Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

High-density lipoproteins, reverse cholesterol transport and atherogenesis

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

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Kannel, W. B., Castelli, W. P. & Gordon, T. Cholesterol in the prediction of atherosclerotic disease. New perspectives based on the Framingham study. Ann. Intern. Med. 90, 85–91 (1979).

    Article  CAS  PubMed  Google Scholar 

  2. Baigent, C. et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 366, 1267–1278 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Cholesterol Treatment Trialists' (CTT) Collaborators. et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 380, 581–590 (2012).

    Article  CAS  Google Scholar 

  4. Stone, N. J. & Grundy, S. M. The 2018 AHA/ACC/Multi-Society Cholesterol guidelines: Looking at past, present and future. Prog. Cardiovasc. Dis. 62, 375–383 (2019).

    Article  PubMed  Google Scholar 

  5. HPS2-THRIVE Collaborative Group. et al. Effects of extended-release niacin with laropiprant in high-risk patients. N. Engl. J. Med. 371, 203–212 (2014).

    Article  CAS  Google Scholar 

  6. AIM-HIGH Investigators. et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N. Engl. J. Med. 365, 2255–2267 (2011).

    Article  CAS  Google Scholar 

  7. Elam, M., Lovato, L. & Ginsberg, H. The ACCORD-Lipid study: implications for treatment of dyslipidemia in Type 2 diabetes mellitus. Clin. Lipidol. 6, 9–20 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. ACCORD Study Group. et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N. Engl. J. Med. 362, 1563–1574 (2010).

    Article  Google Scholar 

  9. Voight, B. F. et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet 380, 572–580 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Nicholls, S. J. et al. Effect of serial infusions of CER-001, a pre-beta high-density lipoprotein mimetic, on coronary atherosclerosis in patients following acute coronary syndromes in the CER-001 atherosclerosis regression acute coronary syndrome trial: a randomized clinical trial. JAMA Cardiol. 3, 815–822 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Nicholls, S. J. et al. Effect of infusion of high-density lipoprotein mimetic containing recombinant apolipoprotein A-I Milano on coronary disease in patients with an acute coronary syndrome in the MILANO-PILOT trial: a randomized clinical trial. JAMA Cardiol. 3, 806–814 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Covey, S. D., Krieger, M., Wang, W., Penman, M. & Trigatti, B. L. Scavenger receptor class B type I-mediated protection against atherosclerosis in LDL receptor-negative mice involves its expression in bone marrow-derived cells. Arterioscler. Thromb. Vasc. Biol. 23, 1589–1594 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Van Eck, M. et al. Differential effects of scavenger receptor BI deficiency on lipid metabolism in cells of the arterial wall and in the liver. J. Biol. Chem. 278, 23699–23705 (2003).

    Article  PubMed  CAS  Google Scholar 

  14. Moore, K. J., Sheedy, F. J. & Fisher, E. A. Macrophages in atherosclerosis: a dynamic balance. Nat. Rev. Immunol. 13, 709–721 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Madsen, C. M., Varbo, A. & Nordestgaard, B. G. Extreme high high-density lipoprotein cholesterol is paradoxically associated with high mortality in men and women: two prospective cohort studies. Eur. Heart J. 38, 2478–2486 (2017).

    Article  CAS  PubMed  Google Scholar 

  16. Ko, D. T. et al. High-density lipoprotein cholesterol and cause-specific mortality in individuals without previous cardiovascular conditions: The CANHEART study. J. Am. Coll. Cardiol. 68, 2073–2083 (2016).

    Article  CAS  PubMed  Google Scholar 

  17. Hamer, M., O’Donovan, G. & Stamatakis, E. High-density lipoprotein cholesterol and mortality: too much of a good thing? Arterioscler. Thromb. Vasc. Biol. 38, 669–672 (2018).

    Article  CAS  PubMed  Google Scholar 

  18. Hui, N., Barter, P. J., Ong, K. L. & Rye, K. A. Altered HDL metabolism in metabolic disorders: insights into the therapeutic potential of HDL. Clin. Sci. 133, 2221–2235 (2019).

    Article  CAS  Google Scholar 

  19. Miettinen, H. E., Rayburn, H. & Krieger, M. Abnormal lipoprotein metabolism and reversible female infertility in HDL receptor (SR-BI)-deficient mice. J. Clin. Invest. 108, 1717–1722 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Havel, R. J., Goldstein, J. L. & Brown, M. S. in Metabolic Control of Disease (eds Bondy, P. E. & Rosenberg, L. E.) 393–493 (Saunders Publishing, 1980).

  21. Edelstein, C., Kezdy, F. J., Scanu, A. M. & Shen, B. W. Apolipoproteins and the structural organization of plasma lipoproteins: human plasma high density lipoprotein-3. J. Lipid Res. 20, 143–153 (1979).

