Your browser doesn't support javascript.
loading
Angiopoietin-like 4 promotes the intracellular cleavage of lipoprotein lipase by PCSK3/furin in adipocytes.
Dijk, Wieneke; Ruppert, Philip M M; Oost, Lynette J; Kersten, Sander.
Affiliation
  • Dijk W; From the Nutrition, Metabolism, and Genomics Group, Division of Human Nutrition and Health, Wageningen University, 6708 WE Wageningen, The Netherlands.
  • Ruppert PMM; From the Nutrition, Metabolism, and Genomics Group, Division of Human Nutrition and Health, Wageningen University, 6708 WE Wageningen, The Netherlands.
  • Oost LJ; From the Nutrition, Metabolism, and Genomics Group, Division of Human Nutrition and Health, Wageningen University, 6708 WE Wageningen, The Netherlands.
  • Kersten S; From the Nutrition, Metabolism, and Genomics Group, Division of Human Nutrition and Health, Wageningen University, 6708 WE Wageningen, The Netherlands sander.kersten@wur.nl.
J Biol Chem ; 293(36): 14134-14145, 2018 09 07.
Article in En | MEDLINE | ID: mdl-30021841
ABSTRACT
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.
Subject(s)
Key words

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Adipocytes / Furin / Angiopoietin-Like Protein 4 / Lipoprotein Lipase Limits: Animals / Humans Language: En Journal: J Biol Chem Year: 2018 Document type: Article Affiliation country:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Adipocytes / Furin / Angiopoietin-Like Protein 4 / Lipoprotein Lipase Limits: Animals / Humans Language: En Journal: J Biol Chem Year: 2018 Document type: Article Affiliation country: