News on the molecular regulation and function of hepatic low-density lipoprotein receptor and LDLR-related protein 1

Abstract

Purpose of review: Clearing of atherogenic lipoprotein particles by the liver requires hepatic low-density lipoprotein receptor (LDLR) and LDLR-related protein 1 (LRP1). This review highlights recent studies that have expanded our understanding of the molecular regulation and metabolic functions of LDLR and LRP1 in the liver.

Recent findings: Various proteins orchestrate the intracellular trafficking of LDLR and LRP1. After internalization, the receptors are redirected via recycling endosomes to the cell surface. Several new endocytic proteins that facilitate the endosomal trafficking of LDLR and consequently the clearance of circulating LDL cholesterol have recently been reported. Mutations in some of these proteins cause hypercholesterolemia in human. In addition, LRP1 controls cellular cholesterol efflux by modulating the expression of ABCA1 and ABCG1, and hepatic LRP1 protects against diet-induced hepatic insulin resistance and steatosis through the regulation of insulin receptor trafficking.

Summary: LDLR and LRP1 have prominent roles in cellular and organismal cholesterol homeostasis. Their functioning, including their trafficking in the cell, is controlled by numerous proteins. Comprehensive studies into the molecular regulation of LDLR and LRP1 trafficking have advanced our fundamental understanding of cholesterol homeostasis, and these insights may lead to novel therapeutic strategies for atherosclerosis, hyperlipidemia and insulin resistance in the future.

Figure 1. Simplified model of the molecular regulation of cellular LDLR trafficking

Cholesterol-rich ApoE and ApoB containing lipoprotein particles bind to LDLR and are together with LDLR internalized and accordingly directed to the endosomes. Endocytosis is mediated by ARH in hepatocytes and recent data indicate that DAB2 facilitates LDLR internalization in sinusoid endothelial cells [13**]. At the endosomes, the CCC and WASH complexes recognize LDLR, sort and redirect LDLR back to the cell surface [19**]. Alternatively, LDLR is sent to the lysosomes for proteolysis, which is mediated by PCSK9 and/or IDOL. Esterified cholesterol is hydrolyzed by lysosomal acid lipase in the lysosomes, from where free cholesterol is further distributed to the plasma membrane and the endoplasmic reticulum [55*]. ARH: autosomal recessive hypercholesterolemia; CCC: COMMD1, CCDC22, CCDC93, C16orf62; DAB2: Disabled homolog 2; IDOL: Inducible degrader of the LDLR; PCSK9: Proprotein convertase subtilisin/kexin type-9; WASH: WASHC1, WASHC2A, WASHC3, WASHC4, and WASHC5.

Figure 2. Hepatic LRP1-mediated pathways

A. Like LDLR (Fig. 1), LRP1 clears cholesterol-rich ApoE containing particles from the circulation. B. LRP1-mediated Cathepsin D (CtsD) uptake is required for processing of Prosaposin (PSAP) into Saposins. Saposins positively controls the translocation of ABCA1 to the transmembrane. ABCA1 is an important hepatic cholesterol efflux transporter, and controls plasma HDL levels. C. Insulin-induced GLUT2 translocation to the plasma membrane depends on LRP1 [52**]. Hepatocyte LRP1 deficiency diminishes surface IR levels and consequently attenuates insulin induced GLUT2 translocation. IR: Insulin receptor.