Metabolic dysfunction is integral to TGFb signaling and tissue fibrosis
Fibrosis, or the accumulation of extracellular matrix, causes loss of organ function and is a common feature of many chronic diseases. To interrogate core molecular pathways underlying fibrosis, we cross–examine human primary cells from various tissues treated with TGFß, as well as rodent kidney and liver fibrosis models. Transcriptome analyses reveal that in addition to the known TGFß signature, cluster of genes involved in fatty acid oxidation are significantly perturbed. Furthermore, defective mitochondrial oxidative phosphorylation and acylcarnitine accumulation are found in fibrotic tissues. Substantial down-regulation of the PGC1a gene is evident in both in vitro and in vivo fibrosis models, suggesting a common node of metabolic signature for all tissue fibrosis. In order to identify suppressors of fibrosis, we carry out a compound library phenotypic screen and identify AMPK and PPAR as highly enriched targets. We further show that pharmacological treatment of MK-8722 (AMPK activator) and MK-4074 (ACC inhibitor) reduce fibrosis in vivo. Altogether, our work demonstrate that metabolic defect is integral to TGFß signaling and fibrosis, targeting which represents a promising therapeutic approach for multiple fibrotic diseases. Overall design: Total RNA from human cells treated with TGFb in vitro, and rodent models of fibrosis (UUO, CCL4, and BDL) was sequenced. Rodent models of fibrosis: UUO: unilateral ureteral obstruction CCL4: carbon tetrachloride BDL: bile duct ligation