Angiopoietin-like 4 promotes the intracellular cleavage of lipoprotein lipase by PCSK3/furin in adipocytes
Open accessAbstract
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.
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In WAT, ANGPTL4 decreases the activity of LPL.
“In WAT, it was shown to stimulate lipolysis via induction of adipose triglyceride lipase [176,193] and to decrease the activity of LPL [178,194].”
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Self-citation
- Authors
- Dijk, W., Ruppert, P. M. M., Oost, L. J., & Kersten, S.
- Affiliations
- Wageningen University & Research (NL)
- Corresponding author
- Kersten, Sander
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2018-09
- Volume
- 293
- Issue
- 36
- Pages
- 14134-14145
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC6130958
- OpenAlex
- W2884453662
- Cited by
- 72
- References
- 52
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 5 · 2023: 5 · 2022: 8 · 2021: 14 · 2020: 14 · 2019: 12 · 2018: 2
- FWCI
- 7.93
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Socio-Environmental Systems Modeling (submittedVersion, cc-by)
- HAL (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, cc-by)
- Funders
- Fondation Leducq (12CVD04)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- ANGPTL4, lipoprotein lipase, furin, adipocytes, adipose tissue, fasting, insulin, triglyceride metabolism
- MeSH terms
- Angiopoietin-Like Protein 4, Animals, Humans, Insulin, Lipoprotein Lipase, Adipocytes, 3T3-L1 Cells, Furin, Mice
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