HDL-C vs HDL-P: How Changing One Letter Could Make a Difference in Understanding the Role of High-Density Lipoprotein in Disease

Before about 2006, most papers focusing on high-density lipoprotein (HDL)2 contained an introductory sentence that touted its protective role against cardiovascular disease (CVD), usually via the reverse transport of cholesterol away from the vessel wall. This was based on a mountain of epidemiological evidence showing an inverse correlation between plasma concentrations of HDL cholesterol (HDL-C) and CVD as well as thousands of in vitro and animal model studies demonstrating the cholesterol-carrying capacity of the particles. More recently, however, confidence in a direct atheroprotective role for HDL has wavered. HDL-targeted drugs such as niacin and 2 different cholesteryl ester transfer protein (CETP) inhibitors have failed in clinical trials, despite raising HDL-C (nicely reviewed in (1)). Furthermore, recent Mendelian randomization analyses suggest that genetic anomalies that raise HDL-C fail to impart the CVD protections predicted by epidemiologic findings (2). This has prompted some to regard HDL as a marker or byproduct of other, more directly atheroprotective, mechanisms. On the other hand, large studies have shown that the cholesterol efflux capacity of primarily HDL-containing [i.e., low-density lipoprotein (LDL)-depleted] serum is a robust predictor of CVD, even better than HDL-C (3), suggesting that HDL's mobilization of cellular cholesterol may indeed be atheroprotective. So why has it been so difficult to determine whether HDL plays a direct protective role in CVD? Some argue that the picture has been clouded by the way HDL has been traditionally quantified. The HDL-C measurement targets only a single HDL component, and a relatively minor one at that: a maximum of 20% of HDL mass is cholesterol or its ester. Ideally, one would like to know the actual number of HDL particles (HDL-P) circulating in plasma, not simply how much cholesterol they are carrying. This is a relatively easy determination for LDL. Because each particle contains a single copy …