HDL Cholesterol Efflux Capacity: Cardiovascular Risk Factor and Potential Therapeutic Target

Abstract

Low high-density lipoprotein cholesterol (HDL-C) levels are associated with incident cardiovascular events; however, many therapies targeting increases in HDL-C have failed to show consistent clinical benefit. Thus, focus has recently shifted toward measuring high-density lipoprotein (HDL) function. HDL is the key mediator of reverse cholesterol transport, the process of cholesterol extraction from foam cells, and eventual excretion into the biliary system. Cholesterol efflux from peripheral macrophages to HDL particles has been associated with atherosclerosis in both animals and humans. We review the mechanism of cholesterol efflux and the emerging evidence on the association between cholesterol efflux capacity and cardiovascular disease in human studies. We also focus on the completed and ongoing trials of novel therapies targeting different aspects of HDL cholesterol efflux.

HDL cholesterol efflux capacity in rheumatoid arthritis patients: contributing factors and relationship with subclinical atherosclerosis

“…In this sense, traditional risk factors reportedly explain only 3% of the variance observed in CEC [8]. Moreover, glucose tolerance status does not appear to impact CEC [28], and CEC cannot be explained by HDL cholesterol or apolipoprotein A-I levels [29]. Similarly, we did not find any association of statins with CEC in patients and control subjects.…”

Relation of High‐Density Lipoprotein Charge Heterogeneity, Cholesterol Efflux Capacity, and the Expression of High‐Density Lipoprotein‐Related Genes in Mononuclear Cells to the HDL‐Cholesterol Level

“…First, several studies have shown an inverse association between the efficiency of patient plasma as a cholesterol acceptor in cholesterol efflux with the manifestation of various cardiovascular events. Cholesterol efflux capacity (CEC) of apoB‐depleted serum or plasma, measured in these studies, was a better predictor of CV events than HDL‐cholesterol (HDL‐C) (Bhatt and Rohatgi, ; Ogura et al, ; Rohatgi, ; Saleheen et al, ). Second, stimulation of the efflux resulted in the regression of atherosclerotic lesions (Bhatt and Rohatgi, ; Chyu and Shah, ; Fisher et al, ).…”

“…Cholesterol efflux capacity (CEC) of apoB‐depleted serum or plasma, measured in these studies, was a better predictor of CV events than HDL‐cholesterol (HDL‐C) (Bhatt and Rohatgi, ; Ogura et al, ; Rohatgi, ; Saleheen et al, ). Second, stimulation of the efflux resulted in the regression of atherosclerotic lesions (Bhatt and Rohatgi, ; Chyu and Shah, ; Fisher et al, ). Despite the primary role of lipid‐free/lipid‐poor apoA‐I with preβ 1 ‐mobility in cholesterol efflux from macrophages, the atheroprotective significance of preβ 1 ‐HDL remains controversial.…”

Human macrophage cathepsin β‐mediated C‐terminal cleavage of apolipoprotein α‐I at Ser228severely impairs antiatherogenic capacity

“…However, to our knowledge, there have been no reports investigating proteolytic cleavage of apoA‐I by primary human macrophages during physiological exposure, as occurs during cholesterol efflux, or its functional consequences. Such investigations are crucial, as several studies have emerged highlighting that improvement of HDL functionality may be more important than solely increasing HDL cholesterol levels to reduce CAD risk, as reviewed recently (20, 21).…”