High-density lipoproteins, reverse cholesterol transport and atherogenesis

Area of Science:

• Cardiovascular Science
• Lipid Metabolism

Background:

• Plasma HDL-cholesterol concentrations are inversely correlated with atherosclerotic cardiovascular disease (ASCVD) risk.
• The traditional model posits HDL's atheroprotective role via reverse cholesterol transport (RCT).
• Recent findings question the efficacy of increasing HDL-cholesterol levels and highlight HDL's functional role, particularly macrophage cholesterol efflux.

Purpose of the Study:

• To investigate the role of HDL function, specifically macrophage cholesterol efflux, in ASCVD.
• To re-evaluate the established reverse cholesterol transport model in light of new evidence.

Main Methods:

• Analysis of existing large-scale studies correlating macrophage cholesterol efflux to HDL with ASCVD.
• Review of research on the kinetics of free cholesterol (FCh) in HDL in mice and humans.
• Examination of the reversibility of FCh transfer between macrophages and HDL.

Main Results:

• Several studies support an inverse correlation between macrophage cholesterol efflux to HDL and ASCVD.
• Evidence indicates rapid clearance of free cholesterol from HDL within minutes, independent of esterification or hepatic uptake.
• The reversibility of FCh transfer suggests a potential role for HDL to macrophage FCh transfer in ASCVD pathogenesis, especially with high HDL-FCh.

Conclusions:

• The established reverse cholesterol transport model may not fully explain HDL's atheroprotective mechanisms.
• Rapid free cholesterol flux and its potential reversal warrant further investigation in the context of ASCVD.
• HDL's functional capacity, beyond cholesterol esterification and hepatic clearance, is critical for cardiovascular health.