Copyright © 2007, European Society of Cardiology
Sterol regulatory element binding proteins downregulate LDL receptor-related protein (LRP1) expression and LRP1-mediated aggregated LDL uptake by human macrophages
aCardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
bDepartamento de Biologia Celular, School of Medicine, Universidad de Barcelona, Spain
* Corresponding author. CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, Sant Antoni Ma Claret, 167, 08025 Barcelona, Spain. Tel.: +34 935565880; fax: +34 935565559. Email address: lbadimon{at}csic-iccc.santpau.es
Objective: In the extracellular intima, extracellular matrix proteoglycans favor LDL retention and aggregation (agLDL). In contrast to native LDL (nLDL), agLDL induces high intracellular cholesteryl ester (CE) accumulation in macrophages. It has been suggested that LDL receptor-related protein (LRP1) is involved in agLDL binding and internalization by macrophages. The aim of this work was to analyze whether sterol regulatory element binding proteins (SREBPs) modulate LRP1 expression and LRP1-mediated agLDL uptake by human monocyte-derived macrophages (HMDM).
Methods and results: The treatment of HMDM with small anti-LRP1 interfering RNA (siRNA-LRP1) led to the specific inhibition of LRP1 mRNA expression and also to the inhibition of LRP1 protein expression in these cells. In siRNA-LRP1-treated HMDM, CE accumulation from agLDL uptake (84.66±5 µg CE/mg protein) was reduced by 95.76±5.22%. This suggests that LRP1 plays a pivotal role in agLDL uptake by HMDM. N-acetyl-leucyl-leucyl-norleucinal (ALLN), an inhibitor of SREBP catabolism, maintained high levels of active SREBP-2 and SREBP-1 even in the presence of nLDL and agLDL. Therefore, ALLN induced LDL receptor (LDLR) upregulation. Concomitantly, a strong downregulation of LRP1 mRNA and LRP1 protein was observed in ALLN-treated macrophages. By decreasing LRP1 expression levels, ALLN reduced CE accumulation from agLDL at all tested concentrations.
Conclusions: These results suggest that high levels of active SREBPs downregulate LRP1 expression and intracellular CE accumulation in HMDM.
KEYWORDS Low density lipoprotein receptor-related protein; Human monocyte-derived macrophages; Cholesterol accumulation; Sterol regulatory element binding proteins
Time for primary review 17 days
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  V. Llorente-Cortes, 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 J. Lipid Res., October 1, 2007; 48(10): 2133 - 2140. [Abstract] [Full Text] [PDF]
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