The Role of Low-Density Lipoprotein Receptor-Related Protein 1 in Lipid Metabolism, Glucose Homeostasis and Inflammation

Abstract

Metabolic syndrome (MetS) is a highly prevalent disorder which can be used to identify individuals with a higher risk for cardiovascular disease and type 2 diabetes. This metabolic syndrome is characterized by a combination of physiological, metabolic, and molecular alterations such as insulin resistance, dyslipidemia, and central obesity. The low-density lipoprotein receptor-related protein 1 (LRP1—A member of the LDL receptor family) is an endocytic and signaling receptor that is expressed in several tissues. It is involved in the clearance of chylomicron remnants from circulation, and has been demonstrated to play a key role in the lipid metabolism at the hepatic level. Recent studies have shown that LRP1 is involved in insulin receptor (IR) trafficking and intracellular signaling activity, which have an impact on the regulation of glucose homeostasis in adipocytes, muscle cells, and brain. In addition, LRP1 has the potential to inhibit or sustain inflammation in macrophages, depending on its cellular expression, as well as the presence of particular types of ligands in the extracellular microenvironment. In this review, we summarize existing perspectives and the latest innovations concerning the role of tissue-specific LRP1 in lipoprotein and glucose metabolism, and examine its ability to mediate inflammatory processes related to MetS and atherosclerosis.

Keywords: cholesterol; endocytosis; lipoprotein; membrane; traffic.

Figure 1

LRP1 role in the lipid metabolisms, glucose homeostasis and inflammation. (A) The loss of LRP1 or sLRP1 production can induce pro-inflammatory factors synthesis in macrophages. LRP1 can also regulate the lipid metabolism by endocytosis of cholesterol and triglyceride-rich lipoproteins, such as chylomicrons (QM), very low-density lipoprotein (VLDL) (represented as orange circles) and aggregated low-density lipoprotein (aggLDL) (pink circles) in hepatocytes, vascular smooth muscle cell (VSMCs) and macrophage, and by signaling activation limiting cholesterol intracellular accumulation in fibroblasts; oxidized LDL (oxLDL) is recognized by scavenger receptors (CD36; SRA; and LOX-1) (B) LRP1 is essential for the signaling activity of the insulin receptor (IR) in brain and liver, and also in the formation and function of GSVs (GLUT4 storage vesicles) in adipocytes and muscle cells; (C) In astrocytes, LRP1 can mediate the GLUT1 trafficking. In neurons and hepatocytes, LRP1 is necessary for GLUT2 and GLUT3 translocation to the plasma membrane. HSPG: Heparan sulfate proteoglycan. SRA: scavenger receptor A. EE: early endosome. NOS: nitric oxide synthase. TGN: trans-Golgi network. *: NP-Xy motif. ?: non-characterized mechanism(s).