Evidence map›Paper›PMID 42475434›Full record

ArticleCirculation2026

Loss of ATP-Dependent Citrate Lyase Drives Left Ventricular Dysfunction by Metabolic Remodeling.

Shijie Liu, Seth T Gammon, Lin Tan, Yaqi Gao, Kyoungmin Kim, Mahmoud H Elbatreek, Adrian Arrieta, Ian K Williamson, Rebecca L Salazar, Janet Pham and 25 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Circulation, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Article
  2. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

35 authors.

Shijie LiuDepartment of Molecular Physiology and Biophysics, Baylor College of Medicine, Texas Heart Institute, Houston, TX (S.L., J.F.M.).
Seth T GammonDepartment of Cancer Systems Imaging (S.T.G., D.P.-W.), University of Texas MD Anderson Cancer Center, Houston.ORCID 0000-0001-8647-0975
Lin TanDepartment of Bioinformatics and Computational Biology (L.T., S.A.M., P.L.L.), University of Texas MD Anderson Cancer Center, Houston.
Yaqi GaoDepartment of Cardiology (Y.G., K.K., I.K.W., R.L.S., J.P., A.D., A.S., L.S.C.C., E.P.K., A.K.), Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA.ORCID 0009-0002-6181-4027
Kyoungmin KimDepartment of Cardiology (Y.G., K.K., I.K.W., R.L.S., J.P., A.D., A.S., L.S.C.C., E.P.K., A.K.), Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA.ORCID 0009-0007-4917-895X
Mahmoud H ElbatreekDepartment of Cardiothoracic Surgery (M.H.E., L.S.C.C., D.J.L.), Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA.ORCID 0000-0003-2437-1773
Adrian ArrietaDepartments of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of California-Los Angeles (A.A.).ORCID 0000-0002-1875-5714
Ian K WilliamsonDepartment of Cardiology (Y.G., K.K., I.K.W., R.L.S., J.P., A.D., A.S., L.S.C.C., E.P.K., A.K.), Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
Rebecca L SalazarDepartment of Cardiology (Y.G., K.K., I.K.W., R.L.S., J.P., A.D., A.S., L.S.C.C., E.P.K., A.K.), Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
Janet PhamDepartment of Cardiology (Y.G., K.K., I.K.W., R.L.S., J.P., A.D., A.S., L.S.C.C., E.P.K., A.K.), Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA.ORCID 0009-0005-9908-4383
Angela DavidianDepartment of Cardiology (Y.G., K.K., I.K.W., R.L.S., J.P., A.D., A.S., L.S.C.C., E.P.K., A.K.), Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
Radhika Khanna NeicherilDepartment of Medicine, Cleveland Clinic Florida, Weston (R.K.).
Benjamin D GouldDepartment of Internal Medicine, Division of Cardiology, McGovern Medical School (B.D.G., H.T.), University of Texas Health Science Center at Houston.ORCID 0000-0001-7181-9994
Heidi VitracLife Sciences Mass Spectrometry, Bruker Daltonics, Billerica, MA (H.V.).ORCID 0000-0002-8858-4914
Alia SadiqDepartment of Cardiology (Y.G., K.K., I.K.W., R.L.S., J.P., A.D., A.S., L.S.C.C., E.P.K., A.K.), Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
An Q DinhCenter for Infectious Diseases, School of Public Health (A.Q.D.), University of Texas Health Science Center at Houston.ORCID 0000-0002-2965-9269
