Beyond High-density Lipoprotein-cholesterol: Unraveling the Complexity of High-density Lipoprotein Functionality

High-density lipoprotein (HDL) levels have long been inversely associated with cardiovascular disease (CVD) and are traditionally evaluated by serum HDL-cholesterol (HDL-C) levels. However, recent studies have raised doubts regarding the causal role of HDL quantity (HDL-C), drawing attention to HDL functionality. Reverse cholesterol transport (RCT) is a major anti-atherosclerotic mechanism involving ATP-binding cassette A1 (ABCA1), ATP-binding cassette G1 (ABCG1), scavenger receptor class B type I (SRB1), and regulatory factors, such as liver X receptor (LXR) and peroxisome proliferator-activated receptor gamma (PPARγ). Notably, HDL-C levels do not necessarily reflect RCT efficiency, and novel regulatory factors, such as microRNAs, endothelial lipase, and ANGPTL3, have been implicated. HDL also exhibits vasoprotective functions by enhancing nitric oxide (NO) production and modulating sphingosine-1-phosphate (S1P) signaling. Furthermore, it exerts anti-inflammatory effects by suppressing adhesion molecules, proinflammatory cytokines, and innate immune activation while modulating adaptive immune responses and attenuating tissue fibrosis. In addition, HDL influences megakaryopoiesis and platelet activation, thereby contributing to its antithrombotic properties. Despite these broad functional spectra, clinical assessments remain largely limited to cholesterol efflux capacity, and other key functional aspects have not been adequately explored. A more comprehensive understanding of HDL's pleiotropic roles, spanning lipid metabolism, vascular biology, inflammation, and hemostasis, is necessary from both the basic and clinical perspectives. Recent studies have further suggested potential roles of HDL in the central nervous system, expanding its relevance beyond cardiovascular prevention and toward broader therapeutic applications.