Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E

Robert W Mahley,Zhong-Sheng Ji

doi:10.1016/s0022-2275(20)33334-4

Abstract

The plasma clearance of intestinally derived remnant lipoproteins by the liver is a process that likely involves three steps. Our model suggests that the initial rapid clearance by the liver begins with sequestration of the remnants within the space of Disse, where apolipoprotein E secreted by hepatocytes enhances remnant binding and uptake. Heparan sulfate proteoglycans (HSPG), which are also abundant in the space of Disse, mediate this enhanced binding. Next, the remnants undergo further processing in the space of Disse by hepatic and lipoprotein lipases, which may also serve as ligands mediating remnant uptake. The final step, endocytosis by hepatocytes, appears to be mediated, at least in part, by the low density lipoprotein (LDL) receptor and by the LDL receptor-related protein (LRP). Cell-surface HSPG play a critical role in remnant uptake, not only in the important initial sequestration or capture step in the space of Disse, but also as an essential or integral component of the HSPG-LRP pathway. In addition, HSPG appear to function alone as a receptor and display unique handling properties for specific isoforms of apolipoprotein E.

Highlights

The plasma clearance of intestinally derived remnant lipoproteins by the liver is a process that likely involves three steps
In animals whose diets are high in fat and cholesterol and in patients with type III hyperlipoproteinemia, chylomicron remnants accumulate in the plasma and have been linked to the development of accelerated atherosclerosis
Very low density lipoproteins (d Ͻ 1.006 g/ml) are synthesized in the liver and, like chylomicrons, fulfill a lipid transport function. The triglycerides in these particles are hydrolyzed by lipoprotein lipase (LPL) in the plasma and in the liver, generating small, cholesterol-enriched lipoproteins known as intermediate density lipoproteins (IDL; d 1.006–1.019 g/ ml) and low density lipoproteins (LDL; d 1.019–1.063 g/ml) (Fig. 1)

Summary

64 Ϯ 11 15 Ϯ 4 22 Ϯ 7

Saline or heparinase (30 units) was allowed to circulate for 5 min before injection of the radiolabeled activated ␣2-macroglobulin, LDL, or ␤-VLDL ϩ apoE. Our in vitro data indicated that activated ␣2-macroglobulin can, to a limited extent, compete with ␤-VLDL for LRP binding [99] In these in vivo studies in mice, inactive ␣2-macroglobulin or saline was injected into a tail vein, followed 1 min later by injection of radiolabeled chylomicron remnants into a contralateral vein. After injection of activated ␣2-macroglobulin and labeled chylomicrons, only about 60% of the remnants appeared in the liver This small but significant decrease indicated that ␣2-macroglobulin can compete for remnant clearance and that the LRP is involved, to some extent, in remnant clearance. When RAP was overexpressed to impair the HSPG-LRP pathway in the LDL receptor-null mice, cholesterol and triglycerides increased more than 10-fold, accompanied by a large increase in remnant lipoproteins in the plasma.

94 Ϯ 10 155 Ϯ 22 254 Ϯ 27 1203 Ϯ 168

Findings

Summary