HDL-ApoE Content Regulates the Displacement of Hepatic Lipase from Cell Surface Proteoglycans

Abstract

Human hepatic lipase (HL) is an interfacial enzyme that must be liberated from cell surface proteoglycans to hydrolyze lipoprotein triglyceride. Both high-density lipoprotein (HDL) and apolipoprotein (apo)A-I can displace HL from cell surface proteoglycans, much like heparin. HL displacement is inhibited by HDL-apoE content. Postprandial HDL is approximately twofold better at displacing HL than is fasting HDL, but only has approximately one-half the apoE content. Enriching native HDL with triglyceride decreases HDL-apoE content and increases HL displacement. Incubation of HDL with the anti-apoE antibody, 6C5, also increases HL displacement. In contrast, enrichment of synthetic HDL with apoE significantly inhibits HL displacement. HDL from fasted female normolipidemic subjects displaces HL approximately twofold better than HDL from male subjects. HDL from female subjects also has significantly less apoE than HDL from males. Normolipidemic females have increased circulating HDL-bound HL. Hyperlipidemia has little effect on the HL displacement ability of HDL from men, whereas HDL from hypercholesterolemic females exhibits impaired HL displacement. HL displacement from liver heparan sulfate proteoglycans therefore appears to be linked to interlipoprotein apoE exchange. Decreased HL displacement is associated with higher HDL-apoE levels and may therefore affect vascular triglyceride hydrolysis. (Am J Pathol

Hepatic Lipase, High Density Lipoproteins, and Hypertriglyceridemia

“…More recently, HDL and serum isolated from postprandial subjects were shown to promote increased HL displacement, relative to samples from fasted subjects. 22 The study showed that, even though postprandial HDL is TG-enriched, the lipoprotein is deficient in ApoE and is more effective than fasting HDL at binding to and displacing cell-surface HL. 22 Hepatic lipase displacement appears to be controlled by HDL apolipoproteins and is stimulated by the ApoA-II content of HDL.…”

“…22 The study showed that, even though postprandial HDL is TG-enriched, the lipoprotein is deficient in ApoE and is more effective than fasting HDL at binding to and displacing cell-surface HL. 22 Hepatic lipase displacement appears to be controlled by HDL apolipoproteins and is stimulated by the ApoA-II content of HDL. 21 ApoA-II increases the release of HL from HSPG by enhancing the association of HL with HDL, and this increased association promotes an inhibition of HL activity.…”

“…30,31 Conversely, HL displacement is inhibited by HDL-ApoE. 22 Young et al 22 showed that HDL isolated from female subjects was significantly better at displacing HL from cell surface HSPG, relative to HDL from male subjects. HDL isolated from the plasma of women also contained less ApoE, compared with that isolated from men.…”

“…The study identified an inverse relationship between HDL-ApoE content and the amount of circulating HL in the bloodstream. 22 Increased ApoE content on HDL results in decreased HL release (Figure 1). Treatment of HDL with monoclonal ApoE antibodies, directed against epitopes in the glutamic acid-enriched N-terminus of ApoE, resulted in greater HL displacement, 22 which sug- gests that the binding of HL to HDL may be sensitive to ApoE-dependent electrostatic properties of the lipoprotein.…”

“…22 Increased ApoE content on HDL results in decreased HL release (Figure 1). Treatment of HDL with monoclonal ApoE antibodies, directed against epitopes in the glutamic acid-enriched N-terminus of ApoE, resulted in greater HL displacement, 22 which sug- gests that the binding of HL to HDL may be sensitive to ApoE-dependent electrostatic properties of the lipoprotein. Other work has shown that HL activity is also dependent on electrostatic events that regulate the association of HL with HDL.…”