    Article  CAS  PubMed  Google Scholar 

  22. Huang, R. et al. Apolipoprotein A-I structural organization in high-density lipoproteins isolated from human plasma. Nat. Struct. Mol. Biol. 18, 416–422 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Li, W. H., Tanimura, M., Luo, C. C., Datta, S. & Chan, L. The apolipoprotein multigene family: biosynthesis, structure, structure-function relationships, and evolution. J. Lipid Res. 29, 245–271 (1988).

    Article  CAS  PubMed  Google Scholar 

  24. Segrest, J. P., Jackson, R. L., Morrisett, J. D. & Gotto, A. M. Jr. A molecular theory of lipid-protein interactions in the plasma lipoproteins. FEBS Lett. 38, 247–258 (1974).

    Article  CAS  PubMed  Google Scholar 

  25. Boguski, M. S., Freeman, M., Elshourbagy, N. A., Taylor, J. M. & Gordon, J. I. On computer-assisted analysis of biological sequences: proline punctuation, consensus sequences, and apolipoprotein repeats. J. Lipid Res. 27, 1011–1034 (1986).

    Article  CAS  PubMed  Google Scholar 

  26. Fielding, C. J., Shore, V. G. & Fielding, P. E. A protein cofactor of lecithin:cholesterol acyltransferase. Biochem. Biophys. Res. Commun. 46, 1493–1498 (1972).

    Article  CAS  PubMed  Google Scholar 

  27. Havel, R. J. et al. Cofactor activity of protein components of human very low density lipoproteins in the hydrolysis of triglycerides by lipoproteins lipase from different sources. Biochemistry 12, 1828–1833 (1973).

    Article  CAS  PubMed  Google Scholar 

  28. Saleheen, D. et al. Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity. Nature 544, 235–239 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Phillips, M. C. Apolipoprotein E isoforms and lipoprotein metabolism. IUBMB Life 66, 616–623 (2014).

    Article  CAS  PubMed  Google Scholar 

  30. Mehta, R., Gantz, D. L. & Gursky, O. Human plasma high-density lipoproteins are stabilized by kinetic factors. J. Mol. Biol. 328, 183–192 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Liang, H. Q., Rye, K. A. & Barter, P. J. Remodelling of reconstituted high density lipoproteins by lecithin: cholesterol acyltransferase. J. Lipid Res. 37, 1962–1970 (1996).

    Article  CAS  PubMed  Google Scholar 

  32. Kee, P., Rye, K. A., Taylor, J. L., Barrett, P. H. & Barter, P. J. Metabolism of apoA-I as lipid-free protein or as component of discoidal and spherical reconstituted HDLs: studies in wild-type and hepatic lipase transgenic rabbits. Arterioscler. Thromb. Vasc. Biol. 22, 1912–1917 (2002).

    Article  CAS  PubMed  Google Scholar 

  33. Rye, K. A., Hime, N. J. & Barter, P. J. Evidence that cholesteryl ester transfer protein-mediated reductions in reconstituted high density lipoprotein size involve particle fusion. J. Biol. Chem. 272, 3953–3960 (1997).

    Article  CAS  PubMed  Google Scholar 

  34. Settasatian, N. et al. The mechanism of the remodeling of high density lipoproteins by phospholipid transfer protein. J. Biol. Chem. 276, 26898–26905 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Rao, R., Albers, J. J., Wolfbauer, G. & Pownall, H. J. Molecular and macromolecular specificity of human plasma phospholipid transfer protein. Biochemistry 36, 3645–3653 (1997).

    Article  CAS  PubMed  Google Scholar 

  36. Lusa, S., Jauhiainen, M., Metso, J., Somerharju, P. & Ehnholm, C. The mechanism of human plasma phospholipid transfer protein-induced enlargement of high-density lipoprotein particles: evidence for particle fusion. Biochem. J. 313, 275–282 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lie, J. et al. Evaluation of phospholipid transfer protein and cholesteryl ester transfer protein as contributors to the generation of pre beta-high-density lipoproteins. Biochem. J. 360, 379–385 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Rye, K. A., Clay, M. A. & Barter, P. J. Remodelling of high density lipoproteins by plasma factors. Atherosclerosis 145, 227–238 (1999).

    Article  CAS  PubMed  Google Scholar 

  39. Marques, P. E. et al. Multimerization and retention of the scavenger receptor sr-b1 in the plasma membrane. Dev. Cell 50, 283–295.e5 (2019).

    Article  CAS  PubMed  Google Scholar 

  40. Gillard, B. K., Bassett, G. R., Gotto, A. M. Jr., Rosales, C. & Pownall, H. J. Scavenger receptor B1 (SR-B1) profoundly excludes high density lipoprotein (HDL) apolipoprotein AII as it nibbles HDL-cholesteryl ester. J. Biol. Chem. 292, 8864–8873 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Vaisar, T. et al. Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL. J. Clin. Invest. 117, 746–756 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Shah, A. S., Tan, L., Long, J. L. & Davidson, W. S. Proteomic diversity of high density lipoproteins: our emerging understanding of its importance in lipid transport and beyond. J. Lipid Res. 54, 2575–2585 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Rosenson, R. S. et al. Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport. Circulation 125, 1905–1919 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Toth, P. P. et al. High-density lipoproteins: a consensus statement from the National Lipid Association. J. Clin. Lipidol. 7, 484–525 (2013).

