α1-antitrypsin combines with plasma fatty acids and induces angiopoietin-like protein 4 expression

• Verfasst von: Frenzel, Eileen [VerfasserIn]
• Verfasst von: Wrenger, Sabine [VerfasserIn]
• Verfasst von: Brügger, Britta [VerfasserIn]
• Verfasst von: Salipalli, Sandeep [VerfasserIn]
• Verfasst von: Immenschuh, Stephan [VerfasserIn]
• Verfasst von: Aggarwal, Nupur [VerfasserIn]
• Verfasst von: Lichtinghagen, Ralf [VerfasserIn]
• Verfasst von: Mahadeva, Ravi [VerfasserIn]
• Verfasst von: Marcondes, A. Mario Q. [VerfasserIn]
• Verfasst von: Dinarello, Charles A. [VerfasserIn]
• Verfasst von: Welte, Tobias [VerfasserIn]
• Verfasst von: Janciauskiene, Sabina [VerfasserIn]
• Titel: α1-antitrypsin combines with plasma fatty acids and induces angiopoietin-like protein 4 expression
• Verf.angabe: Eileen Frenzel, Sabine Wrenger, Britta Brügger, Sandeep Salipalli, Stephan Immenschuh, Nupur Aggarwal, Ralf Lichtinghagen, Ravi Mahadeva, A. Mario Q. Marcondes, Charles A. Dinarello, Tobias Welte and Sabina Janciauskiene
• E-Jahr: 2015
• Jahr: 11 September 2015
• Umfang: 12 S.
• Fussnoten: Gesehen am 26.11.2020
• Titel Quelle: Enthalten in: The journal of immunology
• Ort Quelle: Bethesda, Md. : Soc., 1916
• Jahr Quelle: 2015
• Band/Heft Quelle: 195(2015), 8, Seite 3605-3616
• ISSN Quelle: 1550-6606
• DOI: doi:10.4049/jimmunol.1500740
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1741217482

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.