Cholesterol efflux pathways, inflammation, and atherosclerosis

Plasma levels of high-density lipoprotein (HDL) inversely correlate with the incidence of cardiovascular diseases (CVD). The causal relationship between plasma HDL-cholesterol levels and CVD has been called into question by Mendelian randomization studies and the majority of clinical trials not showing any benefit of plasma HDL-cholesterol raising drugs on CVD. Nonetheless, recent Mendelian randomization studies including an increased number of CVD cases compared to earlier studies have confirmed that HDL-cholesterol levels and CVD are causally linked. Moreover, several studies in large population cohorts have shown that the cholesterol efflux capacity of HDL inversely correlates with CVD. Cholesterol efflux pathways exert anti-inflammatory and anti-atherogenic effects by suppressing proliferation of hematopoietic stem and progenitor cells, and inflammation and inflammasome activation in macrophages. Cholesterol efflux pathways also suppress the accumulation of cholesteryl esters in macrophages, i.e. macrophage foam cell formation. Recent single-cell RNASeq studies on atherosclerotic plaques have suggested that macrophage foam cells have lower expression of inflammatory genes than non-foam cells, probably reflecting liver X receptor activation, upregulation of ATP Binding Cassette A1 and G1 cholesterol transporters and suppression of inflammation. However, when these pathways are defective lesional foam cells may become pro-inflammatory.