| First Author | Steen KA | Year | 2017 |
| Journal | Mol Cell Biol | Volume | 37 |
| Issue | 2 | PubMed ID | 27795298 |
| Mgi Jnum | J:243802 | Mgi Id | MGI:5912581 |
| Doi | 10.1128/MCB.00282-16 | Citation | Steen KA, et al. (2017) FABP4/aP2 Regulates Macrophage Redox Signaling and Inflammasome Activation via Control of UCP2. Mol Cell Biol 37(2) |
| abstractText | 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 alphabeta. 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 1beta (IL-1beta), 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. |