    Article  PubMed  Google Scholar 

  45. Rader, D. J., Alexander, E. T., Weibel, G. L., Billheimer, J. & Rothblat, G. H. The role of reverse cholesterol transport in animals and humans and relationship to atherosclerosis. J. Lipid Res. 50, S189–S194 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Blum, C. B. et al. High density lipoprotein metabolism in man. J. Clin. Invest. 60, 795–807 (1977).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Rodriguez, P. J. et al. Neo high-density lipoprotein produced by the streptococcal serum opacity factor activity against human high-density lipoproteins is hepatically removed via dual mechanisms. Biochemistry 55, 5845–5853 (2016).

    Article  CAS  PubMed  Google Scholar 

  48. Xu, B. et al. ABCA1-derived nascent high-density lipoprotein-apolipoprotein AI and lipids metabolically segregate. Arterioscler. Thromb. Vasc. Biol. 37, 2260–2270 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Macheboeuf, M. Recherches sur les phosphoaminolipides et les sterides du serum et du plasma sanguins: I. Entrainement des phospholipids, des sterols et des sterides par les diverses fractions au cours du fractionnement des proteides du serum. Bull. Soc. Chim. Biol. 223, 99 (1930).

    Google Scholar 

  50. Gofman, J. W., Young, W. & Tandy, R. Ischemic heart disease, atherosclerosis, and longevity. Circulation 34, 679–697 (1966).

    Article  CAS  PubMed  Google Scholar 

  51. Gordon, T., Castelli, W. P., Hjortland, M. C., Kannel, W. B. & Dawber, T. R. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am. J. Med. 62, 707–714 (1977).

    Article  CAS  PubMed  Google Scholar 

  52. Bays, H. E. et al. Blood pressure-lowering effects of extended-release niacin alone and extended-release niacin/laropiprant combination: a post hoc analysis of a 24-week, placebo-controlled trial in dyslipidemic patients. Clin. Ther. 31, 115–122 (2009).

    Article  CAS  PubMed  Google Scholar 

  53. No Authors Listed. Clofibrate and niacin in coronary heart disease. JAMA 231, 360–381 (1975).

    Article  Google Scholar 

  54. Frick, M. H. et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N. Engl. J. Med. 317, 1237–1245 (1987).

    Article  CAS  PubMed  Google Scholar 

  55. Robins, S. J. et al. Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial. JAMA 285, 1585–1591 (2001).

    Article  CAS  PubMed  Google Scholar 

  56. Pownall, H. J. et al. Correlation of serum triglyceride and its reduction by omega-3 fatty acids with lipid transfer activity and the neutral lipid compositions of high-density and low-density lipoproteins. Atherosclerosis 143, 285–297 (1999).

    Article  CAS  PubMed  Google Scholar 

  57. Zhong, S. et al. Increased coronary heart disease in Japanese-American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels. J. Clin. Invest. 97, 2917–2923 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Bruce, C., Sharp, D. S. & Tall, A. R. Relationship of HDL and coronary heart disease to a common amino acid polymorphism in the cholesteryl ester transfer protein in men with and without hypertriglyceridemia. J. Lipid Res. 39, 1071–1078 (1998).

    Article  CAS  PubMed  Google Scholar 

  59. Barter, P. J. et al. Effects of torcetrapib in patients at high risk for coronary events. N. Engl. J. Med. 357, 2109–2122 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Williams, S. A. et al. Improving assessment of drug safety through proteomics: early detection and mechanistic characterization of the unforeseen harmful effects of torcetrapib. Circulation 137, 999–1010 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Schwartz, G. G. et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N. Engl. J. Med. 367, 2089–2099 (2012).

    Article  CAS  PubMed  Google Scholar 

  62. Lincoff, A. M. et al. Evacetrapib and cardiovascular outcomes in high-risk vascular disease. N. Engl. J. Med. 376, 1933–1942 (2017).

    Article  PubMed  Google Scholar 

  63. HPS3/TIMI55–REVEAL Collaborative Group. et al. Effects of anacetrapib in patients with atherosclerotic vascular disease. N. Engl. J. Med. 377, 1217–1227 (2017).

    Article  Google Scholar 

  64. Tall, A. R. & Rader, D. J. Trials and tribulations of CETP inhibitors. Circ. Res. 122, 106–112 (2018).

    Article  CAS  PubMed  Google Scholar 

  65. Kuwano, T. et al. Overexpression and deletion of phospholipid transfer protein reduce HDL mass and cholesterol efflux capacity but not macrophage reverse cholesterol transport. J. Lipid Res. 58, 731–741 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Gotto, A. M. Jr. Establishing the benefit of statins in low-to-moderate–risk primary prevention: the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Atheroscler. Suppl. 8, 3–8 (2007).

