Nuclear ATP-citrate lyase regulates chromatin-dependent activation and maintenance of the myofibroblast gene program.

Myofibroblasts / metabolism ATP Citrate (pro-S)-Lyase / metabolism Animals Fibrosis / metabolism Cell Differentiation / drug effects Histones / metabolism Smad2 Protein / metabolism Acetylation / drug effects Cell Nucleus / metabolism Smad3 Protein / metabolism Cells, Cultured Chromatin / metabolism Mice, Knockout Transforming Growth Factor beta / metabolism Disease Models, Animal Signal Transduction Mice, Inbred C57BL Male Mice Gene Expression Regulation / drug effects

Journal

Nature cardiovascular research
ISSN: 2731-0590
Titre abrégé: Nat Cardiovasc Res
Pays: England
ID NLM: 9918284280206676

Informations de publication

Date de publication:
Jul 2024
Historique:
received: 23 05 2023
accepted: 31 05 2024
medline: 28 8 2024
pubmed: 28 8 2024
entrez: 28 8 2024
Statut: ppublish

Résumé

Differentiation of cardiac fibroblasts to myofibroblasts is necessary for matrix remodeling and fibrosis in heart failure. We previously reported that mitochondrial calcium signaling drives α-ketoglutarate-dependent histone demethylation, promoting myofibroblast formation. Here we investigate the role of ATP-citrate lyase (ACLY), a key enzyme for acetyl-CoA biosynthesis, in histone acetylation regulating myofibroblast fate and persistence in cardiac fibrosis. We show that inactivation of ACLY prevents myofibroblast differentiation and reverses myofibroblasts towards quiescence. Genetic deletion of Acly in post-activated myofibroblasts prevents fibrosis and preserves cardiac function in pressure-overload heart failure. TGFβ stimulation enhances ACLY nuclear localization and ACLY-SMAD2/3 interaction, and increases H3K27ac at fibrotic gene loci. Pharmacological inhibition of ACLY or forced nuclear expression of a dominant-negative ACLY mutant prevents myofibroblast formation and H3K27ac. Our data indicate that nuclear ACLY activity is necessary for myofibroblast differentiation and persistence by maintaining histone acetylation at TGFβ-induced myofibroblast genes. These findings provide targets to prevent and reverse pathological fibrosis.

Identifiants

DOI: 10.1038/s44161-024-00502-3 PMID: 39196175
pubmed: 39196175
doi: 10.1038/s44161-024-00502-3
pii: 10.1038/s44161-024-00502-3
doi:

Substances chimiques

ATP Citrate (pro-S)-Lyase EC 2.3.3.8
Histones 0
Smad2 Protein 0
Smad3 Protein 0
Smad2 protein, mouse 0
Smad3 protein, mouse 0
Chromatin 0
Transforming Growth Factor beta 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

869-882

Informations de copyright

© 2024. The Author(s).

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Auteurs

Michael P Lazaropoulos (MP)

Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA.

Andrew A Gibb (AA)

Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA.

Douglas J Chapski (DJ)

Department of Anesthesiology & Perioperative Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
ORCID: 0000-0002-6730-7627

Abheya A Nair (AA)

Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA.

Allison N Reiter (AN)

Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA.

Rajika Roy (R)

Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA.

Deborah M Eaton (DM)

Cardiovascular Institute and Cardiovascular Medicine Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Kenneth C Bedi (KC)

Cardiovascular Institute and Cardiovascular Medicine Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
ORCID: 0000-0003-3588-9324

Kenneth B Margulies (KB)

Cardiovascular Institute and Cardiovascular Medicine Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
ORCID: 0000-0002-8093-4465

Kathryn E Wellen (KE)

Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Conchi Estarás (C)

Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA.

Thomas M Vondriska (TM)

Department of Anesthesiology & Perioperative Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Departments Medicine/Cardiology and Physiology, and Molecular Biology Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
ORCID: 0009-0000-5238-1245

John W Elrod (JW)

Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA. elrod@temple.edu.
ORCID: 0000-0003-3925-2224

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Classifications MeSH

questionsmedicales.fr › Cellules › Cellules musculaires › Myocytes du muscle lisse › Myofibroblastes › Nuclear ATP-citrate lyase regulates...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › Acyltransferases › ATP citrate (pro-S)-lyase › Nuclear ATP-citrate lyase regulates...
questionsmedicales.fr › Eucaryotes › Animaux › Nuclear ATP-citrate lyase regulates...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Fibrose › Nuclear ATP-citrate lyase regulates...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Différenciation cellulaire › Nuclear ATP-citrate lyase regulates...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Nucléoprotéines › Histone › Nuclear ATP-citrate lyase regulates...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Protéines Smad › Protéines Smad régulées par les récepteurs › Protéine Smad2 › Nuclear ATP-citrate lyase regulates...
questionsmedicales.fr › Métabolisme › Acylation › Acétylation › Nuclear ATP-citrate lyase regulates...
questionsmedicales.fr › Cellules › Structures cellulaires › Espace intracellulaire › Cytoplasme › Structures cytoplasmiques › Organites › Noyau de la cellule › Nuclear ATP-citrate lyase regulates...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Protéines Smad › Protéines Smad régulées par les récepteurs › Protéine Smad-3 › Nuclear ATP-citrate lyase regulates...
questionsmedicales.fr › Cellules › Cellules cultivées › Nuclear ATP-citrate lyase regulates...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Structures de chromosome › Chromatine › Nuclear ATP-citrate lyase regulates...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souris transgéniques › Souris knockout › Nuclear ATP-citrate lyase regulates...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Protéines de la superfamille du TGF bêta › Facteur de croissance transformant bêta › Nuclear ATP-citrate lyase regulates...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › Nuclear ATP-citrate lyase regulates...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Nuclear ATP-citrate lyase regulates...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée C57BL › Nuclear ATP-citrate lyase regulates...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Nuclear ATP-citrate lyase regulates...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Nuclear ATP-citrate lyase regulates...