HDL and apoB: physiological and pathophysiological intersections and interactions

To reexamine why high-density lipoprotein cholesterol (HDL-C) has been widely dismissed as a causal factor for atherosclerotic cardiovascular disease (ASCVD) and to point to evidence of interactions between HDL particles and apolipoprotein B (apoB) that may modify risk.

Notwithstanding the epidemiological evidence of a potent inverse relation between HDL-C and ASCVD risk, neither Mendelian randomization analyses nor randomized clinical trials with multiple classes of agents have confirmed a causal connection. However, this assumes HDL-C is a valid physiological entity, which it is not. HDL-C is a construct, the arithmetic sum of the cholesterol within the HDL particles. Cholesterol is only one constituent of these particles and, at most, cholesterol is a physiological product whereas other elements in the particle would be the physiological actors. HDL-C is only a surrogate for HDL particles. The relation of HDL-C to ASCVD risk persists after triglycerides are accounted for. Evidence of a potentially positive clinical interaction between HDL-C and apoB will be identified.

HDL-C is a useful clinical and research tool but not a biological entity. Any putative biological property of HDL must relate to a specific class or classes of HDL particles. However, HDL-C remains a valid tool to assess the risk of ASCVD.