    CAS  PubMed  Google Scholar 

  67. Carew, T. E. Role of biologically modified low-density lipoprotein in atherosclerosis. Am. J. Cardiol. 64, 18G–22G (1989).

    Article  CAS  PubMed  Google Scholar 

  68. Sawayama, Y., Maeda, S., Ohnishi, H., Okada, K. & Hayashi, J. Effect of probucol on elderly hypercholesterolemic patients in the FAST study. Fukuoka Igaku Zasshi 97, 15–24 (2006).

    PubMed  Google Scholar 

  69. Thun, M. J. et al. Alcohol consumption and mortality among middle-aged and elderly U.S. adults. N. Engl. J. Med. 337, 1705–1714 (1997).

    Article  CAS  PubMed  Google Scholar 

  70. Hartung, G. H., Lawrence, S. J., Reeves, R. S. & Foreyt, J. P. Effect of alcohol and exercise on postprandial lipemia and triglyceride clearance in men. Atherosclerosis 100, 33–40 (1993).

    Article  CAS  PubMed  Google Scholar 

  71. Rauramaa, R. et al. Effects of aerobic physical exercise on inflammation and atherosclerosis in men: the DNASCO study: a six-year randomized, controlled trial. Ann. Intern. Med. 140, 1007–1014 (2004).

    Article  PubMed  Google Scholar 

  72. Ge, H. et al. Activation of G protein-coupled receptor 43 in adipocytes leads to inhibition of lipolysis and suppression of plasma free fatty acids. Endocrinology 149, 4519–4526 (2008).

    Article  CAS  PubMed  Google Scholar 

  73. Nilsson, N. O. & Belfrage, P. Effects of acetate, acetaldehyde, and ethanol on lipolysis in isolated rat adipocytes. J. Lipid Res. 19, 737–741 (1978).

    Article  CAS  PubMed  Google Scholar 

  74. Mineo, C. & Shaul, P. W. Regulation of signal transduction by HDL. J. Lipid Res. 54, 2315–2324 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Stocker, R. & Keaney, J. F. Jr. Role of oxidative modifications in atherosclerosis. Physiol. Rev. 84, 1381–1478 (2004).

    Article  CAS  PubMed  Google Scholar 

  76. Quinn, M. T., Parthasarathy, S., Fong, L. G. & Steinberg, D. Oxidatively modified low density lipoproteins: a potential role in recruitment and retention of monocyte/macrophages during atherogenesis. Proc. Natl Acad. Sci. USA 84, 2995–2998 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Barreto, J., Karathanasis, S. K., Remaley, A. & Sposito, A. C. Role of LOX-1 (lectin-like oxidized low-density lipoprotein receptor 1) as a cardiovascular risk predictor: mechanistic insight and potential clinical use. Arterioscler. Thromb. Vasc. Biol. 41, 153–166 (2021).

    CAS  PubMed  Google Scholar 

  78. Yoshida, H., Kondratenko, N., Green, S., Steinberg, D. & Quehenberger, O. Identification of the lectin-like receptor for oxidized low-density lipoprotein in human macrophages and its potential role as a scavenger receptor. Biochem. J. 334, 9–13 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Steinberg, D. & Witztum, J. L. Oxidized low-density lipoprotein and atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 30, 2311–2316 (2010).

    Article  CAS  PubMed  Google Scholar 

  80. Brooks, C. J., Steel, G., Gilbert, J. D. & Harland, W. A. Lipids of human atheroma. 4. Characterisation of a new group of polar sterol esters from human atherosclerotic plaques. Atherosclerosis 13, 223–237 (1971).

    Article  CAS  PubMed  Google Scholar 

  81. Brown, M. S. & Goldstein, J. L. Receptor-mediated endocytosis: insights from the lipoprotein receptor system. Proc. Natl Acad. Sci. USA 76, 3330–3337 (1979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Parthasarathy, S., Barnett, J. & Fong, L. G. High-density lipoprotein inhibits the oxidative modification of low-density lipoprotein. Biochim. Biophys. Acta 1044, 275–283 (1990).

    Article  CAS  PubMed  Google Scholar 

  83. Roche, M., Rondeau, P., Singh, N. R., Tarnus, E. & Bourdon, E. The antioxidant properties of serum albumin. FEBS Lett. 582, 1783–1787 (2008).

    Article  CAS  PubMed  Google Scholar 

  84. Lonn, M. E., Dennis, J. M. & Stocker, R. Actions of “antioxidants” in the protection against atherosclerosis. Free Radic. Biol. Med. 53, 863–884 (2012).

    Article  CAS  PubMed  Google Scholar 

  85. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360, 23–33 (2002).

