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Mechanisms of Disease: proatherogenic HDL—an evolving field

Nature Clinical Practice Endocrinology & Metabolism volume 2, pages 504–511 (2006)Cite this article

Abstract

It is well known that, in large populations, HDL-cholesterol levels are inversely related to the risk of atherosclerotic clinical events; however, in an individual, the predictive value of an HDL-cholesterol level is far from perfect. As a result, other HDL-associated factors have been investigated, including the quality and function of HDL in contradistinction to the level of HDL-cholesterol. Regarding their quality, HDL particles are highly heterogeneous and contain varying levels of antioxidants or pro-oxidants, which results in variation in HDL function. It has been postulated that HDL functions to promote reverse cholesterol transport. Recent studies support this role for HDL but also indicate that HDL is a modulator of systemic inflammation. In the absence of inflammation, HDL has a complement of antioxidant enzymes that work to maintain an anti-inflammatory state. In the presence of systemic inflammation, these antioxidant enzymes can be inactivated and HDL can accumulate oxidized lipids and proteins that make it proinflammatory. Under these conditions the main protein of HDL, apolipoprotein A-I, can be modified by reactive oxygen species. This modification impairs the ability of HDL to promote cholesterol efflux by the ATP-binding cassette transporter A-1 pathway. Animal studies and small-scale human studies suggest that measures of the quality and novel functions of HDL might provide an improved means of identifying subjects at increased risk for atherosclerotic events, compared with the current practice of only measuring HDL-cholesterol levels. The quality and function of HDL are also attractive targets for emerging therapies.

Key Points

  • Oxidized lipids mediate inflammatory responses in the artery wall; HDL-associated enzymes can destroy these proinflammatory oxidized lipids, but are also inhibited by them

  • Apolipoprotein A-I (apoA-I) is the main protein in HDL and is critical for promoting reverse cholesterol transport (i.e. from peripheral tissues, such as arteries, back to the liver where the excess cholesterol is excreted in the bile)

  • Oxidants produced by macrophage enzymes, such as myeloperoxidase, can damage apoA-I and reduce its ability to promote reverse cholesterol transport

  • HDL-cholesterol levels predict risk for atherosclerosis in large populations, but many individuals with clinical events due to atherosclerosis have normal or even high HDL-cholesterol levels

  • HDL is anti-inflammatory in the absence of inflammation but can become proinflammatory in the presence of a systemic inflammation (such as atherosclerosis) because of the damage to HDL (specifically, apoA-I and HDL-associated enzymes) caused by the oxidants produced in the inflammatory reaction

  • Novel therapies are being tested that will raise HDL-cholesterol levels and/or improve the anti-inflammatory properties of HDL

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Acknowledgements

This work was supported by NIH grants HL-30568 to AM Fogelman, HL-34343 to GM Anantharamaiah, and the Laubisch, Castera, and MK Grey Funds at UCLA to AM Fogelman.

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Authors and Affiliations

  1. David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Mohamad Navab, Gattadahalli M Anantharamaiah, Srinivasa T Reddy, Brian J Van Lenten, Benjamin J Ansell & Alan M Fogelman

  2. University of Alabama, Birmingham, AL, USA

    Mohamad Navab, Gattadahalli M Anantharamaiah, Srinivasa T Reddy, Brian J Van Lenten, Benjamin J Ansell & Alan M Fogelman

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  1. Mohamad Navab
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  2. Gattadahalli M Anantharamaiah
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Correspondence to Mohamad Navab.

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Competing interests

M Navab, GM Anantharamaiah, ST Reddy, and AM Fogelman are principals in Bruin Pharma, BJ Ansell is a stockholder in Bruin Pharma, and AM Fogelman is an officer in Bruin Pharma. BJ Van Lenten declared he has no competing interests.

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Navab, M., Anantharamaiah, G., Reddy, S. et al. Mechanisms of Disease: proatherogenic HDL—an evolving field. Nat Rev Endocrinol 2, 504–511 (2006). https://doi.org/10.1038/ncpendmet0245

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