title: Furin is the primary in vivo convertase of angiopoietin-like 3 and endothelial lipase in hepatocytes.
abstract: The proprotein convertases (PCs) furin, PC5/6, and PACE4 exhibit unique and/or complementary functions. Their knock-out (KO) in mice resulted in strong and specific phenotypes demonstrating that, in vivo, these PCs are unique and essential during development. However, they also exhibit redundant functions. Liver angiopoietin-like 3 (ANGPTL3) inhibits lipolysis by binding to lipoprotein lipases. It is found in the plasma as full length and truncated forms. The latter is more active and generated by cleavage at a furin-like site. Endothelial lipase (EL) binds heparin sulfate proteoglycans on cell surfaces and catalyzes the hydrolysis of HDL phospholipids. EL activity is regulated by two endogenous inhibitors, ANGPTL3 and ANGPTL4, and by PCs that inactivate EL through cleavage releasing the N-terminal catalytic and C-terminal lipid-binding domains. Herein, because furin and PC5/6 complete KOs are lethal, we used mice lacking furin or PC5/6 specifically in hepatocytes (hKO) or mice completely lacking PACE4. In primary hepatocytes, ANGPTL3 was processed into a shorter form of ANGPTL3 intracellularly by furin only, and extracellularly mainly by PACE4. In vivo, the absence of furin in hepatocytes reduced by ∼50% the circulating levels of cleaved ANGPTL3, while the lack of PACE4 had only a minor effect. Analysis of the EL processing in primary hepatocytes and in vivo revealed that it is mostly cleaved by furin. However, the lack of furin or PC5/6 in hepatocytes and complete PACE4 KO did not appreciably modify plasma HDL levels or EL activity. Thus, inhibition of furin in liver would not be expected to modify the plasma lipid profiles.
authors.affiliation: From the Laboratories of Biochemical Neuroendocrinology and.
authors.forename: Rachid
authors.initials: R
authors.lastname: Essalmani
authors.forename: Delia
authors.initials: D
authors.lastname: Susan-Resiga
authors.forename: Ann
authors.initials: A
authors.lastname: Chamberland
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Asselin
authors.forename: Maryssa
authors.initials: M
authors.lastname: Canuel
authors.forename: Daniel
authors.initials: D
authors.lastname: Constam
authors.forename: John W
authors.initials: JW
authors.lastname: Creemers
authors.forename: Robert
authors.initials: R
authors.lastname: Day
authors.forename: Dany
authors.initials: D
authors.lastname: Gauthier
authors.forename: Annik
authors.initials: A
authors.lastname: Prat
authors.forename: Nabil G
authors.initials: NG
authors.lastname: Seidah
mesh_terms: D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D008076:Cholesterol, HDL / Q000378:metabolism; D045683:Furin / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing; D022781:Hepatocytes / Q000201:enzymology*; D008049:Lipase / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010743:Phospholipids / Q000378:metabolism; D045702:Proprotein Convertase 5 / Q000235:genetics
chemical_list: D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; C404495:Angptl3 protein, mouse; D008076:Cholesterol, HDL; D008075:Lipoproteins, HDL; D010743:Phospholipids; D008049:Lipase; C498741:Lipg protein, mouse; D045702:Proprotein Convertase 5; C473805:propeptide convertase 5, mouse; D045683:Furin
keywords: Angiopoietin-like 3; Cholesterol; Endothelial Lipase; Furin; HDL; Knockout Mice; Lipoprotein; Phospholipase; Proprotein Convertases; Protease
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