    Article  Google Scholar 

  86. Swertfeger, D. K. et al. Feasibility of a plasma bioassay to assess oxidative protection of low-density lipoproteins by high-density lipoproteins. J. Clin. Lipidol. 12, 1539–1548 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Yvan-Charvet, L. et al. Combined deficiency of ABCA1 and ABCG1 promotes foam cell accumulation and accelerates atherosclerosis in mice. J. Clin. Invest. 117, 3900–3908 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Zhu, X. et al. Increased cellular free cholesterol in macrophage-specific Abca1 knock-out mice enhances pro-inflammatory response of macrophages. J. Biol. Chem. 283, 22930–22941 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Tang, C., Liu, Y., Kessler, P. S., Vaughan, A. M. & Oram, J. F. The macrophage cholesterol exporter ABCA1 functions as an anti-inflammatory receptor. J. Biol. Chem. 284, 32336–32343 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Khera, A. V. et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N. Engl. J. Med. 364, 127–135 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Rohatgi, A. et al. HDL cholesterol efflux capacity and incident cardiovascular events. N. Engl. J. Med. 371, 2383–2393 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Guerin, M. et al. Association of serum cholesterol efflux capacity with mortality in patients with st-segment elevation myocardial infarction. J. Am. Coll. Cardiol. 72, 3259–3269 (2018).

    Article  PubMed  Google Scholar 

  93. Soria-Florido, M. T. et al. Dysfunctional high-density lipoproteins are associated with a greater incidence of acute coronary syndrome in a population at high cardiovascular risk: a nested case-control study. Circulation 141, 444–453 (2020).

    Article  CAS  PubMed  Google Scholar 

  94. Li, X. M. et al. Paradoxical association of enhanced cholesterol efflux with increased incident cardiovascular risks. Arterioscler. Thromb. Vasc. Biol. 33, 1696–1705 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Khera, A. V. & Rader, D. J. Cholesterol efflux capacity: full steam ahead or a bump in the road? Arterioscler. Thromb. Vasc. Biol. 33, 1449–1451 (2013).

    Article  CAS  PubMed  Google Scholar 

  96. Vasudevan, M. et al. Modest diet-induced weight loss reduces macrophage cholesterol efflux to plasma of patients with metabolic syndrome. J. Clin. Lipidol. 7, 661–670 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Mutharasan, R. K. et al. HDL efflux capacity, HDL particle size, and high-risk carotid atherosclerosis in a cohort of asymptomatic older adults: the Chicago Healthy Aging Study. J. Lipid Res. 58, 600–606 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Josefs, T. et al. High-density lipoprotein cholesterol efflux capacity is not associated with atherosclerosis and prevalence of cardiovascular outcome: The CODAM study. J. Clin. Lipidol. 14, 122–132.e4 (2020).

    Article  PubMed  Google Scholar 

  99. Gillard, B. K. et al. Impaired lipoprotein processing in HIV patients on antiretroviral therapy: aberrant high-density lipoprotein lipids, stability, and function. Arterioscler. Thromb. Vasc. Biol. 33, 1714–1721 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. de la Llera-Moya, M. et al. The ability to promote efflux via ABCA1 determines the capacity of serum specimens with similar high-density lipoprotein cholesterol to remove cholesterol from macrophages. Arterioscler. Thromb. Vasc. Biol. 30, 796–801 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Picardo, M. et al. Partially reassembled high density lipoproteins. Effects on cholesterol flux, synthesis, and esterification in normal human skin fibroblasts. Arteriosclerosis 6, 434–441 (1986).

    Article  CAS  PubMed  Google Scholar 

  102. Johnson, W. J., Mahlberg, F. H., Rothblat, G. H. & Phillips, M. C. Cholesterol transport between cells and high-density lipoproteins. Biochim. Biophys. Acta 1085, 273–298 (1991).

    Article  CAS  PubMed  Google Scholar 

  103. Feng, M. et al. Free cholesterol transfer to high-density lipoprotein (HDL) upon triglyceride lipolysis underlies the U-shape relationship between HDL-cholesterol and cardiovascular disease. Eur. J. Prev. Cardiol. 27, 1606–1616 (2020).

    Article  PubMed  Google Scholar 

  104. Hoang, A. et al. Mechanism of cholesterol efflux in humans after infusion of reconstituted high-density lipoprotein. Eur. Heart J. 33, 657–665 (2012).

    Article  CAS  PubMed  Google Scholar 

  105. Teng, B., Sniderman, A. D., Soutar, A. K. & Thompson, G. R. Metabolic basis of hyperapobetalipoproteinemia. Turnover of apolipoprotein B in low density lipoprotein and its precursors and subfractions compared with normal and familial hypercholesterolemia. J. Clin. Invest. 77, 663–672 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Schwartz, C. C., Halloran, L. G., Vlahcevic, Z. R., Gregory, D. H. & Swell, L. Preferential utilization of free cholesterol from high-density lipoproteins for biliary cholesterol secretion in man. Science 200, 62–64 (1978).

