LRP1 integrates murine macrophage cholesterol homeostasis and inflammatory responses in atherosclerosis

• Published in: eLife 2017-11, Vol.6
• Main Authors: Xian, Xunde, Ding, Yinyuan, Dieckmann, Marco, Zhou, Li, Plattner, Florian, Liu, Mingxia, Parks, John S, Hammer, Robert E, Boucher, Philippe, Tsai, Shirling, Herz, Joachim
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; ABCA1; ABCA1 protein; AKT protein; Analysis; Animals; Antigens; Apoptosis; Arteries; Arteriosclerosis; Atherosclerosis; Atherosclerosis - pathology; ATP Binding Cassette Transporter 1 - metabolism; ATP-binding protein; Blood lipids; Cell Biology; Cell death; Cell surface; Cholesterol; Cholesterol - metabolism; Concerts; Coronary vessels; Disease Models, Animal; Diseases; Endocytosis; Exports; Gene Knock-In Techniques; Growth factors; Heart attack; Homeostasis; Human Biology and Medicine; Inflammation; Inflammation - pathology; International economic relations; Intracellular signalling; Kinases; Lipid metabolism; Lipoproteins; Liver; Low density lipoprotein; Low Density Lipoprotein Receptor-Related Protein-1; Low density lipoproteins; LRP1; macrophage; Macrophages; Macrophages - immunology; Medical research; Mice; Mutation; Novels; nuclear hormone receptor; Phenols (Class of compounds); Phosphates; Phosphorylation; Physiological aspects; Proteins; Receptor density; Receptors, LDL - genetics; Receptors, LDL - metabolism; Rodents; Scientific equipment industry; Signal Transduction; Smooth muscle; Time; Transforming growth factors; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tyrosine
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.29292

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.