title: FABP4/aP2 Regulates Macrophage Redox Signaling and Inflammasome Activation via Control of UCP2.
abstract: Obesity-linked metabolic disease is mechanistically associated with the accumulation of proinflammatory macrophages in adipose tissue, leading to increased reactive oxygen species (ROS) production and chronic low-grade inflammation. Previous work has demonstrated that deletion of the adipocyte fatty acid-binding protein (FABP4/aP2) uncouples obesity from inflammation via upregulation of the uncoupling protein 2 (UCP2). Here, we demonstrate that ablation of FABP4/aP2 regulates systemic redox capacity and reduces cellular protein sulfhydryl oxidation and, in particular, oxidation of mitochondrial protein cysteine residues. Coincident with the loss of FABP4/aP2 is the upregulation of the antioxidants superoxide dismutase (SOD2), catalase, methionine sulfoxide reductase A, and the 20S proteasome subunits PSMB5 and αβ. Reduced mitochondrial protein oxidation in FABP4/aP2-/-macrophages attenuates the mitochondrial unfolded-protein response (mtUPR) as measured by expression of heat shock protein 60, Clp protease, and Lon peptidase 1. Consistent with a diminished mtUPR, FABP4/aP2-/-macrophages exhibit reduced expression of cleaved caspase-1 and NLRP3. Secretion of interleukin 1β (IL-1β), in response to inflammasome activation, is ablated in FABP4/aP2-/-macrophages, as well as in FABP4/aP2 inhibitor-treated cells, but partially rescued in FABP4/aP2-null macrophages when UCP2 is silenced. Collectively, these data offer a novel pathway whereby FABP4/aP2 regulates macrophage redox signaling and inflammasome activation via control of UCP2 expression.
authors: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA.
authors: Kaylee A
authors: KA
authors: Steen
authors: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA.
authors: Hongliang
authors: H
authors: Xu
authors: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA bernl001@umn.edu.
authors: David A
authors: DA
authors: Bernlohr
mesh_terms: D049069:ATP-Dependent Proteases / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D020170:Caspase 1 / Q000378:metabolism; D018834:Chaperonin 60 / Q000378:metabolism; D003545:Cysteine / Q000378:metabolism; D059305:Diet, High-Fat; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism*; D017353:Gene Deletion; D006706:Homeostasis / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D000071246:Uncoupling Protein 2 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000975:Antioxidants; D018834:Chaperonin 60; C493411:Fabp4 protein, mouse; D050556:Fatty Acid-Binding Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D021122:Protein Subunits; D012333:RNA, Messenger; D000071246:Uncoupling Protein 2; D006861:Hydrogen Peroxide; D049069:ATP-Dependent Proteases; D020170:Caspase 1; D046988:Proteasome Endopeptidase Complex; D003545:Cysteine
keywords: FABP; UCP2; inflammasome; inflammation; mitochondrial metabolism; obesity