EAS 2012 MILAN
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Dr Van Eck and Professor Tall
will take part in the
EAS 2012 Plenary Session
27 May, 2012, 08:30-10:30
LIPOPROTEINS AND ATHEROGENESIS: NEW INSIGHTS
Chaired by
Professor Arnold Von Eckardstein, Switzerland and
Professor Olov Wiklund, Sweden

Focus on... EAS 2012

As we count down to this year's Congress, each week we highlight speakers who will participate in EAS 2012.
This week the speakers in the spotlight are:

Dr Miranda van Eck

THE MACROPHAGE LIPOPROTEIN INTERACTIONS – FOR GOOD OR FOR BAD

Miranda Van Eck is Associate Professor, Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands. Her research is focused upon the role of macrophage genes in the development of atherosclerosis with special emphasis on the function of genes involved in high-density lipoprorein (HDL) metabolism and reverse cholesterol transport, in particular the role of the ATP-binding cassette (ABC) transporters and scavenger receptor BI (SR-BI) in this process..

Targeting macrophage foam cell formation by modulating ABC-transporter and SR-BI expression may have therapeutic potential for preventing atherosclerosis. Such therapies should also aim to improve both the quantity and quality of HDL. One approach is to increase hepatic SR-BI expression by activation of the nuclear receptors farnesoid X receptor and liver receptor homolog 1. Alternatively, targeting macrophage cholesterol efflux via upregulation of the expression of ABCG1 – and indirectly ABCA1 - by activation of the transcription factors liver X receptors (LXR) may be beneficial. Assuming problems of increased fatty liver can be resolved, these agents may offer therapeutic promise. Future research aims to elucidate which of these targets are viable in the clinical setting.

HDL-mediated cholesterol efflux from macrophage foam cells is crucial for the prevention of atherosclerosis. Key mediators for macrophage cholesterol homeostasis include scavenger receptors and the ABC transporters, ABCA1 and ABCG1, which facilitate the influx and efflux of lipids. The role of macrophage ABCG1 in the development of atherosclerosis may be more complex, as experimental studies suggest that ABCG1 may be both anti-atherogenic and pro-atherogenic, depending on the stage of atherogenesis. Furthermore, local and systemic factors, including inflammation and diabetes, also influence the expression of cholesterol transporters on macrophage foam cells.

Key references

1. Van Eck M , Singaraja RR, Ye D et al. Macrophage ATP-binding cassette transporter A1 overexpression inhibits atherosclerotic lesion progression in low-density lipoprotein receptor knockout mice. Arterioscler Thromb Vasc Biol 2006;26:929-34.

2. Van Eck M , Hoekstra M, Out R et al. Scavenger receptor BI facilitates the metabolism of VLDL lipoproteins in vivo. J Lipid Res 2008;49:136-46.

3. Ye D, Lammers B, Zhao Y, Meurs I, Van Berkel TJ, Van Eck M , ATP-binding cassette transporters A1 and G1, HDL metabolism, cholesterol efflux, and inflammation: important targets for the treatment of atherosclerosis. Curr Drug Targets 2011;12:647-60.

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.