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LRP1 integrates murine macrophage cholesterol homeostasis and inflammatory responses in atherosclerosis.

LRP1 integrates murine macrophage cholesterol homeostasis and inflammatory responses in atherosclerosis.
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Xian X, Ding Y, Dieckmann M, Zhou L, Plattner F, Liu M, Parks JS, Hammer RE, Boucher P, Tsai S, Herz J,


Xian X, Ding Y, Dieckmann M, Zhou L, Plattner F, Liu M, Parks JS, Hammer RE, Boucher P, Tsai S, Herz J, (click to view)

Xian X, Ding Y, Dieckmann M, Zhou L, Plattner F, Liu M, Parks JS, Hammer RE, Boucher P, Tsai S, Herz J,

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eLife 2017 11 166() doi 10.7554/eLife.29292
Abstract

Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional cell surface receptor with diverse physiological roles, ranging from cellular uptake of lipoproteins and other cargo by endocytosis to sensor of the extracellular environment and integrator of a wide range of signaling mechanisms. As a chylomicron remnant receptor, LRP1 controls systemic lipid metabolism in concert with the LDL receptor in the liver, whereas in smooth muscle cells (SMC) LRP1 functions as a co-receptor for TGFβ and PDGFRβ in reverse cholesterol transport and the maintenance of vascular wall integrity. Here we used a knockin mouse model to uncover a novel atheroprotective role for LRP1 in macrophages where tyrosine phosphorylation of an NPxY motif in its intracellular domain initiates a signaling cascade along an LRP1/SHC1/PI3K/AKT/PPARγ/LXR axis to regulate and integrate cellular cholesterol homeostasis through the expression of the major cholesterol exporter ABCA1 with apoptotic cell removal and inflammatory responses.

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