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

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.