Molecular Profiling Reveals a Common Metabolic Signature of Tissue Fibrosis

Fibrosis, or the accumulation of extracellular matrix, 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 TGF-β, as well as kidney and liver fibrosis models. Transcriptome analyses reveal that genes involved in fatty acid oxidation are significantly perturbed. Furthermore, mitochondrial dysfunction and acylcarnitine accumulation are found in fibrotic tissues. Substantial downregulation of the PGC1α gene is evident in both in vitro and in vivo fibrosis models, suggesting a common node of metabolic signature for 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 TGF-β signaling and fibrosis. [Display omitted] Profiling of multiple fibrosis models reveals a common fatty acid oxidation defectDownregulation of PGC1α expression in both in vitro and in vivo fibrosis modelsCompound library screen identifies AMPK and PPAR as enriched targets for fibrosisMK-8722 and MK-4074 treatment reduces liver fibrosis in a NASH model Fibrosis, also known as scarring of the tissue, is a common feature of many chronic diseases. Zhang et al. combine transcriptome profiling, metabolomics, metabolic flux analyses, and high-throughput compound library phenotypic screening to show that metabolic defect is a common feature of tissue fibrosis.