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Angiopoietin-like 4 promotes the intracellular cleavage of lipoprotein lipase by PCSK3/furin in adipocytes

The Journal of biological chemistry, 2018-09, Vol.293 (36), p.14134-14145 [Peer Reviewed Journal]

2018 © 2018 Dijk et al. ;2018 Dijk et al. ;Distributed under a Creative Commons Attribution 4.0 International License ;2018 Dijk et al. 2018 Dijk et al. ;Wageningen University & Research ;ISSN: 0021-9258 ;EISSN: 1083-351X ;DOI: 10.1074/jbc.RA118.002426 ;PMID: 30021841

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Title:
Angiopoietin-like 4 promotes the intracellular cleavage of lipoprotein lipase by PCSK3/furin in adipocytes
Author: Dijk, Wieneke ; Ruppert, Philip M.M. ; Oost, Lynette J. ; Kersten, Sander
Subjects: 3T3-L1 Cells ; Adipocytes - metabolism ; Afdeling Humane voeding ; Angiopoietin-like 4 Protein - physiology ; Animals ; Biochemistry, Molecular Biology ; Cellular Biology ; Chair Nutrition Metabolism and Genomics ; Furin - metabolism ; HNE Nutrition, Metabolism and Genomics ; HNE Voeding, Metabolisme en Genomics ; Human Nutrition ; Human Nutrition & Health ; Human Nutrition (HNE) ; Humane Voeding ; Humane Voeding & Gezondheid ; Humans ; Insulin - pharmacology ; Life Sciences ; Lipids ; Lipoprotein Lipase - metabolism ; Mice ; Nutrition, Metabolism and Genomics ; VLAG ; Voeding, Metabolisme en Genomica
Is Part Of: The Journal of biological chemistry, 2018-09, Vol.293 (36), p.14134-14145
Description: Lipoprotein lipase (LPL) catalyzes the breakdown of circulating triglycerides in muscle and fat. LPL is inhibited by several proteins, including angiopoietin-like 4 (ANGPTL4), and may be cleaved by members of the proprotein convertase subtilisin/kexin (PCSK) family. Here, we aimed to investigate the cleavage of LPL in adipocytes by PCSKs and study the potential involvement of ANGPTL4. A substantial portion of LPL in mouse and human adipose tissue was cleaved into N- and C-terminal fragments. Treatment of different adipocytes with the PCSK inhibitor decanoyl-RVKR-chloromethyl ketone markedly decreased LPL cleavage, indicating that LPL is cleaved by PCSKs. Silencing of Pcsk3/furin significantly decreased LPL cleavage in cell culture medium and lysates of 3T3-L1 adipocytes. Remarkably, PCSK-mediated cleavage of LPL in adipocytes was diminished by Angptl4 silencing and was decreased in adipocytes and adipose tissue of Angptl4−/− mice. Differences in LPL cleavage between Angptl4−/− and WT mice were abrogated by treatment with decanoyl-RVKR-chloromethyl ketone. Induction of ANGPTL4 in adipose tissue during fasting enhanced PCSK-mediated LPL cleavage, concurrent with decreased LPL activity, in WT but not Angptl4−/− mice. In adipocytes, after removal of cell surface LPL by heparin, levels of N-terminal LPL were still markedly higher in WT compared with Angptl4−/− adipocytes, suggesting that stimulation of PCSK-mediated LPL cleavage by ANGPTL4 occurs intracellularly. Finally, treating adipocytes with insulin increased full-length LPL and decreased N-terminal LPL in an ANGPTL4-dependent manner. In conclusion, ANGPTL4 promotes PCSK-mediated intracellular cleavage of LPL in adipocytes, likely contributing to regulation of LPL in adipose tissue. Our data provide further support for an intracellular action of ANGPTL4 in adipocytes.
Publisher: United States: Elsevier Inc
Language: English
Identifier: ISSN: 0021-9258
EISSN: 1083-351X
DOI: 10.1074/jbc.RA118.002426
PMID: 30021841
Source: MEDLINE
PubMed Central
Alma/SFX Local Collection

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Angiopoietin-like 4 promotes the intracellular cleavage of lipoprotein lipase by PCSK3/furin in adipocytes

2018 © 2018 Dijk et al. ;2018 Dijk et al. ;Distributed under a Creative Commons Attribution 4.0 International License ;2018 Dijk et al. 2018 Dijk et al. ;Wageningen University & Research ;ISSN: 0021-9258 ;EISSN: 1083-351X ;DOI: 10.1074/jbc.RA118.002426 ;PMID: 30021841

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