title: α1-Antitrypsin Combines with Plasma Fatty Acids and Induces Angiopoietin-like Protein 4 Expression.
abstract: α1-Antitrypsin (A1AT) purified from human plasma upregulates expression and release of angiopoietin-like protein 4 (Angptl4) in adherent human blood monocytes and in human lung microvascular endothelial cells, providing a mechanism for the broad immune-regulatory properties of A1AT independent of its antiprotease activity. In this study, we demonstrate that A1AT (Prolastin), a potent inducer of Angptl4, contains significant quantities of the fatty acids (FA) linoleic acid (C18:2) and oleic acid (C18:1). However, only trace amounts of FAs were present in preparations that failed to increase Angplt4 expression, for example, A1AT (Zemaira) or M-type A1AT purified by affinity chromatography. FA pull-down assays with Western blot analysis revealed a FA-binding ability of A1AT. In human blood-adherent monocytes, A1AT-FA conjugates upregulated expression of Angptl4 (54.9-fold, p < 0.001), FA-binding protein 4 (FABP4) (11.4-fold, p < 0.001), and, to a lesser degree, FA translocase (CD36) (3.1-fold, p < 0.001) relative to A1AT devoid of FA (A1AT-0). These latter effects of A1AT-FA were blocked by inhibitors of peroxisome proliferator-activated receptor (PPAR) β/δ (ST247) and PPARγ (GW9662). When compared with controls, cell pretreatment with ST247 diminished the effect of A1AT-LA on Angptl4 mRNA (11.6- versus 4.1-fold, p < 0.001) and FABP4 mRNA (5.4- versus 2.8-fold, p < 0.001). Similarly, preincubation of cells with GW9662 inhibited inducing effect of A1AT-LA on Angptl4 mRNA (by 2-fold, p < 0.001) and FABP4 mRNA (by 3-fold, p < 0.001). Thus, A1AT binds to FA, and it is this form of A1AT that induces Angptl4 and FABP4 expression via a PPAR-dependent pathway. These findings provide a mechanism for the unexplored area of A1AT biology independent of its antiprotease properties.
authors.affiliation: Department of Respiratory Medicine, Hannover Medical School, 30625 Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover, Member of the German Center for Lung Research, 30626 Hannover, Germany;
authors.forename: Eileen
authors.initials: E
authors.lastname: Frenzel
authors.affiliation: Department of Respiratory Medicine, Hannover Medical School, 30625 Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover, Member of the German Center for Lung Research, 30626 Hannover, Germany;
authors.forename: Sabine
authors.initials: S
authors.lastname: Wrenger
authors.affiliation: Biochemistry Center, Heidelberg University, 69120 Heidelberg, Germany;
authors.forename: Britta
authors.initials: B
authors.lastname: Brügger
authors.affiliation: Department of Respiratory Medicine, Hannover Medical School, 30625 Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover, Member of the German Center for Lung Research, 30626 Hannover, Germany;
authors.forename: Sandeep
authors.initials: S
authors.lastname: Salipalli
authors.affiliation: Institute for Transfusion Medicine, Hannover Medical School, 30625 Hannover, Germany;
authors.forename: Stephan
authors.initials: S
authors.lastname: Immenschuh
authors.affiliation: Department of Respiratory Medicine, Hannover Medical School, 30625 Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover, Member of the German Center for Lung Research, 30626 Hannover, Germany;
authors.forename: Nupur
authors.initials: N
authors.lastname: Aggarwal
authors.affiliation: Institute of Clinical Chemistry, Hannover Medical School, 30625 Hannover, Germany;
authors.forename: Ralf
authors.initials: R
authors.lastname: Lichtinghagen
authors.affiliation: Department of Respiratory Medicine, University of Cambridge, Cambridge CB2 0QQ, United Kingdom;
authors.forename: Ravi
authors.initials: R
authors.lastname: Mahadeva
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA 98195; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109;
authors.forename: A Mario Q
authors.initials: AM
authors.lastname: Marcondes
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, CO 80045; and Department of Medicine, Radboud University Medical Centre, Nijmegen 30625, the Netherlands.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.affiliation: Department of Respiratory Medicine, Hannover Medical School, 30625 Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover, Member of the German Center for Lung Research, 30626 Hannover, Germany;
authors.forename: Tobias
authors.initials: T
authors.lastname: Welte
authors.affiliation: Department of Respiratory Medicine, Hannover Medical School, 30625 Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover, Member of the German Center for Lung Research, 30626 Hannover, Germany; janciauskiene.sabina@mh-hannover.de.
authors.forename: Sabina
authors.initials: S
authors.lastname: Janciauskiene
mesh_terms: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000097:blood / Q000276:immunology*; D050556:Fatty Acid-Binding Proteins / Q000097:blood / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D019787:Linoleic Acid / Q000097:blood / Q000276:immunology*; D008297:Male; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D019301:Oleic Acid / Q000097:blood / Q000276:immunology*; D047495:PPAR gamma / Q000276:immunology / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000096:biosynthesis / Q000276:immunology*
chemical_list: C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C493410:FABP4 protein, human; D050556:Fatty Acid-Binding Proteins; D047495:PPAR gamma; D000515:alpha 1-Antitrypsin; D019301:Oleic Acid; D019787:Linoleic Acid