Molecular Profiling Reveals a Common Metabolic Signature of Tissue Fibrosis.
Cell Rep Med
; 1(4): 100056, 2020 07 21.
Article
in En
| MEDLINE
| ID: mdl-33205063
ABSTRACT
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-ß, 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-ß signaling and fibrosis.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Fibrosis
/
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
Cell Rep Med
Year:
2020
Type:
Article
Affiliation country:
United States