Journal article
Angiopoietin-like 4 Modifies the Interactions between Lipoprotein Lipase and Its Endothelial Cell Transporter GPIHBP1
The Journal of biological chemistry, Vol.290(19), pp.11865-11877
05/08/2015
DOI: 10.1074/jbc.M114.623769
PMCID: PMC4424327
PMID: 25809481
Abstract
Background:
Lipoprotein lipase (LPL) function is modified by interactions with its transporter GPIHBP1 and the inhibitor angiopoietin-like 4 (ANGPTL4).
Results:
ANGPTL4 inactivated GPIHBP1-bound LPL. Inactivated LPL could not bind GPIHBP1.
Conclusion:
ANGPTL4 inactivation of LPL reduces the affinity of LPL for GPIHBP1 causing dissociation.
Significance:
Understanding ANGPTL4's interactions with LPL in a physiological context is vital to clarifying ANGPTL4's role in triglyceride metabolism.
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.
Details
- Title: Subtitle
- Angiopoietin-like 4 Modifies the Interactions between Lipoprotein Lipase and Its Endothelial Cell Transporter GPIHBP1
- Creators
- Xun Chi - From the Department of Biochemistry, Fraternal Order of Eagles Diabetes Research Center and Obesity Research and Education Initiative, University of Iowa, Iowa City, Iowa 52242Shwetha K Shetty - From the Department of Biochemistry, Fraternal Order of Eagles Diabetes Research Center and Obesity Research and Education Initiative, University of Iowa, Iowa City, Iowa 52242Hannah W Shows - From the Department of Biochemistry, Fraternal Order of Eagles Diabetes Research Center and Obesity Research and Education Initiative, University of Iowa, Iowa City, Iowa 52242Alexander J Hjelmaas - From the Department of Biochemistry, Fraternal Order of Eagles Diabetes Research Center and Obesity Research and Education Initiative, University of Iowa, Iowa City, Iowa 52242Emily K Malcolm - From the Department of Biochemistry, Fraternal Order of Eagles Diabetes Research Center and Obesity Research and Education Initiative, University of Iowa, Iowa City, Iowa 52242Brandon S. J Davies - 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
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.290(19), pp.11865-11877
- DOI
- 10.1074/jbc.M114.623769
- PMID
- 25809481
- PMCID
- PMC4424327
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- American Society for Biochemistry and Molecular Biology
- Alternative title
- Functional Interactions between GPIHBP1, ANGPTL4, and LPL
- Language
- English
- Date published
- 05/08/2015
- Academic Unit
- Anesthesia; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology
- Record Identifier
- 9984025273702771
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