ANGPTL8 promotes the ability of ANGPTL3 to bind and inhibit lipoprotein lipase

Xun Chi; Emily C Britt; Hannah W Shows; Alexander J Hjelmaas; Shwetha K Shetty; Emily M Cushing; Wendy Li; Alex Dou; Ren Zhang; Brandon S.J Davies

doi:10.1016/j.molmet.2017.06.014

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ANGPTL8 promotes the ability of ANGPTL3 to bind and inhibit lipoprotein lipase

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ANGPTL8 promotes the ability of ANGPTL3 to bind and inhibit lipoprotein lipase

Xun Chi, Emily C Britt, Hannah W Shows, Alexander J Hjelmaas, Shwetha K Shetty, Emily M Cushing, Wendy Li, Alex Dou, Ren Zhang and Brandon S.J Davies

Molecular metabolism (Germany), Vol.6(10), pp.1137-1149

10/2017

DOI: 10.1016/j.molmet.2017.06.014

PMCID: PMC5641604

PMID: 29031715

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Abstract

Several members of the angiopoietin-like (ANGPTL) family of proteins, including ANGPTL3 and ANGPTL8, regulate lipoprotein lipase (LPL) activity. Deficiency in either ANGPTL3 or ANGPTL8 reduces plasma triglyceride levels and increases LPL activity, whereas overexpression of either protein does the opposite. Recent studies suggest that ANGPTL8 may functionally interact with ANGPTL3 to alter clearance of plasma triglycerides; however, the nature of this interaction has remained elusive. We tested the hypothesis that ANGPTL8 forms a complex with ANGPTL3 and that this complex is necessary for the inhibition of vascular LPL by ANGPTL3. We analyzed the interactions of ANGPTL3 and ANGPTL8 with each other and with LPL using co-immunoprecipitation, western blotting, lipase activity assays, and the NanoBiT split-luciferase system. We also used adenovirus injection to overexpress ANGPTL3 in mice that lacked ANGPTL8. We found that ANGPTL3 or ANGPTL8 alone could only inhibit LPL at concentrations that far exceeded physiological levels, especially when LPL was bound to its endothelial cell receptor/transporter GPIHBP1 (glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1). Physical interaction was observed between ANGPTL3 and ANGPTL8 when the proteins were co-expressed, and co-expression with ANGPTL3 greatly enhanced the secretion of ANGPTL8. Importantly, ANGPTL3–ANGPTL8 complexes had a dramatically increased ability to inhibit LPL compared to either protein alone. Adenovirus experiments showed that 2-fold overexpression of ANGPTL3 significantly increased plasma triglycerides only in the presence of ANGPTL8. Protein interaction assays showed that ANGPTL8 greatly increased the ability of ANGPTL3 to bind LPL. Together, these data indicate that ANGPTL8 binds to ANGPTL3 and that this complex is necessary for ANGPTL3 to efficiently bind and inhibit LPL. •ANGPTL3 by itself is not a potent inhibitor of LPL.•When co-expressed, ANGPTL3 and ANGPTL8 form a complex.•ANGPTL3 facilitates the secretion of ANGPTL8.•ANGPTL3–ANGPTL8 complexes bind to LPL much better than either protein alone.•ANGPTL3 requires ANGPTL8 to efficiently inhibit LPL both in vitro and in vivo.

Lipase inhibition

Lipoprotein metabolism

Lipolysis

Plasma triglycerides

Details

Title: Subtitle: ANGPTL8 promotes the ability of ANGPTL3 to bind and inhibit lipoprotein lipase
Creators: Xun Chi - Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Emily C Britt - Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Hannah W Shows - Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Alexander J Hjelmaas - Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Shwetha K Shetty - Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Emily M Cushing - Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Wendy Li - Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Alex Dou - Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Ren Zhang - Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, 540 East Canfield Street, Detroit, MI 48201, USA
Brandon S.J Davies - Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Resource Type: Journal article
Publication Details: Molecular metabolism (Germany), Vol.6(10), pp.1137-1149
DOI: 10.1016/j.molmet.2017.06.014
PMID: 29031715
PMCID: PMC5641604
NLM abbreviation: Mol Metab
ISSN: 2212-8778
eISSN: 2212-8778
Publisher: Elsevier GmbH
Language: English
Date published: 10/2017
Academic Unit: Anesthesia; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology
Record Identifier: 9984024518602771

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