Abstract

The release of fatty acids from plasma triglycerides for tissue uptake is critically dependent on the enzyme lipoprotein lipase (LPL). Hydrolysis of plasma triglycerides by LPL can be disrupted by the protein angiopoietin-like 4 (ANGPTL4), and ANGPTL4 has been shown to inactivate LPL in vitro. However, in vivo LPL is often complexed to glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) on the surface of capillary endothelial cells. GPIHBP1 is responsible for trafficking LPL across capillary endothelial cells and anchors LPL to the capillary wall during lipolysis. How ANGPTL4 interacts with LPL in this context is not known. In this study, we investigated the interactions of ANGPTL4 with LPL-GPIHBP1 complexes on the surface of endothelial cells. We show that ANGPTL4 was capable of binding and inactivating LPL complexed to GPIHBP1 on the surface of endothelial cells. Once inactivated, LPL dissociated from GPIHBP1. We also show that ANGPTL4-inactivated LPL was incapable of binding GPIHBP1. ANGPTL4 was capable of binding, but not inactivating, LPL at 4 °C, suggesting that binding alone was not sufficient for ANGPTL4's inhibitory activity. We observed that although the N-terminal coiled-coil domain of ANGPTL4 by itself and full-length ANGPTL4 both bound with similar affinities to LPL, the N-terminal fragment was more potent in inactivating both free and GPIHBP1-bound LPL. These results led us to conclude that ANGPTL4 can both bind and inactivate LPL complexed to GPIHBP1 and that inactivation of LPL by ANGPTL4 greatly reduces the affinity of LPL for GPIHBP1.

Highlights

  • Lipoprotein lipase (LPL) function is modified by interactions with its transporter glycosylphosphatidylinositolanchored high density lipoprotein-binding protein 1 (GPIHBP1) and the inhibitor angiopoietin-like 4 (ANGPTL4)

  • We investigated the interactions of ANGPTL4 with lipoprotein lipase (LPL)-GPIHBP1 complexes on the surface of endothelial cells

  • These results led us to conclude that ANGPTL4 can both bind and inactivate LPL complexed to GPIHBP1 and that inactivation of LPL by ANGPTL4 greatly reduces the affinity of LPL for GPIHBP1

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Summary

Background

Lipoprotein lipase (LPL) function is modified by interactions with its transporter GPIHBP1 and the inhibitor angiopoietin-like 4 (ANGPTL4). In vivo LPL is often complexed to glycosylphosphatidylinositolanchored high density lipoprotein-binding protein 1 (GPIHBP1) on the surface of capillary endothelial cells. We investigated the interactions of ANGPTL4 with LPL-GPIHBP1 complexes on the surface of endothelial cells. We show that ANGPTL4 was capable of binding and inactivating LPL complexed to GPIHBP1 on the surface of endothelial cells. Delivery of dietary fat is crucially dependent on the activity of lipoprotein lipase (LPL), which hydrolyzes plasma triglycerides, liberating fatty acids for tissue uptake. In addition to GPIHBP1, LPL interacts with a number of extracellular factors that modulate its activity and function [6, 7, 19] One of these factors, ANGPTL4 (angiopoietin-like 4), has emerged as an important regulator of triglyceride clearance. Because it is important to understand the ability of ANGPTL4 to interact with LPL in physiological contexts, we investigated how ANGPTL4 interacts with LPL bound to the surface of endothelial cells by GPIHBP1, as well as how these interactions modify LPL-GPIHBP1 complexes

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