Dataset Information

Molecular Profiling Reveals a Common Metabolic Signature of Tissue Fibrosis.

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-?, 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 PGC1? 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-? signaling and fibrosis.

SUBMITTER: Zhang J

PROVIDER: S-EPMC7659620 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Molecular Profiling Reveals a Common Metabolic Signature of Tissue Fibrosis.

Zhang Ji J Muise Eric S ES Han Seongah S Kutchukian Peter S PS Costet Philippe P Zhu Yonghua Y Kan Yanqing Y Zhou Haihong H Shah Vinit V Huang Yongcheng Y Saigal Ashmita A Akiyama Taro E TE Shen Xiao-Lan XL Cai Tian-Quan TQ Shah Kashmira K Carballo-Jane Ester E Zycband Emanuel E Yi Lan L Tian Ye Y Chen Ying Y Imbriglio Jason J Smith Elizabeth E Devito Kristine K Conway James J Ma Li-Jun LJ Hoek Maarten M Sebhat Iyassu K IK Peier Andrea M AM Talukdar Saswata S McLaren David G DG Previs Stephen F SF Jensen Kristian K KK Pinto Shirly S

Cell reports. Medicine 20200721 4

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 ...[more]

PMID: 33205063

Similar Datasets

Project description:BACKGROUND:Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease of unknown etiology. Patients present loss of lung function, dyspnea and dry cough. Diagnosis requires compatible radiologic imaging and, in undetermined cases, invasive procedures such as bronchoscopy and surgical lung biopsy. The pathophysiological mechanisms of IPF are not completely understood. Lung injury with abnormal alveolar epithelial repair is thought to be a major cause for activation of profibrotic pathways in IPF. Metabolic signatures might indicate pathological pathways involved in disease development and progression. Reliable serum biomarker would help to improve both diagnostic approach and monitoring of drug effects. METHOD:The global metabolic profiles measured by ultra high-performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS) of ten stable IPF patients were compared to the ones of ten healthy participants. The results were validated in an additional study of eleven IPF patients and ten healthy controls. RESULTS:We discovered 10 discriminative metabolic features using multivariate and univariate statistical analysis. Among them, we identified one metabolite at a retention time of 9.59 min that was two times more abundant in the serum of IPF patients compared to healthy participants. Based on its ion pattern, a lysophosphatidylcholine (LysoPC) was proposed. LysoPC is a precursor of lysophosphatidic acid (LPA) - a known mediator for lung fibrosis with its pathway currently being evaluated as new therapeutic drug target for IPF and other fibrotic diseases. CONCLUSIONS:We identified a LysoPC by UHPLC-HRMS as potential biomarker in serum of patients with IPF. Further validation studies in a larger cohort are necessary to determine its role in IPF. TRIAL REGISTRATION:Serum samples from IPF patients have been obtained within the clinical trial NCT02173145 at baseline and from the idiopathic interstitial pneumonia (IIP) cohort study. The study was approved by the Swiss Ethics Committee, Bern (KEK 002/14 and 246/15 or PB_2016-01524).

Dataset Information

Molecular Profiling Reveals a Common Metabolic Signature of Tissue Fibrosis.

Publications

Molecular Profiling Reveals a Common Metabolic Signature of Tissue Fibrosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets