HDL Particle Size and Functional Heterogeneity
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Classic clinical and epidemiological studies have long ago established the presence of an inverse relationship between high-density lipoprotein cholesterol (HDLC) levels and cardiovascular disease (CVD) risk, and thus, it was assumed that measures that increase HDLC levels would afford protection against atherosclerosis-based CVD.1,2 However, trials of drugs, such as cholesterol ester transfer protein inhibitors and niacin, have failed to provide evidence of cardiovascular benefit in patients on statin therapy, indicating that HDLC increases from 30% to 120% are not able to modify risk when low-density lipoprotein is kept very low. Moreover, genetic polymorphisms that associate with increased HDLC do not predict reduced CVD risk,3–5 and isolated low HDL does not predict risk when low-density lipoprotein and triglyceride levels are completely normal.6 Therefore, although a causal role for HDL in arterial homeostasis is still widely accepted, current discussions highlight the necessity to identify novel HDL metrics linked to CVD risk and targetable for diagnostic or therapeutic development.
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Despite the spectacular collapse of the HDLC hypothesis and the paucity of alternative strategies in the clinical space, the field as a whole has experienced a groundbreaking shift in the understanding of the basic biology and metabolism of HDL. Advances have been made in the areas of HDL functionality as it relates to particle heterogeneity, biogenesis, and variations in lipid and protein cargo.
The central functions of HDL are believed to be the ability to quell local oxidative and inflammatory events and to accept excess cholesterol from cells via specific efflux mechanisms mediated by transmembrane transporters, such as ABCA1, ABCG1 and SR-B1. The ABCA1 pathway is important in humans because lipid-laden macrophages—abundant in atherosclerotic plaques—will turn on ABCA1 gene transcription in an effort to maximize sterol losses. Our current understanding of sterol efflux …