Molecular Profiling Reveals a Common Metabolic Signature of Tissue Fibrosis
| Autor: | David G. McLaren, Lan Yi, Shirly Pinto, Ye Tian, Kristian K. Jensen, Kristine Devito, Elizabeth Smith, Philippe Costet, Iyassu K. Sebhat, Stephen F. Previs, Emanuel Zycband, James Conway, Eric S. Muise, Seongah Han, Yongcheng Huang, Kashmira Shah, Ying Chen, Jason E. Imbriglio, Ji Zhang, Vinit Shah, Peter S. Kutchukian, Haihong Zhou, Tian-Quan Cai, Li-Jun Ma, Yonghua Zhu, Yanqing Kan, Taro E. Akiyama, Ester Carballo-Jane, Maarten Hoek, Xiaolan Shen, Saswata Talukdar, Andrea M. Peier, Ashmita Saigal |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
TGF-β
AMPK Male MK-8722 Pyridines Phenotypic screening Peroxisome proliferator-activated receptor Gene Expression Biology Kidney PPAR General Biochemistry Genetics and Molecular Biology Article Extracellular matrix Transcriptome Rats Sprague-Dawley Mice Downregulation and upregulation Fibrosis Transforming Growth Factor beta PGC1α medicine Animals Humans Beta oxidation fatty acid oxidation Cells Cultured chemistry.chemical_classification MK-4074 lcsh:R5-920 Gene Expression Profiling fibrosis Adenylate Kinase medicine.disease Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Extracellular Matrix Rats Mice Inbred C57BL chemistry Organ Specificity Cancer research Benzimidazoles lcsh:Medicine (General) metabolism Signal Transduction |
| Zdroj: | Cell Reports Medicine Cell Reports Medicine, Vol 1, Iss 4, Pp 100056-(2020) |
| ISSN: | 2666-3791 |
| Popis: | Summary 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. Graphical Abstract Highlights Profiling of multiple fibrosis models reveals a common fatty acid oxidation defect Downregulation of PGC1α expression in both in vitro and in vivo fibrosis models Compound library screen identifies AMPK and PPAR as enriched targets for fibrosis MK-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. |
| Databáze: | OpenAIRE |
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