    Article  CAS  PubMed  Google Scholar 

  107. Lund-Katz, S., Hammerschlag, B. & Phillips, M. C. Kinetics and mechanism of free cholesterol exchange between human serum high- and low-density lipoproteins. Biochemistry 21, 2964–2969 (1982).

    Article  CAS  PubMed  Google Scholar 

  108. Halloran, L. G., Schwartz, C. C., Vlahcevic, Z. R., Nisman, R. M. & Swell, L. Evidence for high-density lipoprotein-free cholesterol as the primary precursor for bile-acid synthesis in man. Surgery 84, 1–7 (1978).

    CAS  PubMed  Google Scholar 

  109. Schwartz, C. C., VandenBroek, J. M. & Cooper, P. S. Lipoprotein cholesteryl ester production, transfer, and output in vivo in humans. J. Lipid Res. 45, 1594–1607 (2004).

    Article  CAS  PubMed  Google Scholar 

  110. Ji, Y. et al. Hepatic scavenger receptor BI promotes rapid clearance of high density lipoprotein free cholesterol and its transport into bile. J. Biol. Chem. 274, 33398–33402 (1999).

    Article  CAS  PubMed  Google Scholar 

  111. van der Velde, A. E. et al. Regulation of direct transintestinal cholesterol excretion in mice. Am. J. Physiol. Gastrointest. Liver Physiol. 295, G203–G208 (2008).

    Article  PubMed  CAS  Google Scholar 

  112. Cedo, L. et al. LDL receptor regulates the reverse transport of macrophage-derived unesterified cholesterol via concerted action of the HDL-LDL axis: insight from mouse models. Circ. Res. 127, 778–792 (2020).

    Article  CAS  PubMed  Google Scholar 

  113. Bowe, B. et al. High density lipoprotein cholesterol and the risk of all-cause mortality among U.S. Veterans. Clin. J. Am. Soc. Nephrol. 11, 1784–1793 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Grundy, S. M. et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 112, 2735–2752 (2005).

    Article  PubMed  Google Scholar 

  115. Agarwala, A. P. et al. High-density lipoprotein (HDL) phospholipid content and cholesterol efflux capacity are reduced in patients with very high HDL cholesterol and coronary disease. Arterioscler. Thromb. Vasc. Biol. 35, 1515–1519 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Dole, V. S. et al. Thrombocytopenia and platelet abnormalities in high-density lipoprotein receptor-deficient mice. Arterioscler. Thromb. Vasc. Biol. 28, 1111–1116 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Holm, T. M. et al. Failure of red blood cell maturation in mice with defects in the high-density lipoprotein receptor SR-BI. Blood 99, 1817–1824 (2002).

    Article  CAS  PubMed  Google Scholar 

  118. Braun, A. et al. Loss of SR-BI expression leads to the early onset of occlusive atherosclerotic coronary artery disease, spontaneous myocardial infarctions, severe cardiac dysfunction, and premature death in apolipoprotein E-deficient mice. Circ. Res. 90, 270–276 (2002).

    Article  CAS  PubMed  Google Scholar 

  119. Huszar, D. et al. Increased LDL cholesterol and atherosclerosis in LDL receptor-deficient mice with attenuated expression of scavenger receptor B1. Arterioscler. Thromb. Vasc. Biol. 20, 1068–1073 (2000).

    Article  CAS  PubMed  Google Scholar 

  120. Trigatti, B. et al. Influence of the high density lipoprotein receptor SR-BI on reproductive and cardiovascular pathophysiology. Proc. Natl Acad. Sci. USA 96, 9322–9327 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Ma, K., Forte, T., Otvos, J. D. & Chan, L. Differential additive effects of endothelial lipase and scavenger receptor-class B type I on high-density lipoprotein metabolism in knockout mouse models. Arterioscler. Thromb. Vasc. Biol. 25, 149–154 (2005).

    Article  CAS  PubMed  Google Scholar 

  122. Thuahnai, S. T., Lund-Katz, S., Williams, D. L. & Phillips, M. C. Scavenger receptor class B, type I-mediated uptake of various lipids into cells. Influence of the nature of the donor particle interaction with the receptor. J. Biol. Chem. 276, 43801–43808 (2001).

    Article  CAS  PubMed  Google Scholar 

  123. Rigotti, A. et al. A targeted mutation in the murine gene encoding the high density lipoprotein (HDL) receptor scavenger receptor class B type I reveals its key role in HDL metabolism. Proc. Natl Acad. Sci. USA 94, 12610–12615 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Thacker, S. G. et al. Increased plasma cholesterol esterification by LCAT reduces diet-induced atherosclerosis in SR-BI knockout mice. J. Lipid Res. 56, 1282–1295 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Braun, A. et al. Probucol prevents early coronary heart disease and death in the high-density lipoprotein receptor SR-BI/apolipoprotein E double knockout mouse. Proc. Natl Acad. Sci. USA 100, 7283–7288 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Rosales, C., Tang, D., Gillard, B. K., Courtney, H. S. & Pownall, H. J. Apolipoprotein E mediates enhanced plasma high-density lipoprotein cholesterol clearance by low-dose streptococcal serum opacity factor via hepatic low-density lipoprotein receptors in vivo. Arterioscler. Thromb. Vasc. Biol. 31, 1834–1841 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Matyus, S. P. et al. HDL particle number measured on the Vantera(R), the first clinical NMR analyzer. Clin. Biochem. 48, 148–155 (2015).

