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

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.Hepatic lipase (HL) is an interfacial enzyme that is bound to the surface of hepatocytes by heparan sulfate proteoglycans (HSPG).¹ HL hydrolyzes both triglycerides (TG) and phospholipids in plasma lipoproteins. HL activity is undetectable in fasted plasma and can only be measured after HL is released from the liver with an injection of heparin. Elevated postheparin HL activities are considered to be a risk factor of heart disease and correspond to a pro-atherogenic lipid profile. Patients with familial hyperlipidemia² and type 2 diabetes patients,³ who are at a higher risk for heart disease, also have elevated postheparin HL activity. Other heart disease risk factors have also been linked to a higher postheparin HL activity including smoking,⁴ visceral obesity,⁵ and sedentary lifestyle.⁶ An increase in androgenous hormones, such as testosterone, leads to an increase in postheparin HL activity^7,8 and an increase in estrogen can lower postheparin HL activity.^9,10 Women consequently tend to have a lower postheparin activity than men.¹¹HL must be liberated from cell surface HSPG to hydrolyze lipoprotein TG.¹² A higher postheparin activity therefore appears to be a marker for a larger liver depot of inactive HSPG-bound HL. High-density lipoprotein (HDL) has been shown to displace HL from the cell surface much like heparin^12,13,14; however, the composition of the HDL can affect its ability to displace HL. While apolipoprotein A-I (apoA-I), apolipoprotein A-II (apoA-II) and apolipoprotein C-I (apoC-I) appear to stimulate HL displacement, other apoproteins had the opposite effect and blocked HDL from displacing cell surface HL.^12,13,14 Apolipoprotein E (apoE) is an exchangeable apolipoprotein present on both HDL- and TG-rich lipoproteins. Plasma apoE levels appear to correlate to postheparin HL activity.^15,16 It has been shown that women have lower plasma apoE levels than men^15,16 and that hyperlipidemic patients have higher amounts of plasma apoE than normolipidemic subjects.^17,18,19 Subjects with very high levels of plasma apoE have also been shown to be hypertriglyceridemic¹⁷ and high levels of apoE can increase cardiovascular disease mortality, specifically in the older population.²⁰In this study, we show that increasing apoE content of synthetic HDL directly inhibits HL displacement. Conversely, HDL isolated at the peak of a postprandial response contains less apoE and is more effective at displacing HL, than HDL isolated from fasted plasma. HDL isolated from females contains lower levels of apoE and displaces more HL from cell-surface HSPG, than HDL isolated from males. Women were also shown to have significantly more HDL-bound HL circulating in their bloodstream. Interlipoprotein apoE movement therefore plays central role in regulating the displacement and hydrolytic activity of HL.