Plenary speakers in the spotlight: Miranda van Eck, Alan Tall

Professor Alan Tall

NOVEL ANTI-ATHEROGENIC FUNCTIONS OF HDL

Alan Tall is Tilden Weger Bieler Professor of Medicine, at Columbia University, New York USA. He is internationally recognized for his work in plasma lipoprotein metabolism and atherosclerosis, in particular the regulation and metabolism of plasma high density lipoproteins (HDL). His research identifying mutations in the cholesteryl ester transfer protein (CETP) gene associated with markedly elevated HDL levels established a key role for CETP in the regulation of HDL levels. More recently, his research has focused on the molecular mechanisms of cellular cholesterol efflux, mediated by the ATP binding cassette transporters, ABCA1 and ABCG1.

The functionality of HDL is relevant to its ability to promote cholesterol efflux from macrophage foam cells. Although multiple mechanisms are likely to be involved, these effects may in part be related to the role of the ABC transporters, ABCA1 and ABCG1, in cholesterol efflux. Further investigation has led to elucidation of a class of specialised transcription factors (LXRs) that co-ordinate the regulation of cellular cholesterol efflux and reverse cholesterol transport.

HDL possess other beneficial activities including inhibition of LDL oxidation, smooth muscle cell migration and platelet aggregation. ABCG1 and, to a lesser extent, ABCA1, may play a role in preserving endothelial function.

Finally, HDL exhibit anti-inflammatory properties in endothelial cells and macrophages that may be relevant to their atheroprotective effects. Accumulating evidence links these anti-inflammatory effects to cholesterol efflux pathways. Studies suggest that the ABCA1 transporters are implicated in the control of hematopoietic stem cell proliferation, monocytosis and neutrophilia, as well as activation of monocytes and neutrophils.

Thus, the ABC transporters ABCA1 and ABCG1 have important effects in reducing macrophage foam cell formation, inflammation, and atherosclerosis. Pharmacologic approaches for increasing cholesterol efflux may offer therapeutic potential for preventing atherosclerosis.

Key references

1. Tall AR, Yvan-Charvet L, Terasaka N, Pagler T, Wang N. HDL, ABC transporters, and cholesterol efflux: implications for the treatment of atherosclerosis. Cell Metab 2008;7:365-75.

2. Tall AR. Functions of cholesterol ester transfer protein and relationship to coronary artery disease risk. J Clin Lipidol 2010;4:389-93.

3. Terasaka N, Westerterp M, Koetsveld J, Fernández-Hernando C, Yvan-Charvet L, Wang N, Sessa WC, Tall AR. ATP-binding cassette transporter G1 and high-density lipoprotein promote endothelial NO synthesis through a decrease in the interaction of caveolin-1 and endothelial NO synthase. Arterioscler Thromb Vasc Biol 2010;30:2219-25.

4. Murphy AJ, Akhtari M, Tolani S, Pagler T, Bijl N, Kuo CL, Wang M, Sanson M, Abramowicz S, Welch C, Bochem AE, Kuivenhoven JA, Yvan-Charvet L, Tall AR. ApoE regulates hematopoietic stem cell proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice. J Clin Invest. 2011 Oct;121(10):4138-49. PubMed PMID: 21968112; PubMed Central PMCID: PMC3195472.

5. Tsuchiya K, Banks AS, Liang CP, Tabas I, Tall AR, Accili D. Homozygosity for an allele encoding deacetylated FoxO1 protects macrophages from cholesterol-induced inflammation without increasing apoptosis. Arterioscler Thromb Vasc Biol. 2011 Dec;31(12):2920-8. Epub 2011 Sep 22. PubMed PMID: 21940942; PubMed Central PMCID: PMC3220790.

Forrás: The European Atherosclerosis Society website