Indeed, cholesterol accounts for only about 20% of total HDL mass, and there is ample evidence that potentially important HDL subspecies contain little cholesterol. Alternatively, it has been argued that HDL-C shows a consistent but weak correlation with cardioprotection because the cholesterol portion of HDL does not fully reflect the functionality of all particle types in the HDL family. 10 These results are discordant with human epidemiology, leading some to conclude that HDL-C is a bystander, a nonfunctional secondary marker of a more integral beneficial pathway. 4–9 Additionally, Mendelian randomization studies have not supported the hypothesis that HDL-C is in the causal pathway of CHD. Pharmacological interventions targeting HDL-C have not produced the expected reduction in coronary events despite the 2- to 3-fold increase in HDL-C. However, this dogma has hit some major speed bumps in the last decade. This underpins the long-held assertion that HDL, as quantified by its cholesterol content, is an active cardioprotective entity. Thousands of in vitro studies have also demonstrated HDL properties that are predicted to be antiatherogenic. 3 Furthermore, numerous animal model studies have shown that raising HDL-C by infusion or overexpression of the major HDL protein, apolipoprotein AI (apoAI), reduces atherosclerosis. Indeed, the risk of CHD increases by 3% in men and 2% in women with each 1 mg/dL drop in HDL-C. LOOKING BEYOND HIGH-DENSITY LIPOPROTEIN CHOLESTEROLįrom the Framingham Heart Study in the 1970s 1 to the Atherosclerosis Risk in Communities (ARIC) study 3 decades later, 2 epidemiologic studies have consistently shown that low serum high-density lipoprotein cholesterol (HDL-C) is a strong, independent risk factor for coronary heart disease (CHD). If these particles can be isolated and their compositions and functions fully elucidated, it may become possible to manipulate the levels of these specific particles or target the protective functions to reduce the incidence of coronary heart disease. Finally, we call for more detailed studies examining the impact of T2D on specific HDL subspecies and their functions. We discuss mechanistic aspects of how insulin resistance may alter lipoprotein profiles and how this may impact the ability of HDL to mitigate both atherosclerotic disease and diabetes itself. In this review, we examine type 2 diabetes (T2D) and explore our current understanding of how obesity, insulin resistance, and hyperglycemia affect, and may be affected by, HDL subspeciation. With the advent of advanced lipid-testing techniques and methods that allow both the quantitation and recovery of individual particle populations, we are beginning to connect the functionality of HDL subspecies with chronic metabolic diseases. However, there is an evolving appreciation that this lipoprotein class is highly heterogeneous with regard to composition and functionality. Plasma cholesterol levels of high-density lipoproteins (HDL) have been associated with cardioprotection for decades.
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