Departments of Molecular Genetics, UT Southwestern Medical Center, Dallas, United States; Key Laboratory of Medical Electrophysiology, Ministry of Education of China, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
Marco Dieckmann
Departments of Molecular Genetics, UT Southwestern Medical Center, Dallas, United States
Li Zhou
Departments of Molecular Genetics, UT Southwestern Medical Center, Dallas, United States
Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, United States; Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, United States
Mingxia Liu
Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina
Departments of Molecular Genetics, UT Southwestern Medical Center, Dallas, United States; Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, United States; Department of Neuroscience, UT Southwestern, Dallas, United States; Department of Neurology and Neurotherapeutics, UT Southwestern, Dallas, United States
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.
