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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 TGF? and PDGFR? 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/PPAR?/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.

SUBMITTER: Xian X

PROVIDER: S-EPMC5690284 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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

Xian Xunde X Ding Yinyuan Y Dieckmann Marco M Zhou Li L Plattner Florian F Liu Mingxia M Parks John S JS Hammer Robert E RE Boucher Philippe P Tsai Shirling S Herz Joachim J

eLife 20171116

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 ...[more]

PMID: 29144234

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Project description:To investigate the relationship between hypercholesterolemia, foam cell formation and inflammation, we performed lipidomic and transcriptomic analyses of elicited peritoneal macrophages in wild type (WT) or LDL receptor knockout (LDLR KO) mice fed either a normal cholesterol, normal fat (NCNF) diet or a high cholesterol, high fat (HCHF) 'Western' style diet. The combination of the LDLR KO genotype and the HCHF diet results in the formation of macrophage foam cells in the elicited peritoneal macrophage population. Analysis of macrophages from the above four experimental groups revealed massive reprogramming of the lipidome in response to both diet and genotype. These studies confirmed and extended prior knowledge regarding the roles of SREBP and LXR signaling in cholesterol and fatty acid homeostasis. Unexpectedly, peritoneal macrophage foam cells exhibited a strongly 'deactivated' phenotype, with marked suppression of pro-inflammatory mediators that are normally characteristic of the inflammatory responses associated with atherosclerotic lesions. Many of these changes in gene expression and lipid metabolism appear to be related to the paradoxical accumulation of high levels of desmosterol, the last intermediate in the Bloch pathway of cholesterol biosynthesis. WT or LDLR KO mice were fed either a NCNF diet or a HCHF diet for twelve weeks to establish four experimental groups (WT-NCNF diet, WT-HCHF diet, KO-NCNF diet, and KO-HCHF diet). As expected, the combination of the HCHF diet and LDLR KO genotype resulted in a synergistic effect on serum lipid levels. Elicited peritoneal macrophages (92-96% F4/80-positive) were immediately prepared for analysis, thereby preserving in vivo gene expression and lipid profiles. Macrophages derived from LDLR KO mice fed the HCHF diet contained nearly four-fold more total cholesterol than cells from WT mice fed the same diet. Quantitative analysis of 245 lipid species revealed significant changes in nearly all major lipid classes. Using a two-way ANOVA model, we found that 176 (72%) of the lipids analyzed were significantly affected by the HCHF diet, 133 (54%) by the LDLR KO genotype, and 114 (46%) by interactions between the HCHF diet and LDLR KO genotype. Many of the observed interactions (60%) were synergistic.

Project description:Background and aimsApolipoprotein A-I (ApoA-I), the main component of high-density lipoprotein (HDL), not only promotes reverse cholesterol transport (RCT) in atherosclerosis but also increases insulin secretion in pancreatic β-cells, suggesting that interventions which raise HDL levels may be beneficial in diabetes-associated cardiovascular disease (CVD). Previously, we showed that TNF-related apoptosis-inducing ligand (TRAIL) deletion in Apolipoprotein Eknockout (Apoe-/- ) mice results in diabetes-accelerated atherosclerosis in response to a "Western" diet. Here, we sought to identify whether reconstituted HDL (rHDL) could improve features of diabetes-associated CVD in Trail-/-Apoe-/- mice.Methods and resultsTrail-/-Apoe-/- and Apoe-/- mice on a "Western" diet for 12 weeks received 3 weekly infusions of either PBS (vehicle) or rHDL (containing ApoA-I (20 mg/kg) and 1-palmitoyl-2-linoleoyl phosphatidylcholine). Administration of rHDL reduced total plasma cholesterol, triglyceride, and glucose levels in Trail-/-Apoe-/- but not in Apoe-/- mice, with no change in weight gain observed. rHDL treatment also improved glucose clearance in response to insulin and glucose tolerance tests. Immunohistological analysis of pancreata revealed increased insulin expression/production and a reduction in macrophage infiltration in mice with TRAIL deletion. Furthermore, atherosclerotic plaque size in Trail-/-Apoe-/- mice was significantly reduced associating with increased expression of the M2 macrophage marker CD206, suggesting HDL's involvement in the polarization of macrophages. rHDL also increased vascular mRNA expression of RCT transporters, ABCA1 and ABCG1, in Trail-/-Apoe-/- but not in Apoe-/- mice. Conclusions. rHDL improves features of diabetes-associated atherosclerosis in mice. These findings support the therapeutic potential of rHDL in the treatment of atherosclerosis and associated diabetic complications. More studies are warranted to understand rHDL's mechanism of action.

Dataset Information

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

Publications

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

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