LRP1 integrates murine macrophage cholesterol homeostasis and inflammatory responses in atherosclerosis

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.

TLR Crosstalk Activates LRP1 to Recruit Rab8a and PI3Kγ for Suppression of Inflammatory Responses

“…Indeed, the changes to individual cytokines are comparable in response to the loss of either PI3Kg or LRP1, and both overall result in a pro-inflammatory bias. The equivalent in vivo cytokine responses for PI3Kg and LRP1 KOs have each been published using LPS challenge in PI3Kg À/À mice (Kaneda et al, 2016b) or in two mouse models of macrophage-directed deletion of LRP1 (Mantuano et al, 2016;Xian et al, 2017). In both cases, the findings correlate with our in vitro data showing that loss of PI3Kg or LRP1 produces a similar, pro-inflammatory cytokine bias.…”

“…the phosphorylation of this second tyrosine (Y4507) occurs during atherosclerosis and is required for initiating a signaling cascade along an LRP1/SHC1/PI3K/AKT/ PPARg/LXR axis for cellular cholesterol homeostasis (Xian et al, 2017). Therefore, our reported molecular and functional interaction between the phospho-Y4507 of LRP1 and Rab8 could also provide an underlying molecular link between LRP1 and PI3Kg/Akt during atherosclerosis.…”

“…As evidence for this, our experiments show that (1) LRP1 is not activated by LPS in TLR4 À/À BMMs; (2) that LRP1 is activated by multiple TLR ligands, all of which would be unlikely as direct LRP1 ligands; and (3) LPS-induced phosphorylation of the 85-kDa form of LRP1, which lacks ligand binding domains. In immune-and metabolically activated macrophages, inflammation can also be constrained by activation of LRP1 via its endogenous agonists and antagonists, influencing lipid uptake and regulation, Akt signaling, cytokine production, or cell differentiation (Gaultier et al, 2008;Mantuano et al, 2016;Turvey et al, 2015;Xian et al, 2017). It will be interesting in the future to determine whether these other pathways for activating LRP1 also involve Rab8a or PI3Kg.…”

“…LRP1 is synthesized as a >600-kDa precursor with an 85-kDa transmembrane subunit produced by furin cleavage, and additional cleavage releases a soluble extracellular domain (Zurhove et al, 2008). Although previously unconnected with either Rab8a or PI3Kg, LRP1 has nevertheless been linked with TLRs through nuclear factor kB (NF-kB)-dependent signaling outputs, where, like Rab8a and PI3Kg, it is a negative regulator of inflammation (Mantuano et al, 2016;Xian et al, 2017;Yang et al, 2016).…”

Intracellular lipid metabolism impairs β cell compensation during diet-induced obesity

“…So the basal levels of LRP1 act as an essential gatekeeper for β cells during DIO. Two recent studies demonstrated LRP1 as a PPARγ coactivator in endothelial cells (45) and in macrophages (46). In contrast, in the context of the β cell, we show here that LRP1 suppresses PPARγ2.…”