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

Abstract

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.-Llorente-Cortés, V., T. Royo, O. Juan-Babot, and L. Badimon. Adipocyte differentiation-related protein is induced by LRP1-mediated aggregated LDL internalization in human vascular smooth muscle cells and macrophages.

Direct interaction of Plin2 with lipids on the surface of lipid droplets: a live cell FRET analysis

“…Lipids from CFP-Plin2 overexpressing and control cell homogenates including CE, DG, TG, Chol, and total phospholipids were extracted and analyzed as described in MATERIALS AND METHODS. Consistent with other work that shows increased expression of Plin2 promotes cellular lipid accumulation (29,48,50,51), levels of TG and CE, interior core neutral lipids, were increased 1.9-and 1.7-fold, respectively in CFP-Plin2-expressing cells (Fig. 6A, P Ͻ 0.02), In addition, levels of total phospholipids, found in the surface layer of lipid droplets, were each increased 1.5-fold in CFP-Plin2-expressing cells (Fig.…”

K Domain CR9 of Low Density Lipoprotein (LDL) Receptor-related Protein 1 (LRP1) Is Critical for Aggregated LDL-induced Foam Cell Formation from Human Vascular Smooth Muscle Cells

“…This, in turn, induces LRP1 overexpression (34,42,43) and thus a positive feedback loop that efficiently transforms hVSMCs into foam cells (29,30). These foam cells synthesize and release increased amounts of tissue factor, a key element in the prothrombotic transformation of the vascular wall and thus in the progression of atherosclerosis to thrombosis (44).…”

“…The C-terminal half of LRP1 domain CR9 Is Crucial for AgLDL-induced SREBP-2 Down-regulation and LRP1 Overexpression in hVSMCs-Previous studies from our group have demonstrated that AgLDL positively modulates LRP1 gene expression and protein levels (34,42,43), generating a positive feedback loop that efficiently transforms hVSMCs into foam cells (30). Down-regulation of sterol regulatory element-binding protein 2 (SREBP-2) plays a crucial role in the positive modulation of LRP1 by AgLDL (34,42,43).…”

“…However, LRP1 overexpression has been associated with atherosclerosis in both animal (22) and human models of atherosclerosis (23)(24)(25). In particular, LRP1 efficiently transfers cholesteryl esters (CE) from aggregated LDL (AgLDL) into human coronary VSMCs (26 -28), transforming them into foam cells (29,30). The formation of AgLDL, detected and isolated from human atherosclerotic lesions (31), is promoted through the interaction between retained LDL particles and proteoglycans in the arterial intima (32).…”

Urinary Biomarkers for the Early Diagnosis of Kidney Cancer

“…38,39 Lipid droplets, in addition to accumulated glycogen granules, account for the histologic clearness of the cells. Moreover, papillary carcinomas are associated with abundant lipid-laden macrophages.…”