Evan C LienKoch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge (E.C.L., M.G.V.H.).ORCID 0000-0001-7866-4761
Francisca N de Luna VitorinoDepartment of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, MO (F.N.d.L.V., J.M.G., B.A.G.).ORCID 0000-0001-8543-2299
Joanna M GongoraDepartment of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, MO (F.N.d.L.V., J.M.G., B.A.G.).
Sara A MartinezDepartment of Bioinformatics and Computational Biology (L.T., S.A.M., P.L.L.), University of Texas MD Anderson Cancer Center, Houston.ORCID 0000-0002-4389-5604
Melanie T OdenkirkDepartment of Chemistry (M.T.O.), North Carolina State University, Raleigh.ORCID 0000-0003-4526-5152
Anna K BoatmanDepartment of Chemistry, University of North Carolina at Chapel Hill (A.K.B., E.M.B.).ORCID 0000-0003-2582-0622
Jessie R ChappelDepartment of Biological Sciences (J.R.C.), North Carolina State University, Raleigh.
Lawrence S C CzerDepartment of Cardiology (Y.G., K.K., I.K.W., R.L.S., J.P., A.D., A.S., L.S.C.C., E.P.K., A.K.), Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA.ORCID 0000-0001-5744-2625
Evan P KransdorfDepartment of Cardiology (Y.G., K.K., I.K.W., R.L.S., J.P., A.D., A.S., L.S.C.C., E.P.K., A.K.), Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA.ORCID 0000-0002-0507-2412
David J LeferDepartment of Cardiothoracic Surgery (M.H.E., L.S.C.C., D.J.L.), Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA.ORCID 0009-0006-1025-7004
Blake M HansonDepartment of Epidemiology, Human Genetics, and Environmental Sciences (B.H.), University of Texas Health Science Center at Houston.ORCID 0000-0003-2949-7818
Benjamin A GarciaDepartment of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, MO (F.N.d.L.V., J.M.G., B.A.G.).ORCID 0000-0003-3596-4750
Erin M BakerDepartment of Chemistry, University of North Carolina at Chapel Hill (A.K.B., E.M.B.).ORCID 0000-0001-5246-2213
Matthew G Vander HeidenKoch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge (E.C.L., M.G.V.H.).ORCID 0000-0002-6702-4192
Philip L LorenziDepartment of Bioinformatics and Computational Biology (L.T., S.A.M., P.L.L.), University of Texas MD Anderson Cancer Center, Houston.ORCID 0000-0003-0385-7774
Heinrich TaegtmeyerDepartment of Internal Medicine, Division of Cardiology, McGovern Medical School (B.D.G., H.T.), University of Texas Health Science Center at Houston.ORCID 0000-0002-5434-6360
David Piwnica-WormsDepartment of Cancer Systems Imaging (S.T.G., D.P.-W.), University of Texas MD Anderson Cancer Center, Houston.ORCID 0000-0002-2120-7217
James F MartinDepartment of Molecular Physiology and Biophysics, Baylor College of Medicine, Texas Heart Institute, Houston, TX (S.L., J.F.M.).ORCID 0000-0002-7842-9857
Anja KarlstaedtDepartment of Cardiology (Y.G., K.K., I.K.W., R.L.S., J.P., A.D., A.S., L.S.C.C., E.P.K., A.K.), Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA.ORCID 0000-0001-5689-3571

