TY - JOUR T1 - Orphan nuclear receptor COUP-TFII drives the myofibroblast metabolic shift leading to fibrosis JF - bioRxiv DO - 10.1101/2020.06.05.135889 SP - 2020.06.05.135889 AU - Li Li AU - Pierre Galichon AU - Xiaoyan Xiao AU - Ana C Figueroa-Ramirez AU - Diana Tamayo AU - Jake June-Koo Lee AU - Marian Kalocsay AU - David Gonzalez-Sanchez AU - Maria S Chancay AU - Kyle McCracken AU - Dario Lemos AU - Nathan Lee AU - Takaharu Ichimura AU - Yutaro Mori AU - M. Todd Valerius AU - Xiaoming Sun AU - Elazer R Edelman AU - Joseph V Bonventre Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/06/05/2020.06.05.135889.abstract N2 - Recent studies demonstrated that metabolic disturbance, such as augmented glycolysis, contributes to fibrosis. The molecular regulation of this metabolic perturbation in fibrosis, however, has been elusive. COUP-TFII (also known as NR2F2) is an important regulator of glucose and lipid metabolism. Its contribution to organ fibrosis is undefined. Here, we found increased COUP-TFII expression in myofibroblasts in kidneys of patients with chronic kidney disease, fibrotic lungs of patients with idiopathic pulmonary fibrosis, fibrotic human kidney organoids, and fibrotic mouse kidneys after injury. Genetic ablation of COUP-TFII in mice resulted in attenuation of injury-induced kidney fibrosis. A non-biased proteomic study revealed the suppression of fatty acid oxidation and the enhancement of glycolysis pathways in COUP-TFII overexpressing fibroblasts. Overexpression of COUP-TFII in fibroblasts was sufficient to enhance glycolysis and increase alpha smooth muscle actin (αSMA) and collagen1 levels. Knockout of COUP-TFII decreased glycolysis and collagen1 levels in fibroblasts. Chip-qPCR assays revealed the binding of COUP-TFII on the promoter of PGC1α, a critical regulator of mitochondrial genesis and oxidative metabolism. Overexpression of COUP-TFII reduced the cellular level of PGC1α. In conclusion, COUP-TFII mediates fibrosis by serving as a key regulator of the shift in cellular metabolism of interstitial pericytes/fibroblasts from oxidative respiration to aerobic glycolysis. The fibrogenic response may share a common pathway in different organ injury and failure. Targeting COUP-TFII serves as a novel treatment approach for mitigating fibrosis in chronic kidney disease and potential other organ fibrosis. ER -