has occurred in the pathological conditions. Conversely, contradictory results have also been reported wherein lower HDL3 subfracion is associated with increased ASCVD risk ¹⁶⁾ . From the aspect of biological activities, small, dense, protein-rich HDL particles are thought to display potent atheroprotective properties ¹⁰⁾ . It has been demonstrated that HDL3 particles are closely associated with paraoxonase 1 (PON1) and are strong antioxidants ¹⁷⁾ . These discrepancy in the relationship between HDL particle size and ASCVD risk may be accounted for by different techniques for evaluation of HDL subclasses, such as ultracentrifugation, gel electrophoresis, ion mobility, and NMR spectroscopy. Moreover, because HDL particles are highly heterogeneous in structure, composition, metabolism, and biological activity, measurement of particle size may be insufficient to assess HDL characterization for ASCVD risk discrimination. For instance, phospholipids are major components of the mature HDL, accounting for 40%–60% of the total HDL lipids, and phospholipid content of HDL particle is a major factor determining cholesterol removing capacity of HDL ^{18 , 19)} . Alternatively, cholesterol-overloaded, larger HDL particle was associated with the progression of carotid atherosclerosis and increased risk of cardiovascular death ^{20 , 21)} .

Fig.1.

The complex relationship between HDL particle size and atherosclerosis

 

In the present issue of the JAT, the INTERLIPID study has found that high consumption of fish among Japanese was related to lower the quantity of the smallest HDL particles. Although precise mechanisms underlying the modification of HDL particle size by omega-3 fatty acids remain unclear, previous studies also demonstrate that the increase of fish consumption correlated with the increased concentration of large HDL particles ²²⁾ . On the other hand, recent studies have revealed that EPA also modified biological activities of HDL. The orally administered EPA was efficiently incorporated into the HDL particles, increased activity of anti-oxidative enzyme, PON1, and augmented anti-inflammatory properties and cholesterol efflux capacity of HDL ²³⁾ . In addition, the EPA-enriched HDL particles exhibit cardioprotective properties via the production of anti-inflammatory lipid metabolites, resolvin E3 ²⁴⁾ . However, because the INTERLIPID study was a cross-sectional study, the authors were not able to conclude if the effect of fish-derived omega-3 fatty acids intake on HDL subclass distribution is beneficial or not against atherosclerosis. Further investigations are required to elucidate whether HDL modification induced by fish consumption actually contributes to the reduction of ASCVD incidence.

Conflict of Interest

The Division of Evidence-based Laboratory Medicine, Kobe University Graduate School of Medicine, was established by an endowment fund from the Sysmex Corporation.