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High-density lipoproteins, reverse cholesterol transport and atherogenesis

Nature Reviews Cardiology volume 18, pages 712–723 (2021)Cite this article

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Abstract

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.

Key points

  • High plasma HDL-cholesterol concentrations and the esterification of free cholesterol (FCh) contained in HDL are central to traditional models of reverse cholesterol transport and prevention of atherosclerotic cardiovascular disease (ASCVD).

  • Interventions that increase plasma HDL-cholesterol concentrations do not reduce ASCVD, and most FCh in HDL is hepatically extracted without esterification.

  • Studies on the relationship between macrophage cholesterol efflux, plasma HDL concentrations and ASCVD have been contradictory.

  • In mouse models and humans with dysregulated HDL metabolism, a high bioavailability of FCh in HDL correlates with ASCVD; differences in HDL–FCh bioavailability might underlie the disparate findings on the role of macrophage cholesterol efflux in ASCVD.

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Fig. 1: Simplified structure and dynamics of HDL.
Fig. 2: Traditional LCAT-centric model of reverse cholesterol transport.
Fig. 3: Updated model of the metabolism of FCh from HDL.

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Acknowledgements

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.

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  1. Center for Bioenergetics, Department of Medicine, Houston Methodist Research Institute, Houston, TX, USA

    Henry J. Pownall, Corina Rosales & Baiba K. Gillard

  2. Weill Cornell Medicine, New York, NY, USA

    Antonio M. Gotto Jr

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A.M.G. is a member of the board at Esperion Therapeutics, a consultant for Kowa and a member of the Data Safety Monitoring Board at Ionis Pharmaceuticals. The other authors declare no competing interests.

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Nature Reviews Cardiology thanks J. C. Escola-Gil, M. Jauhianen, D. Sviridov and A. von Eckardstein for their contribution to the peer review of this work.

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Pownall, H.J., Rosales, C., Gillard, B.K. et al. High-density lipoproteins, reverse cholesterol transport and atherogenesis. Nat Rev Cardiol 18, 712–723 (2021). https://doi.org/10.1038/s41569-021-00538-z

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