Beginning to understand high-density lipoproteins

HDL were widely considered to be beneficial regarding CVD because there is an inversecorrelation between HDL-C levels and CVD risk, because HDL exert atheroprotectiveeffects in vitro and in animal models, and because initial proof-of-conceptstudies in humans show that infusion of HDL reduces atherosclerosis. However,recent data question HDL-C as a relevant therapeutic target because genetic andpopulation studies have not universally shown the usual inverse correlation betweenHDL-C and CVD risk, and because clinical trials have not demonstrated a reductionin CVD risk with certain HDL-related pharmacologic therapies. The main problem is that sensitive in vivo markers of HDL function are lacking. Giventhat the amount of cholesterol carried by an HDL particle is not likely to confer atheroprotection,serum HDL-C levels (or the change in them) may not be the properparameter for assessment of the contribution of HDL to CVD risk. Besides, staticmeasurements, such as HDL-C or apoA-I, do not accurately reflect a dynamic processsuch as RCT. Therefore, too much emphasis has been placed on HDL-C as a surrogatemarker of HDL metabolism/action, when in fact HDL-C is a poor marker of HDLfunction. Thus, research should focus on more sensitive markers of HDL metabolismthat truly reflect and are responsible for the actual beneficial effects of HDL, such asthe concentration of HDL-P. Finally, therapeutic strategies that increase HDL-C without expanding the pool ofHDL-P, with its rich proteome/lipidome, do not seem to be an effective strategy toreduce CVD risk. Ongoing discussion of this topic should have some impact on thebasic research about HDL metabolism and on the current and emerging therapiestargeting HDL.