Funding

Tumor Evolution and Metastasis ProgramP30CA016672 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI DIANE BODURKA · 1985 to 2026
$290.8M
VIRUS PRODUCTION COREP30CA014051 · NCI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI Jacqueline A. Lees · 1985 to 2026
$93.9M
Single cell, multi-parametric high throughput platform to classify endocrine disruptor potential of mixturesP42ES027704 · NIEHS · TEXAS A&M UNIVERSITY · PI Efstratios Pistikopoulos · 2017 to 2026
$21.2M
Understanding the role of lipids in structure and function of membrane proteinsRM1GM145416 · NIGMS · TEXAS A&M UNIVERSITY · PI Erin S Baker, Arthur D Laganowsky · 2022 to 2026
$7.4M
SWITCHING OF METABOLIC GENES IN UNLOADED HEARTR01HL061483 · NHLBI · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · PI TAEGTMEYER, HEINRICH · 1999 to 2021
$6.2M
Understanding the role of metabolism in cancerR35CA242379 · NCI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI VANDER HEIDEN, MATTHEW G. · 2019 to 2025
$5.8M
Quantitative mass spectrometry for comprehending epigenetic mechanisms in a new underlying neurological developmental disorderR01HD106051 · NICHD · WASHINGTON UNIVERSITY · PI Benjamin A Garcia · 2022 to 2026
$2.6M
Computational Tools for Analysis and Visualization of Quality Control Issues in Metabolomic DataU01CA235510 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI AKBANI, REHAN, BROOM, BRADLEY MCINTOSH · 2018 to 2021
$1.6M
Development and Application of Chemical Biology Approaches for Understanding Protein ArginylationR01HL177113 · NHLBI · WASHINGTON UNIVERSITY · PI Benjamin A Garcia, Zongtao Lin · 2025 to 2026
$1.2M
Increasing the Coverage, Sensitivity and Specificity of Rapid Lipidomic MeasurementsR01GM141277 · NIGMS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI BAKER, ERIN S · 2022 to 2025
$1.2M
Regulation of cardiac metabolism during LeukemiaR01HL177461 · NHLBI · CEDARS-SINAI MEDICAL CENTER · PI Anja Karlstaedt · 2025 to 2026
$1.1M
Orbitrap Elite High-Resolution Mass Spectrometer for Proteomics and MetabolomicsS10OD012304 · OD · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI HAWKE, DAVID H · 2013 to 2013
$877k
NCI NIH HHS P30 CA014051NCI NIH HHS P30 CA016672NCI NIH HHS R35 CA242379NCI NIH HHS U01 CA235510NHLBI NIH HHS K99 HL141702NHLBI NIH HHS R00 HL141702NHLBI NIH HHS R01 HL061483NHLBI NIH HHS R01 HL177113NHLBI NIH HHS R01 HL177461NIAID NIH HHS K01 AI148593NICHD NIH HHS R01 HD106051NIEHS NIH HHS P42 ES027704NIGMS NIH HHS R01 GM141277NIGMS NIH HHS RM1 GM145416NIH HHS S10 OD012304
6 · The paper itself

Abstract

backgroundMetabolic adaptation and maladaptation are hallmarks of the failing heart and may be a target for therapeutic interventions. For example, sustained glucose oxidation during cardiac stress is associated with increased activity and abundance of ACL (ATP-dependent citrate lyase,

methodsWe used human heart tissue samples from healthy donors and patients with nonischemic cardiomyopathy. Next, we used CRISPR (clustered, regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated 9) gene editing to inactivate

resultsWe observed reduced ACL abundance and activity in human heart tissue samples from patients with nonischemic cardiomyopathy, which correlated with decreased abundance of Krebs cycle intermediates. Using CRISPR/Cas9 gene editing, we found that cardiac-specific loss of ACL reduces acetyl-CoA synthesis, leading to altered cardiac metabolism characterized by increased glucose uptake and oxidation, impaired energy flux, and elevated AMP to ATP ratios, which collectively promote left ventricular dysfunction. Transcriptomic and mass spectrometry-based metabolomics, as well as proteomic data, reveal compensatory cardiac lipid remodeling and reduced histone 3 acetylation. This metabolic stress promotes activation of AMPK (AMP kinase) and PKA (protein kinase A), which in turn mediates YAP (Yes-associated protein) inhibition through phosphorylation. Stable isotope tracer studies combined with CardioNet simulations demonstrated that increased IDH1 (isocitrate dehydrogenase 1) activity prevents allosteric inhibition of glycolysis from cytosolic citrate accumulation. AAV9-mediated cardiac

conclusionsOur findings suggest that ACL plays a pivotal role in cardiac metabolism through regulating lipid synthesis and cardiac function. Exploiting compensatory pathways of citrate metabolism may improve cardiac function during heart failure.

Indexed as

ATP Citrate (pro-S)-LyaseVentricular Dysfunction, LeftAnimalsCardiomyopathiesEnergy MetabolismFemaleHumansMaleMiceMyocytes, CardiacATP Citrate (pro-S)-LyaseATP-dependent citrate lyasecardio-oncologymetabolismsystems biology

Identifiers

PMID42475434
PMCPMC13378756

What Socratic holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.