The Dual Role of Low-Density Lipoprotein Receptor-Related Protein 1 in Atherosclerosis

Abstract

Low-density lipoprotein receptor–related protein-1 (LRP1) is a large endocytic and signaling receptor belonging to the LDL receptor (LDLR) gene family and that is widely expressed in several tissues. LRP1 comprises a large extracellular domain (ECD; 515 kDa, α chain) and a small intracellular domain (ICD; 85 kDa, β chain). The deletion of LRP1 leads to embryonic lethality in mice, revealing a crucial but yet undefined role in embryogenesis and development. LRP1 has been postulated to participate in numerous diverse physiological and pathological processes ranging from plasma lipoprotein homeostasis, atherosclerosis, tumor evolution, and fibrinolysis to neuronal regeneration and survival. Many studies using cultured cells and in vivo animal models have revealed the important roles of LRP1 in vascular remodeling, foam cell biology, inflammation and atherosclerosis. However, its role in atherosclerosis remains controversial. LRP1 not only participates in the removal of atherogenic lipoproteins and proatherogenic ligands in the liver but also mediates the uptake of aggregated LDL to promote the formation of macrophage- and vascular smooth muscle cell (VSMC)-derived foam cells, which causes a prothrombotic transformation of the vascular wall. The dual and opposing roles of LRP1 may also represent an interesting target for atherosclerosis therapeutics. This review highlights the influence of LRP1 during atherosclerosis development, focusing on its dual role in vascular cells and immune cells.

Decreased low-density lipoprotein receptor-related protein 1 expression in pro-inflammatory monocytes is associated with subclinical atherosclerosis

“…On the other hand, LRP1 can help to suppress atherosclerosis by inhibiting the PDGF-β signaling pathway and blocking the cell proliferation of VSMCs ( 25 ). A similar dual role it has been shown in macrophages in which LRP1 could mainly have an atheroprotective effect mainly by decreasing inflammation, facilitating efferocytosis and promoting cholesterol efflux ( 9 , 22 ), but it also promotes the macrophages-derived foam cell formation through the binding and internalization of aggLDL ( 26 , 27 ). In the present study, we found decreased LRP1 levels at cell surface in total monocytes and monocyte subsets, particularly in classical monocytes, in asymptomatic individuals with CVD risk factors (IR group) and with atherosclerotic plaque detected by carotid ultrasound (CU) and CAC score > 1 (SCA group) respect to individuals with low CVD risk factors (LR group).…”

“…Several studies have shown that LRP1 plays a dual role in the development and regression of atherosclerosis ( 9 , 22 ). In VSMCs, LRP1 mediates the foam cells formation through the uptake of aggregated LDL (aggLDL) inducing intracellular cholesteryl ester accumulation ( 23 , 24 ).…”

Metabolism of tissue macrophages in homeostasis and pathology

“…Peritoneal macrophages from LDLR −/− mice carrying LRP1 Y63F bone marrow show enhanced intracellular lipid accumulation and decreased clearance of apoptotic cells during disease progression due to a reduction in LXR- and ABCA1-mediated cholesterol efflux. Overall, the contradictory roles of the same pathway/receptor in atherosclerosis are possibly related to the different stages of atherosclerosis (regression vs. progression) [ 240 ].…”

New insights into the pathological development of dyslipidemia in patients with hypothyroidism

“…On the other hand, PCSK9 could also interact with low-density lipoprotein receptor related protein 1 (LRP1). As shown in previous studies, LRP1 has been postulated to participate in numerous diverse physiological and pathological processes ranging from plasma lipoprotein homeostasis, atherosclerosis, tumor evolution, and fibrinolysis to neuronal regeneration and survival [63]. Aside from the direct functions in modulating serum metabolism of lipid profiles, LRP1 could also compete with LDLR and induce the risk of dyslipidemia [64].…”