TY - JOUR
T1 - High-density lipoproteins, reverse cholesterol transport and atherogenesis
AU - Pownall, Henry J.
AU - Rosales, Corina
AU - Gillard, Baiba K.
AU - Gotto, Antonio M.
N1 - Funding Information:
The authors are supported, in part, by grants from the NIH (HL129767 and HL149804) to H.J.P. and C.R. and by the Houston Methodist Hospital Foundation.
Publisher Copyright:
© 2021, Springer Nature Limited.
PY - 2021/10
Y1 - 2021/10
N2 - Plasma HDL-cholesterol concentrations correlate negatively with the risk of atherosclerotic cardiovascular disease (ASCVD). According to a widely cited model, HDL elicits its atheroprotective effect through its role in reverse cholesterol transport, which comprises the efflux of cholesterol from macrophages to early forms of HDL, followed by the conversion of free cholesterol (FCh) contained in HDL into cholesteryl esters, which are hepatically extracted from the plasma by HDL receptors and transferred to the bile for intestinal excretion. Given that increasing plasma HDL-cholesterol levels by genetic approaches does not reduce the risk of ASCVD, the focus of research has shifted to HDL function, especially in the context of macrophage cholesterol efflux. In support of the reverse cholesterol transport model, several large studies have revealed an inverse correlation between macrophage cholesterol efflux to plasma HDL and ASCVD. However, other studies have cast doubt on the underlying reverse cholesterol transport mechanism: in mice and humans, the FCh contained in HDL is rapidly cleared from the plasma (within minutes), independently of esterification and HDL holoparticle uptake by the liver. Moreover, the reversibility of FCh transfer between macrophages and HDL has implicated the reverse process — that is, the transfer of FCh from HDL to macrophages — in the aetiology of increased ASCVD under conditions of very high plasma HDL–FCh concentrations.
AB - Plasma HDL-cholesterol concentrations correlate negatively with the risk of atherosclerotic cardiovascular disease (ASCVD). According to a widely cited model, HDL elicits its atheroprotective effect through its role in reverse cholesterol transport, which comprises the efflux of cholesterol from macrophages to early forms of HDL, followed by the conversion of free cholesterol (FCh) contained in HDL into cholesteryl esters, which are hepatically extracted from the plasma by HDL receptors and transferred to the bile for intestinal excretion. Given that increasing plasma HDL-cholesterol levels by genetic approaches does not reduce the risk of ASCVD, the focus of research has shifted to HDL function, especially in the context of macrophage cholesterol efflux. In support of the reverse cholesterol transport model, several large studies have revealed an inverse correlation between macrophage cholesterol efflux to plasma HDL and ASCVD. However, other studies have cast doubt on the underlying reverse cholesterol transport mechanism: in mice and humans, the FCh contained in HDL is rapidly cleared from the plasma (within minutes), independently of esterification and HDL holoparticle uptake by the liver. Moreover, the reversibility of FCh transfer between macrophages and HDL has implicated the reverse process — that is, the transfer of FCh from HDL to macrophages — in the aetiology of increased ASCVD under conditions of very high plasma HDL–FCh concentrations.
KW - Animals
KW - Atherosclerosis/epidemiology
KW - Biological Transport
KW - Cholesterol/metabolism
KW - Humans
KW - Lipoproteins, HDL/blood
KW - Mice
KW - Risk Assessment
UR - http://www.scopus.com/inward/record.url?scp=85104059377&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85104059377&partnerID=8YFLogxK
U2 - 10.1038/s41569-021-00538-z
DO - 10.1038/s41569-021-00538-z
M3 - Review article
C2 - 33833449
AN - SCOPUS:85104059377
SN - 1759-5002
VL - 18
SP - 712
EP - 723
JO - Nature Reviews Cardiology
JF - Nature Reviews Cardiology
IS - 10
ER -