    Article  CAS  PubMed  Google Scholar 

  128. Franceschini, G., Sirtori, C. R., Capurso, A. 2nd, Weisgraber, K. H. & Mahley, R. W. A-IMilano apoprotein. Decreased high density lipoprotein cholesterol levels with significant lipoprotein modifications and without clinical atherosclerosis in an Italian family. J. Clin. Invest. 66, 892–900 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Rader, D. J. Lecithin: cholesterol acyltransferase and atherosclerosis: another high-density lipoprotein story that doesn’t quite follow the script. Circulation 120, 549–552 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Davidson, W. S. et al. Effects of acceptor particle size on the efflux of cellular free cholesterol. J. Biol. Chem. 270, 17106–17113 (1995).

    Article  CAS  PubMed  Google Scholar 

  131. Johnson, W. J. et al. The bidirectional flux of cholesterol between cells and lipoproteins. Effects of phospholipid depletion of high density lipoprotein. J. Biol. Chem. 261, 5766–5776 (1986).

    Article  CAS  PubMed  Google Scholar 

  132. Phillips, M. C., Johnson, W. J. & Rothblat, G. H. Mechanisms and consequences of cellular cholesterol exchange and transfer. Biochim. Biophys. Acta 906, 223–276 (1987).

    Article  CAS  PubMed  Google Scholar 

  133. Orekhov, A. N. et al. Artificial HDL as an anti-atherosclerotic drug. Lancet 2, 1149–1150 (1984).

    Article  CAS  PubMed  Google Scholar 

  134. Tchoua, U., Gillard, B. K. & Pownall, H. J. HDL superphospholipidation enhances key steps in reverse cholesterol transport. Atherosclerosis 209, 430–435 (2010).

    Article  CAS  PubMed  Google Scholar 

  135. Newton, R. S. & Krause, B. R. HDL therapy for the acute treatment of atherosclerosis. Atheroscler. Suppl. 3, 31–38 (2002).

    Article  CAS  PubMed  Google Scholar 

  136. Pownall, H. J., Van Winkle, W. B., Pao, Q., Rohde, M. & Gotto, A. M. Jr. Action of lecithin:cholesterol acyltransferase on model lipoproteins. Preparation and characterization of model nascent high density lipoprotein. Biochim. Biophys. Acta 713, 494–503 (1982).

    Article  CAS  PubMed  Google Scholar 

  137. Matz, C. E. & Jonas, A. Micellar complexes of human apolipoprotein A-I with phosphatidylcholines and cholesterol prepared from cholate-lipid dispersions. J. Biol. Chem. 257, 4535–4540 (1982).

    Article  CAS  PubMed  Google Scholar 

  138. Chen, C. H. & Albers, J. J. Characterization of proteoliposomes containing apoprotein A-I: a new substrate for the measurement of lecithin: cholesterol acyltransferase activity. J. Lipid Res. 23, 680–691 (1982).

    Article  CAS  PubMed  Google Scholar 

  139. Lerch, P. G., Fortsch, V., Hodler, G. & Bolli, R. Production and characterization of a reconstituted high density lipoprotein for therapeutic applications. Vox Sang. 71, 155–164 (1996).

    Article  CAS  PubMed  Google Scholar 

  140. Tardif, J. C. et al. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. JAMA 297, 1675–1682 (2007).

    Article  PubMed  Google Scholar 

  141. Diditchenko, S. et al. Novel formulation of a reconstituted high-density lipoprotein (CSL112) dramatically enhances ABCA1-dependent cholesterol efflux. Arterioscler. Thromb. Vasc. Biol. 33, 2202–2211 (2013).

    Article  CAS  PubMed  Google Scholar 

  142. Herzog, E. et al. Reconstituted high-density lipoprotein can elevate plasma alanine aminotransferase by transient depletion of hepatic cholesterol: role of the phospholipid component. J. Appl. Toxicol. 36, 1038–1047 (2016).

    Article  CAS  PubMed  Google Scholar 

  143. Gille, A., D’Andrea, D., Tortorici, M. A., Hartel, G. & Wright, S. D. CSL112 (Apolipoprotein A-I [Human]) enhances cholesterol efflux similarly in healthy individuals and stable atherosclerotic disease patients. Arterioscler. Thromb. Vasc. Biol. 38, 953–963 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Pownall, H. J., Hu, A., Gotto, A. M. Jr., Albers, J. J. & Sparrow, J. T. Activation of lecithin:cholesterol acyltransferase by a synthetic model lipid-associating peptide. Proc. Natl Acad. Sci. USA 77, 3154–3158 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Gomaraschi, M. et al. Anti-inflammatory and cardioprotective activities of synthetic high-density lipoprotein containing apolipoprotein A-I mimetic peptides. J. Pharmacol. Exp. Ther. 324, 776–783 (2008).

