Triglyceride Rich Lipoprotein -LPL-VLDL Receptor and Lp(a)-VLDL Receptor Pathways for Macrophage Foam Cell Formation

Abstract

Very low-density lipoprotein (VLDL) receptor is a member of the low-density lipoprotein (LDL) receptor family. It binds triglyceride rich lipoprotein (TGRL) but not LDL, because it recognizes apolipoprotein (apo)E only but not apoB. The VLDL receptor functions as a peripheral lipoprotein receptor in concert with lipoprotein lipase (LPL) in heart, muscle, adipose tissue and macrophages. In contrast to the LDL receptor, VLDL receptor binds apo E2/2 VLDL and apoE3/3 VLDL particles, and its expression is not down-regulated by intracellular lipoproteins. It has been reported that both LDL-cholesterol (LDL-C) and postprandial triglyceride (chyromicron and VLDL remnants) are risk factors for human atherosclerotic cardiovascular disease (ASCVD). True ligands such as lipoprotein particles of the VLDL receptor are chyromicron remnant (CMR) and VLDL remnant (postprandial hyperlipidemia). Although the oxidized LDL (oxLDL)-scavenger receptors pathway is considered to be the main mechanism for macrophage foam cell formation, it seems that the TGRL-LPL-VLDL receptor pathway is also involved. Since Lp(a) is one of the ligands for the VLDL receptor, the Lp(a)-VLDL receptor pathway is another potential alternative. The expression of VLDL receptor protein in mouse macrophages is modest compared to that in rabbit and human macrophages, both in vitro and in vivo. Therefore, we need to elucidate the mechanism of human ASCVD not by using the mouse model and scavenger receptors pathway but instead using the rabbit model and VLDL receptor pathway, respectively.

Keywords: Atherosclerosis; Lipoprotein lipase; Lp(a); Macrophage foam cell formation; VLDL receptor.

Fig. 1.

Structure of the VLDL receptor and the LDL receptory¹⁰⁾. PCSK9 binds the EGF-A site of both LDL receptor and VLDL receptor.

Fig. 2

Top: Non-fasting serum triglyceride (TG) in LDL-R KO and double KO mice (n = 6). Bottom: HPLC profile during 24 h fasting times in LDL-R KO and double KO mice.

Fig. 3.

Schematic diagram of the putative TGRL-LPL-VLDL receptor and Lp(a)-VLDL receptor pathways for macrophage foam cell formation. CM: chyromicron, CMR: chyromicron remnant, VLDL: very low-density lipoprotein, IDL: intermediate-density lipoprotein, LPL: lipoprotein lipase, ECs: endothelial cells, SMCs: smooth muscle cells