Between Bedside and Bench | Published:

The not-so-simple HDL story

Is it time to revise the HDL cholesterol hypothesis?

Nature Medicine volume 18, pages 13441346 (2012) | Download Citation

Formation of plaques in artery walls, or atherogenesis, is known to lead to cardiovascular disease risk and heart disease. Low-density lipoproteins (LDLs), which deliver cholesterol to inflammatory cells in blood vessels, are linked to disease, which is commonly managed using cholesterol-lowering therapies. Whether increasing levels of high-density lipoproteins (HDLs), which remove cholesterol from the circulation, can be cardioprotective has not been clear, despite early clinical studies showing evidence for a positive effect in cardiovascular disease. In 'Bench to Bedside', Daniel J. Rader and Alan R. Tall discuss how the field should focus on promoting reverse cholesterol transport that would result in cholesterol efflux from macrophages to biliary excretion rather than simply trying to increase HDL cholesterol levels. Understanding how different molecular mechanisms operate in this 'HDL flux hypothesis' will uncover ways to develop HDL-targeted therapeutics that will protect from cardiovascular and heart disease. In 'Bedside to Bench', Jay W. Heinecke peruses clinical studies to propose better and simpler ways to measure reverse cholesterol transport in the clinic. Genetic alterations and factors involved in HDL functionality may be useful for quantifying HDL function and finding effective drugs to lower cardiovascular disease risk.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    , , , & J. Lipid Res. 50 Suppl, S189–S194 (2009).

  2. 2.

    , , & Biochim. Biophys. Acta 1821, 513–521 (2012).

  3. 3.

    et al. Circulation 108, 661–663 (2003).

  4. 4.

    et al. J. Am. Med. Assoc. 290, 2292–2300 (2003).

  5. 5.

    et al. J. Clin. Invest. 117, 2216–2224 (2007).

  6. 6.

    et al. J. Clin. Invest. 117, 3900–3908 (2007).

  7. 7.

    et al. Circulation 113, 90–97 (2006).

  8. 8.

    et al. J. Clin. Invest. 121, 2921–2931 (2011).

  9. 9.

    et al. Science 328, 1689–1693 (2010).

  10. 10.

    et al. Cell Stem Cell 11, 195–206 (2012).

  11. 11.

    et al. Nature 487, 325–329 (2012).

  12. 12.

    AIM-HIGH Investigators et al. N. Engl. J. Med. 365, 2255–2267 (2011).

  13. 13.

    et al. Am. Heart J. 158, 896–901 (2009).

  14. 14.

    et al. Lancet 380, 572–580 (2012).

  15. 15.

    , , & J. Am. Med. Assoc. 298, 299–308 (2007).

  16. 16.

    et al. Arterioscler. Thromb. Vasc. Biol. 30, 1430–1438 (2010).

  17. 17.

    et al. N. Engl. J. Med. 364, 127–135 (2011).

  18. 18.

    J. Lipid Res. 47, 1339–1351 (2006).

Download references

Author information


  1. Daniel J. Rader is at the Institute for Translational Medicine and Therapeutics, the Cardiovascular Institute, and the Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Daniel J Rader
  2. Alan R. Tall is in the Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York, USA.

    • Alan R Tall


  1. Search for Daniel J Rader in:

  2. Search for Alan R Tall in:

Competing interests

A.R.T. is a consultant for Merck, Pfizer, Roche, Amgen, CSL and Arisaph and receives research support from CSL.

Corresponding authors

Correspondence to Daniel J Rader or Alan R Tall.

About this article

Publication history



Further reading

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