Molecular Profiling Reveals a Common Metabolic Signature of Tissue Fibrosis

Cell Reports Medicine
Ji ZhangShirly Pinto

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-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.

References

Dec 1, 1991·American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation·S Klahr
Apr 1, 1988·Journal of Clinical Pathology·T AshcroftV Timbrell
Sep 30, 1993·The New England Journal of Medicine·UNKNOWN Diabetes Control and Complications Trial Research GroupC Siebert
Apr 20, 2001·Proceedings of the National Academy of Sciences of the United States of America·W R OliverT M Willson
Dec 18, 2004·Bioorganic & Medicinal Chemistry Letters·John J ActonHarold B Wood
Aug 2, 2005·Cell Metabolism·Jiandie LinBruce M Spiegelman
Mar 3, 2007·The Journal of Clinical Investigation·John P Iredale
Apr 2, 2008·The New England Journal of Medicine·UNKNOWN ONTARGET InvestigatorsCraig Anderson
Apr 12, 2008·Nature Reviews. Drug Discovery·Jeffrey A Winkles
May 15, 2008·BioTechniques·Ralf-Harto HübnerBurkhard Bewig
Jun 11, 2010·Essays in Biochemistry·François R Jornayvaz, Gerald I Shulman
Sep 8, 2010·The New England Journal of Medicine·Lawrence J AppelUNKNOWN AASK Collaborative Research Group
Jul 5, 2011·Cell Metabolism·Hariom YadavSushil G Rane
Jul 10, 2012·Nature Medicine·Thomas A Wynn, Thirumalai R Ramalingam
Sep 25, 2012·Nature Reviews. Drug Discovery·Rosemary J Akhurst, Akiko Hata
Jan 11, 2013·Science Translational Medicine·Scott L FriedmanShelia Violette
Mar 26, 2013·American Journal of Respiratory Cell and Molecular Biology·Bethany B MooreCory M Hogaboam
Aug 27, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Xuefeng YinMary Simcox
Apr 18, 2014·The New England Journal of Medicine·Edward W GreggLinda Geiss
Jun 4, 2014·The Journal of Clinical Investigation·Jeremy S Duffield
Jun 4, 2014·The Journal of Clinical Investigation·Thomas M Coffman
Dec 4, 2014·Cell Stem Cell·Rafael KramannBenjamin D Humphreys
Dec 17, 2014·Human Molecular Genetics·Ramesh S YadavaMani S Mahadevan
Mar 19, 2015·The New England Journal of Medicine·Don C RockeyJoseph A Hill
May 28, 2015·American Journal of Physiology. Endocrinology and Metabolism·Haihong ZhouDavid E Kelley
Jun 6, 2015·Methods in Molecular Biology·Valerie M Harris
Jun 23, 2015·The Journal of Clinical Investigation·Lisa M RiceRobert Lafyatis
Sep 5, 2015·Nature Reviews. Drug Discovery·Carmel B NanthakumarSimon J F Macdonald
Nov 10, 2015·The New England Journal of Medicine·UNKNOWN SPRINT Research GroupWalter T Ambrosius
Feb 26, 2016·Frontiers in Physiology·Ping WangTatiana Kisseleva
Mar 31, 2016·Journal of the American Society of Nephrology : JASN·Ivan G GomezJeremy S Duffield
Oct 22, 2016·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Jeffrey Cui For The Genetics Of Nafld In Twins Consortium
Jun 23, 2016·Digestive Diseases·Yukinori KoyamaDavid A Brenner
Sep 21, 2016·Journal of the American Society of Nephrology : JASN·James VoelkerJulia B Lewis
Dec 19, 2016·Seminars in Nephrology·Matthew D Breyer, Katalin Susztak
Feb 6, 2017·Endocrine Practice : Official Journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists·Paul S JellingerMichael A Bush
Jun 14, 2017·Trends in Cancer·Chi LuoPere Puigserver
Jul 16, 2017·Kidney International·Beom Jin LimAgnes B Fogo

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Citations

Aug 31, 2021·The International Journal of Biochemistry & Cell Biology·Chuin Ying UngTanya J Shaw
Oct 5, 2021·Frontiers in Cell and Developmental Biology·Wasco WruckJames Adjaye
Sep 24, 2021·JCI Insight·Mahbubul H ShihanMelinda K Duncan

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Datasets Mentioned

BETA
GSE152250

Methods Mentioned

BETA
RNA-seq
ELISA
PCR

Key Resources (RRID) Mentioned

IMSR_JAX
RGD_1566440

Software Mentioned

GraphPad Prism
PANTHER
Omicsoft Array Studio
Ensembl
Morpheus
Omicsoft Aligner
TargetLynx
Pipeline Pilot

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