Universitat Rovira i Virgili, Spain
Our main long-term goal is to identify new targets to limit both the accumulation and the toxicity of cholesterol in foam cells to prevent atherosclerosis development. Plasma levels of low-density lipoprotein (LDL) cholesterol are directly related to the development of atherosclerosis and to the risk of cardiovascular disease. The more circulating LDL, the more that can accumulate in the intima of the arteries, where it can be oxidized and induce changes in endothelial cells that promote the recruitment of circulating monocytes. Monocyte/macrophages take-up the oxidized LDL and store a large portion of their lipids in cytoplasmic lipid droplets. These lipid-laden macrophages, commonly known as foam cells, play a central role in atherogenesis. However, the actual effects of lipids on foam cells are not clear yet, and to date the foam cell has been an elusive target for therapeutic interventions. Intracellular lipid droplets consist of a core of neutral lipid stabilized and circumscribed by phospholipids, free cholesterol and proteins. The main structural lipid droplet-associated proteins are the members of the PAT-family, and in macrophages the most abundant PAT-protein is adipose differentiation-related protein (ADFP). We have shown that ADFP plays a key role in foam cell formation, and its absence severely restricts the ability of macrophages to become foam cells in vitro and in vivo. ADFP is upregulated in human and mouse atherosclerotic lesions, and ADFP ablation in apolipoprotein E-null mice is atheroprotective. Mechanistically, ADFP-deficient macrophages do not accumulate as much cholesterol in the form of cholesterol esters in lipid droplets, and efflux more cholesterol to extracellular acceptors. Currently we are performing a broad-based analysis on the role of ADFP in lipid droplet biology, foam cell formation and atherosclerosis development, including in vivo and in vitro studies, from which we expect to obtain a breadth of understanding that may help to set-up the bases for novel strategies to target the foam cell to prevent atherosclerosis development.
- Paul A, Ko KWS, Li L, Yechoor V, McCrory MA, Szalai AJ, Chan L. C-reactive protein accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice. Circulation 2004;109:647-55.
- Chang BH, Li L, Paul A, Taniguchi S, Nannegari V, Heird WC and Chan L. Protection against fatty liver but normal adipogenesis in mice lacking adipose differentiation-related protein. Molecular and Cellular Biology 2006;26:1063-76.
- Oka K, Belalcazar LM, Dieker C, Nour EA, Nuno-Gonzalez P, Paul A, Cormier S, Shin JK, Finegold M and Chan L. Sustained phenotypic correction in a mouse model of hypoalphalipoproteinemia with a helper-dependent adenovirus vector. Gene Therapy 2007;14:191-202.
- Paul A, Chang BH, Li L, Yechoor VK and Chan L. Deficiency of Adipose Differentiation-Related Protein Impairs Foam Cell Formation and Protects Against Atherosclerosis. Circulation Research 2008; 102:1492-501.
Editorial comment on this Manuscript:
Daugherty A, Rateri DL. and Lu H. As Macrophages Indulge, Atherosclerotic Lesions Bulge. Circulation Research 2008;102:1445-7.
- Paul A*, Yechoor V, Raja R, Li L and Chan L*. Microarray Gene Expression Profiling of Laser-Captured Cells: a New Tool to Study Atherosclerosis in Mice. Atherosclerosis 2008;200:257-63.
- Yechoor V, Liu V, Espiritu C, Paul A, Oka K, Kojima H and Chan L. Neurogenin3 is Sufficient for Transdetermination of Hepatic Progenitor Cells into neo-islets in vivo but not Transdifferentiation of Hepatocytes. Developmental Cell 2009; 16:358-73.
- Yechoor V, Liu V, Paul A, Lee J, Buras E, Ozer K, Samson S and Chan L. Gene therapy with Neurogenin3 and betacellulin reverses major metabolic problems in insulin-deficient diabetic mice. Endocrinology 2009;150:4863-73.
- Wu H, Gower RM, Wang H, Perrard XYD, Ma R, Burns AR, Paul A, Smith CW, Simon SI, and Ballantyne CM. Functional role of CD11c+ monocytes in atherogenesis associated with hypercholesterolemia. Circulation 2009;119:2708-17.
- Ko KW, Corry DB, Brayton CF, Paul A and Chan L. Extravascular inflammation does not increase atherosclerosis in apoE-deficient mice. Biochemical and Biophysical Research Communications 2009;384:93-9.
- Li R*, Paul A*, Ko K, Sheldon M, Rich B, Terashima T, Dieker C, Cormier S, Li L, Nour E, Chan L and Oka K. Interleukin-7 induces recruitment of monocytes/macrophages to endothelium. European Heart Journal 2012;33:3114-23.
* Shared 1st authorship.
- Son SH, Goo YH, Chang BH and Paul A. Perilipin 2 (PLIN2)-deficiency does not increase cholesterol-induced toxicity in macrophages. PLoS ONE 2012; 2012;7(3):e33063.
- Goo YH, Son SH, Kreienberg PB and Paul A. Novel lipid droplet-associated serine hydrolase regulates macrophage cholesterol mobilization. Arteriosclerosis, Thrombosis and Vascular Biology. 2014;34:386-96.