title: Angiopoietin-like 4 promotes intracellular degradation of lipoprotein lipase in adipocytes.
abstract: LPL hydrolyzes triglycerides in triglyceride-rich lipoproteins along the capillaries of heart, skeletal muscle, and adipose tissue. The activity of LPL is repressed by angiopoietin-like 4 (ANGPTL4) but the underlying mechanisms have not been fully elucidated. Our objective was to study the cellular location and mechanism for LPL inhibition by ANGPTL4. We performed studies in transfected cells, ex vivo studies, and in vivo studies with Angptl4(-/-) mice. Cotransfection of CHO pgsA-745 cells with ANGPTL4 and LPL reduced intracellular LPL protein levels, suggesting that ANGPTL4 promotes LPL degradation. This conclusion was supported by studies of primary adipocytes and adipose tissue explants from wild-type and Angptl4(-/-) mice. Absence of ANGPTL4 resulted in accumulation of the mature-glycosylated form of LPL and increased secretion of LPL. Blocking endoplasmic reticulum (ER)-Golgi transport abolished differences in LPL abundance between wild-type and Angptl4(-/-) adipocytes, suggesting that ANGPTL4 acts upon LPL after LPL processing in the ER. Finally, physiological changes in adipose tissue ANGPTL4 expression during fasting and cold resulted in inverse changes in the amount of mature-glycosylated LPL in wild-type mice, but not Angptl4(-/-) mice. We conclude that ANGPTL4 promotes loss of intracellular LPL by stimulating LPL degradation after LPL processing in the ER.
authors.affiliation: Nutrition, Metabolism, and Genomics Group, Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands.
authors.forename: Wieneke
authors.initials: W
authors.lastname: Dijk
authors.affiliation: Departments of Medicine David Geffen School of Medicine, University of California, Los Angeles, CA.
authors.forename: Anne P
authors.initials: AP
authors.lastname: Beigneux
authors.affiliation: Departments of Medicine David Geffen School of Medicine, University of California, Los Angeles, CA.
authors.forename: Mikael
authors.initials: M
authors.lastname: Larsson
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY.
authors.forename: André
authors.initials: A
authors.lastname: Bensadoun
authors.affiliation: Departments of Medicine David Geffen School of Medicine, University of California, Los Angeles, CA Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Young
authors.affiliation: Nutrition, Metabolism, and Genomics Group, Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands Division of Nutritional Sciences, Cornell University, Ithaca, NY sander.kersten@wur.nl.
authors.forename: Sander
authors.initials: S
authors.lastname: Kersten
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003593:Cytoplasm / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism*; D008074:Lipoproteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D059748:Proteolysis; D014280:Triglycerides / Q000235:genetics* / Q000378:metabolism
chemical_list: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C407088:Angptl4 protein, mouse; D008074:Lipoproteins; D014280:Triglycerides; C030087:lipoprotein triglyceride; D008071:Lipoprotein Lipase
keywords: adipose tissue; intracellular processing; lipid metabolism; vascular biology