    Article  CAS  PubMed  Google Scholar 

  146. Sviridov, D. O., Drake, S. K., Freeman, L. A. & Remaley, A. T. Amphipathic polyproline peptides stimulate cholesterol efflux by the ABCA1 transporter. Biochem. Biophys. Res. Commun. 471, 560–565 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Amar, M. J. et al. 5A apolipoprotein mimetic peptide promotes cholesterol efflux and reduces atherosclerosis in mice. J. Pharmacol. Exp. Ther. 334, 634–641 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Kilsdonk, E. P. et al. Cellular cholesterol efflux mediated by cyclodextrins. J. Biol. Chem. 270, 17250–17256 (1995).

    Article  CAS  PubMed  Google Scholar 

  149. Atger, V. M. et al. Cyclodextrins as catalysts for the removal of cholesterol from macrophage foam cells. J. Clin. Invest. 99, 773–780 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Zimmer, S. et al. Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming. Sci. Transl. Med. 8, 333ra350 (2016).

    Article  CAS  Google Scholar 

  151. Bijsterbosch, M. K. et al. Enhanced hepatic uptake and processing of cholesterol esters from low density lipoprotein by specific lactosaminated Fab fragments. Arterioscler. Thromb. 11, 1806–1813 (1991).

    Article  CAS  PubMed  Google Scholar 

  152. Mims, M. P. et al. A nonexchangeable apolipoprotein E peptide that mediates binding to the low density lipoprotein receptor. J. Biol. Chem. 269, 20539–20547 (1994).

    Article  CAS  PubMed  Google Scholar 

  153. Sankaranarayanan, S. et al. A sensitive assay for ABCA1-mediated cholesterol efflux using BODIPY-cholesterol. J. Lipid Res. 52, 2332–2340 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Schaefer, E. J. Clinical, biochemical, and genetic features in familial disorders of high density lipoprotein deficiency. Arteriosclerosis 4, 303–322 (1984).

    Article  CAS  PubMed  Google Scholar 

  155. Simonelli, S. et al. Recombinant human LCAT normalizes plasma lipoprotein profile in LCAT deficiency. Biologicals 41, 446–449 (2013).

    Article  CAS  PubMed  Google Scholar 

  156. Calabresi, L. et al. The molecular basis of lecithin:cholesterol acyltransferase deficiency syndromes: a comprehensive study of molecular and biochemical findings in 13 unrelated Italian families. Arterioscler. Thromb. Vasc. Biol. 25, 1972–1978 (2005).

    Article  CAS  PubMed  Google Scholar 

  157. Tanigawa, H. et al. Lecithin: cholesterol acyltransferase expression has minimal effects on macrophage reverse cholesterol transport in vivo. Circulation 120, 160–169 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Tanigawa, H. et al. Expression of cholesteryl ester transfer protein in mice promotes macrophage reverse cholesterol transport. Circulation 116, 1267–1273 (2007).

    Article  CAS  PubMed  Google Scholar 

  159. Alaupovic, P., Schaefer, E. J., McConathy, W. J., Fesmire, J. D. & Brewer, H. B. Jr. Plasma apolipoprotein concentrations in familial apolipoprotein A-I and A-II deficiency (Tangier disease). Metabolism 30, 805–809 (1981).

    Article  CAS  PubMed  Google Scholar 

  160. Serfaty-Lacrosniere, C. et al. Homozygous Tangier disease and cardiovascular disease. Atherosclerosis 107, 85–98 (1994).

    Article  CAS  PubMed  Google Scholar 

  161. Frikke-Schmidt, R. et al. Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease. JAMA 299, 2524–2532 (2008).

    Article  CAS  PubMed  Google Scholar 

  162. Brousseau, M. E. et al. Common variants in the gene encoding ATP-binding cassette transporter 1 in men with low HDL cholesterol levels and coronary heart disease. Atherosclerosis 154, 607–611 (2001).

    Article  CAS  PubMed  Google Scholar 

  163. Santos, R. D. et al. Characterization of high density lipoprotein particles in familial apolipoprotein A-I deficiency. J. Lipid Res. 49, 349–357 (2008).

    Article  CAS  PubMed  Google Scholar 

  164. Zanoni, P. et al. Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. Science 351, 1166–1171 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  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

Authors
  1. Henry J. Pownall
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Corina Rosales
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Baiba K. Gillard
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Antonio M. Gotto Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed substantially to all aspects of the article.

Corresponding authors

Correspondence to Henry J. Pownall or Antonio M. Gotto Jr.

Ethics declarations

Competing interests

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.

Additional information

Peer review information

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.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41569-021-00538-z

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing