Dichloroacetate reverses sepsis-induced hepatic metabolic dysfunction

  1. Rabina Mainali
  2. Manal Zabalawi
  3. David Long
  4. Nancy Buechler
  5. Ellen Quillen
  6. Chia-Chi Key
  7. Xuewei Zhu
  8. John S Parks
  9. Cristina Furdui
  10. Peter W Stacpoole
  11. Jennifer Martinez
  12. Charles E McCall  Is a corresponding author
  13. Matthew A Quinn  Is a corresponding author
  1. Wake Forest School of Medicine, United States
  2. University of Florida School of Medicine, United States
  3. National Institute of Environmental Health Sciences, United States

Abstract

Metabolic reprogramming between resistance and tolerance occurs within the immune system in response to sepsis. While metabolic tissues such as the liver are subject to damage during sepsis, how their metabolic and energy reprogramming ensures survival is unclear. Employing comprehensive metabolomic, lipidomic, and transcriptional profiling in a mouse model of sepsis, we show that hepatocyte lipid metabolism, mitochondrial TCA energetics, and redox balance are significantly reprogramed after cecal ligation and puncture (CLP). We identify increases in TCA cycle metabolites citrate, cis-aconitate, and itaconate with reduced fumarate and triglyceride accumulation in septic hepatocytes. Transcriptomic analysis of liver tissue supports and extends the hepatocyte findings. Strikingly, the administration of the pyruvate dehydrogenase kinase (PDK) inhibitor dichloroacetate (DCA) reverses dysregulated hepatocyte metabolism and mitochondrial dysfunction. In summary, our data indicate sepsis promotes hepatic metabolic dysfunction and that targeting the mitochondrial PDC/PDK energy homeostat rebalances transcriptional and metabolic manifestations of sepsis within the liver.

Data availability

Sequencing data have been deposited in GEO under accession code GSE167127

The following data sets were generated

Article and author information

Author details

  1. Rabina Mainali

    Pathology, Wake Forest School of Medicine, Winston Salem, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Manal Zabalawi

    Internal Medicine, Wake Forest School of Medicine, Winston Salem, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. David Long

    Internal Medicine, Wake Forest School of Medicine, Winston Salem, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Nancy Buechler

    Pathology, Wake Forest School of Medicine, Winston Salem, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Ellen Quillen

    Internal Medicine, Wake Forest School of Medicine, Winston Salem, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Chia-Chi Key

    Internal Medicine, Wake Forest School of Medicine, Winston Salem, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0669-2936
  7. Xuewei Zhu

    Department of Internal Medicine-Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. John S Parks

    Department of Internal Medicine-Section on Molecular Medicine, Wake Forest School of Medicine, Winston Salem, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5227-8915
  9. Cristina Furdui

    Internal Medicine, Wake Forest School of Medicine, Winston Salem, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Peter W Stacpoole

    Biochemistry and Molecular Biology, University of Florida School of Medicine, Gainseville, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Jennifer Martinez

    Inflammation and Immunology Disease Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Charles E McCall

    Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, United States
    For correspondence
    chmccall@wakehealth.edu
    Competing interests
    The authors declare that no competing interests exist.
  13. Matthew A Quinn

    Pathology/Internal Medicine, Wake Forest School of Medicine, Winston Salem, United States
    For correspondence
    mquinn@wakehealth.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3528-6569

Funding

National Institute of Environmental Health Sciences (1ZIAES10328601)

  • Jennifer Martinez

National Heart, Lung, and Blood Institute (R01 HL132035)

  • Xuewei Zhu

National Institute of Diabetes and Digestive and Kidney Diseases (K01 DK117069)

  • Chia-Chi Key

National Institute on Aging (K01 AG056663)

  • Ellen Quillen

National Institute of Allergy and Infectious Diseases (R01 AI065791)

  • Charles E McCall

National Institute of General Medical Sciences (R01 GM102497)

  • Charles E McCall

National Institute of General Medical Sciences (R35 GM126922)

  • Charles E McCall

National Heart, Lung, and Blood Institute (R01 HL119962)

  • John S Parks

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Zsolt Molnár, University of Pécs, Medical School, Hungary

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (A19-097) Wake Forest School of Medicine.

Version history

  1. Received: November 4, 2020
  2. Accepted: February 17, 2021
  3. Accepted Manuscript published: February 22, 2021 (version 1)
  4. Version of Record published: February 23, 2021 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Rabina Mainali
  2. Manal Zabalawi
  3. David Long
  4. Nancy Buechler
  5. Ellen Quillen
  6. Chia-Chi Key
  7. Xuewei Zhu
  8. John S Parks
  9. Cristina Furdui
  10. Peter W Stacpoole
  11. Jennifer Martinez
  12. Charles E McCall
  13. Matthew A Quinn
(2021)
Dichloroacetate reverses sepsis-induced hepatic metabolic dysfunction
eLife 10:e64611.
https://doi.org/10.7554/eLife.64611

Share this article

https://doi.org/10.7554/eLife.64611

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