title: Proteolytic processing of angiopoietin-like protein 4 by proprotein convertases modulates its inhibitory effects on lipoprotein lipase activity.
abstract: Angiopoietin-like protein 4 (ANGPTL4) has been associated with a variety of diseases. It is known as an endogenous inhibitor of lipoprotein lipase (LPL), and it modulates lipid deposition and energy homeostasis. ANGPTL4 is cleaved by unidentified protease(s), and the biological importance of this cleavage event is not fully understood with respect to its inhibitory effect on LPL activity. Here, we show that ANGPTL4 appears on the cell surface as the full-length form, where it can be released by heparin treatment in culture and in vivo. ANGPTL4 protein is then proteolytically cleaved into several forms by proprotein convertases (PCs). Several PCs, including furin, PC5/6, paired basic amino acid-cleaving enzyme 4, and PC7, are able to cleave human ANGPTL4 at a consensus site. PC-specific inhibitors block the processing of ANGPTL4. Blockage of ANGPTL4 cleavage reduces its inhibitory effects on LPL activity and decreases its ability to raise plasma triglyceride levels. In summary, the cleavage of ANGPTL4 by these PCs modulates its inhibitory effect on LPL activity.
authors.affiliation: Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, New York 11203, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Lei
authors.forename: Fujun
authors.initials: F
authors.lastname: Shi
authors.forename: Debapriya
authors.initials: D
authors.lastname: Basu
authors.forename: Afroza
authors.initials: A
authors.lastname: Huq
authors.forename: Sophie
authors.initials: S
authors.lastname: Routhier
authors.forename: Robert
authors.initials: R
authors.lastname: Day
authors.forename: Weijun
authors.initials: W
authors.lastname: Jin
mesh_terms: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D043484:Proprotein Convertases / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood / Q000235:genetics
chemical_list: C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C407088:Angptl4 protein, mouse; D014280:Triglycerides; C548261:LPL protein, human; D008071:Lipoprotein Lipase; D043484:Proprotein Convertases