High-Density Lipoprotein Function in Cardiovascular Disease and Diabetes Mellitus

Abstract

e10C ardiovascular disease (CVD) is the most common cause of death worldwide.1 Major CVD risk factors are hypertension, smoking, physical inactivity, abnormal glucose levels/diabetes mellitus, and dyslipidemia. Among these, dyslipidemia characterized by a low level of HDL-C (high-density lipoprotein cholesterol) is strongly and inversely correlated with CVD risk, 2-4 and low HDL-C levels is part of the atherogenic dyslipidemia complex associated with diabetes mellitus.5 These observations triggered intense interest in increasing HDL-C levels for therapeutic intervention of CVD.6,7 However, several recent lines of evidence now suggest that the association between HDL-C levels and CVD status may be indirect or more complicated than previously recognized. 7 Thus, human genetic studies demonstrate that genetically altered HDL-C levels do not necessarily translate to an altered risk of CVD. [8][9][10][11][12] Phase III clinical trials of drugs that elevate HDL-C, such as niacin and CETP (cholesteryl ester transfer protein) inhibitors, also have largely failed to reduce CVD events in statin-treated subjects with established CVD. [13][14][15] For several CETP inhibitors, improvement in CVD prevention was unsuccessful because of off-target effects (torcetrapib) or lack of efficacy (dalcetrapib and evacetrapib). 14,[16][17][18] The exception is the recent REVEAL trial (Randomized Evaluation of the Effects of Anacetrapib Through Lipid-Modification), which included more subjects and was performed for longer than previous CETP inhibitor trials. The REVEAL demonstrated that the CETP inhibitor anacetrapib exhibited beneficial effects on cardiovascular outcomes on top of those of statin therapy, although the risk reduction was moderate 19,20 and might have been due, at least in part, to a reduction in non-HDL-C rather than elevated HDL-C. 21 Considering these cumulative observations, it remains uncertain whether increased HDL-C directly impacts atherosclerosis and the risk of cardiovascular events. It has become quite apparent that other metrics of HDL levels and functions, and specifically of HDL antiatherogenic functions, must be considered.HDL is a heterogeneous population of particles with sizes ranging from 7 nm to 14 nm diameter. The largest HDL particles contain the most cholesterol.22 Therefore, HDL-C levels do not always correlate with HDL particle concentration, and furthermore, do not provide information on differences in HDL subpopulations. For example, in a recent study published in ATVB, the effects of 2 different bariatric surgery procedures on HDL metrics were compared. Sleeve gastrectomy increased HDL-C levels more than did Roux-en-Y gastric bypass surgery, calculated as differences from baseline, but reduced HDL particle concentrations. 23 The increase in HDL-C was most likely a reflection of a relative increase in HDL particle size. 23Scientists are now therefore increasingly considering HDLassociated metrics other than HDL-C, such as HDL particle concentration, HDL composition, and HDL function as more like...

Coagulatory Defects in Type-1 and Type-2 Diabetes

“…However, recent evidence has shown that a low HDL concentration is associated with an increased cardiovascular risk, but that a high HDL concentration does not have a protective effect and could even be dangerous, as has been shown in the general population and in individuals with T1DM [106,116,117]. These unexpected results may be explained by the existence of different HDL subspecies with different functions [118]. Thus, it may be beneficial to directly measure HDL function, such as its role in promoting reverse cholesterol transport (the net movement of cholesterol from peripheral tissues to the liver to be excreted through the bile) [118].…”

“…These unexpected results may be explained by the existence of different HDL subspecies with different functions [118]. Thus, it may be beneficial to directly measure HDL function, such as its role in promoting reverse cholesterol transport (the net movement of cholesterol from peripheral tissues to the liver to be excreted through the bile) [118]. For example, when the macrophages present in artery walls accumulate excess cholesterol, the ATP-binding cassette transporters A1 and G1 are induced and this results in the efflux of cholesterol from the macrophages to the HDL [118].…”

“…Thus, it may be beneficial to directly measure HDL function, such as its role in promoting reverse cholesterol transport (the net movement of cholesterol from peripheral tissues to the liver to be excreted through the bile) [118]. For example, when the macrophages present in artery walls accumulate excess cholesterol, the ATP-binding cassette transporters A1 and G1 are induced and this results in the efflux of cholesterol from the macrophages to the HDL [118]. HDL efflux has been found to be a better predictor of cardiovascular disease than HDL levels [119][120][121][122], although other studies have disputed this [123][124][125][126].…”

“…This may be because reactive oxygen species, which are increased in individuals with diabetes, can impact HDL function [130]. Beyond its role in cholesterol efflux, HDL also has an anti-atherosclerotic effect as it promotes nitric oxide production in endothelial cells, an essential feature for endothelial function [118]. HDL also has anti-inflammatory and antioxidant effects [118].…”

An Ethnic Comparison of Arginine Dimethylation and Cardiometabolic Factors in Healthy Black and White Youth: The ASOS and African-PREDICT Studies

“…High-density lipoprotein (HDL) is generally considered to be anti-atherogenic and is known to prevent endothelial dysfunction [51]. Free SDMA has been reported to cause the transformation of physiological HDL to an abnormal atherogenic HDL, which reduces endothelial NO availability by enhancing endothelial superoxide production via activation of the toll-like receptor-2 (TLR-2) [52].…”