title: Angiopoietin-like 4 Modifies the Interactions between Lipoprotein Lipase and Its Endothelial Cell Transporter GPIHBP1.
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.
authors: From the Department of Biochemistry, Fraternal Order of Eagles Diabetes Research Center and Obesity Research and Education Initiative, University of Iowa, Iowa City, Iowa 52242.
authors: Xun
authors: X
authors: Chi
authors: From the Department of Biochemistry, Fraternal Order of Eagles Diabetes Research Center and Obesity Research and Education Initiative, University of Iowa, Iowa City, Iowa 52242.
authors: Shwetha K
authors: SK
authors: Shetty
authors: From the Department of Biochemistry, Fraternal Order of Eagles Diabetes Research Center and Obesity Research and Education Initiative, University of Iowa, Iowa City, Iowa 52242.
authors: Hannah W
authors: HW
authors: Shows
authors: From the Department of Biochemistry, Fraternal Order of Eagles Diabetes Research Center and Obesity Research and Education Initiative, University of Iowa, Iowa City, Iowa 52242.
authors: Alexander J
authors: AJ
authors: Hjelmaas
authors: From the Department of Biochemistry, Fraternal Order of Eagles Diabetes Research Center and Obesity Research and Education Initiative, University of Iowa, Iowa City, Iowa 52242.
authors: Emily K
authors: EK
authors: Malcolm
authors: From the Department of Biochemistry, Fraternal Order of Eagles Diabetes Research Center and Obesity Research and Education Initiative, University of Iowa, Iowa City, Iowa 52242 Brandon-davies@uiowa.edu.
authors: Brandon S J
authors: BS
authors: Davies
mesh_terms: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000737:chemistry; D042783:Endothelial Cells / Q000166:cytology / Q000201:enzymology*; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D008066:Lipolysis; D008071:Lipoprotein Lipase / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D018110:Receptors, Lipoprotein / Q000378:metabolism*; D014280:Triglycerides / Q000737:chemistry
chemical_list: C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D017077:Culture Media, Conditioned; C523701:GPIHBP1 protein, human; D018110:Receptors, Lipoprotein; D014280:Triglycerides; D008071:Lipoprotein Lipase
keywords: Endothelial Cell; Lipase; Lipolysis; Lipoprotein Metabolism; Triglyceride