Abstract
BackgroundATP-binding cassette transporter A1 mediates apolipoprotein AI-dependent efflux of cholesterol and thereby removes cholesterol from peripheral tissues. ABCA1 expression is tightly regulated and deficiency of this cholesterol transporter results in cholesterol accumulation within cells. Low-density lipoprotein receptor-related protein 1 (LRP1) participates in lipid metabolism and energy homeostasis by endocytosis of apolipoprotein E-containing lipoproteins and modulation of cellular proliferation signals.Methods and Principal FindingsIn the present study, we demonstrate a new role for LRP1 in reverse cholesterol transport. Absence of LRP1 expression results in increased PDGFRβ signaling and sequential activation of the mitogen-activated protein kinase signaling pathway, which increases phosphorylation of cytosolic phospholipase A2 (cPLA2). Phosphorylated and activated cPLA2 releases arachidonic acid from the phospholipid pool. Overproduction of arachidonic acid suppresses the activation of LXR/RXR heterodimers bound to the promoter of LXR regulated genes such as ABCA1, resulting in greatly reduced ABCA1 expression.Conclusions and SignificanceLRP1 regulates LXR-mediated gene transcription and participates in reverse cholesterol transport by controlling cPLA2 activation and ABCA1 expression. LRP1 thus functions as a physiological integrator of cellular lipid homeostasis with signals that regulate cellular proliferation and vascular wall integrity.
Highlights
Cholesterol is an essential component of cell membrane and necessary for normal cellular function, including cell proliferation [1]
Using gas chromatography and mass spectrometry (GC/MS), we found a significant increase in total cholesterol in the aortas of smLRP12/2 mice (Figure 1 and Figure S1)
Aortas lacking any morphologically discernible atherosclerotic lesions or plaques were analyzed. These increased cholesterol levels are not caused by the presence of cholesterol in plaques or advanced lesions, but reflect either increased lipoprotein uptake or the inability of lipoprotein receptor-related protein 1 (LRP1)-deficient smooth muscle cells to export endogenous cholesterol in the presence of an intact endothelium
Summary
Cholesterol is an essential component of cell membrane and necessary for normal cellular function, including cell proliferation [1]. ABCA1 facilitates the formation of HDL via apolipoprotein AI (apoAI)-mediated efflux of cholesterol and phospholipids from many tissues [7,8,9]. This constitutes the initial step of reverse cholesterol transport, and leads to the elimination of cholesterol from the body [10,11,12]. Functional defects in the ABCA1 protein that impair its ability to mediate cellular cholesterol efflux can result in deposition of cholesterol within the tissues. ATP-binding cassette transporter A1 mediates apolipoprotein AI-dependent efflux of cholesterol and thereby removes cholesterol from peripheral tissues. Low-density lipoprotein receptor-related protein 1 (LRP1) participates in lipid metabolism and energy homeostasis by endocytosis of apolipoprotein E-containing lipoproteins and modulation of cellular proliferation signals
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