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Journal of Lipid Research, Vol. 48, 2133-2140, October 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Adipocyte differentiation-related protein is induced by LRP1-mediated aggregated LDL internalization in human vascular smooth muscle cells and macrophages

V. Llorente-Cortés^*, T. Royo, O. Juan-Babot^* and L. Badimon^1,*

^* Cardiovascular Research Center, Consejo Superior de Investigaciones Científicas-Instituto Catalán de Ciencias Cardiovasculares, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Departamento de Biologia Celular, School of Medicine, Universidad de Barcelona, Spain

Published, JLR Papers in Press, July 9, 2007.

¹ To whom correspondence should be addressed. e-mail: lbadimon{at}csic-iccc.santpau.es

Aggregated LDL (agLDL) is internalized by LDL receptor-related protein (LRP1) in vascular smooth muscle cells (VSMCs) and human monocyte-derived macrophages (HMDMs). AgLDL is, therefore, a potent inducer of massive intracellular cholesteryl ester accumulation in lipid droplets. The adipocyte differentiation-related protein (ADRP) has been found on the surface of lipid droplets. The objectives of this work were to analyze whether agLDL uptake modulates ADRP expression levels and whether the effect of agLDL internalization on ADRP expression depends on LRP1 in human VSMCs and HMDMs. AgLDL strongly upregulates ADRP mRNA (real-time PCR) and protein expression (Western blot) in human VSMCs (mRNA: by 3.06-fold; protein: 8.58-fold) and HMDMs (mRNA: by 3.5-fold; protein: by 3.71-fold). Treatment of VSMCs and HMDMs with small anti-LRP1-interfering RNA (siRNA-LRP1) leads to specific inhibition of LRP1 expression. siRNA-LRP1 treatment significantly reduced agLDL-induced ADRP overexpression in HMDMs (by 69%) and in VSMCs (by 53%). Immunohystochemical studies evidence a colocolocalization between ADRP/macrophages and ADRP/VSMCs in advanced lipid-enriched atherosclerotic plaques. These results demonstrate that agLDL-LRP1 engagement induces ADRP overexpression in both HMDMs and human VSMCs and that ADRP is highly expressed in advanced lipid-enriched human atherosclerotic plaques. Therefore, LRP1-mediated agLDL uptake might play a pivotal role in vascular foam cell formation.

Supplementary key words adipocyte differentiation-related protein • aggregated LDL • LDL receptor-related protein • adipophilin • human vascular smooth muscle cells • macrophages

Abbreviations: ADRP, adipocyte differentiation-related protein; agLDL, aggregated LDL; CE, cholesteryl ester; HMDMs, human monocyte-derived macrophages; LDLR, LDL receptor; LRP1, LDL receptor-related protein; nLDL, native LDL; siRNA-LRP1, small anti-LRP1-interfering RNA; VSMCs, vascular smooth muscle cells

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