Abstract
The lipoprotein HDL has two important roles: first, it promotes reverse cholesterol transport, and second, it modulates inflammation. Epidemiological studies show that HDL-cholesterol levels are inversely correlated with the risk of cardiovascular events. However, many patients who experience a clinical event have normal, or even high, levels of HDL cholesterol. Measuring HDL-cholesterol levels provides information about the size of the HDL pool, but does not predict HDL composition or function. The main component of HDL, apolipoprotein A-I (apo A-I), is largely responsible for reverse cholesterol transport through the macrophage ATP-binding cassette transporter ABCA1. Apo A-I can be damaged by oxidative mechanisms, which render the protein less able to promote cholesterol efflux. HDL also contains a number of other proteins that are affected by the oxidative environment of the acute-phase response. Modification of the protein components of HDL can convert it from an anti-inflammatory to a proinflammatory particle. Small peptides that mimic some of the properties of apo A-I have been shown in preclinical models to improve HDL function and reduce atherosclerosis without altering HDL-cholesterol levels. Robust assays to evaluate the function of HDL are needed to supplement the measurement of HDL-cholesterol levels in the clinic.
Key Points
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HDL-cholesterol levels are inversely correlated with the risk of clinical events resulting from atherosclerosis, although many patients who experience cardiovascular events have normal, or even high, levels of HDL cholesterol
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HDL-cholesterol levels provide a measure of the size of the HDL pool, but do not predict the composition or function of HDL
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A major function of HDL is to promote cholesterol efflux and reverse cholesterol transport, which are mediated by interaction with the macrophage ATP-binding cassette transporters ABCA1 and ABCG1
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The main protein component of HDL, apolipoprotein A-I, can be damaged by oxidative mechanisms that render it less able to promote cholesterol efflux
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HDL contains several other proteins that are affected by the oxidative environment of the acute-phase response, causing HDL to change from an anti-inflammatory particle to a proinflammatory particle
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Peptides that mimic the lipid-binding properties of apolipoprotein A-I have been shown in preclinical models to improve HDL function and reduce atherosclerosis without altering HDL-cholesterol levels
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Acknowledgements
This work was supported in part by USPHS Grant HL 30568, and the Laubisch Fund and M. K. Gray Fund at UCLA.
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M. Navab and A. M. Fogelman contributed to discussion of content for the article, researched data to include in the manuscript, wrote the article, reviewed and edited the manuscript before submission, and revised the manuscript in response to the peer-reviewers' comments. S. T. Reddy and B. J. Van Lenten reviewed and edited the manuscript before submission.
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M. Navab and S. T. Reddy are principals in Bruin Pharmaceuticals, and A. M. Fogelman is an officer for Bruin Pharmaceuticals. B. J. Van Lenten declares no competing interests.
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Navab, M., Reddy, S., Van Lenten, B. et al. HDL and cardiovascular disease: atherogenic and atheroprotective mechanisms. Nat Rev Cardiol 8, 222–232 (2011). https://doi.org/10.1038/nrcardio.2010.222
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