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Glutathione synthesis in the mouse liver supports lipid abundance through NRF2 repression

Author

Listed:
  • Gloria Asantewaa

    (University of Rochester Medical Center
    University of Rochester Medical Center
    University of Rochester Medical Center)

  • Emily T. Tuttle

    (University of Rochester Medical Center
    University of Rochester Medical Center)

  • Nathan P. Ward

    (Moffitt Cancer Center and Research Institute)

  • Yun Pyo Kang

    (Moffitt Cancer Center and Research Institute)

  • Yumi Kim

    (Moffitt Cancer Center and Research Institute)

  • Madeline E. Kavanagh

    (The Scripps Research Institute
    Leiden University)

  • Nomeda Girnius

    (Harvard Medical School)

  • Ying Chen

    (Yale School of Public Health)

  • Katherine Rodriguez

    (University of Rochester Medical Center
    University of Rochester Medical Center)

  • Fabio Hecht

    (University of Rochester Medical Center
    University of Rochester Medical Center)

  • Marco Zocchi

    (University of Rochester Medical Center
    University of Rochester Medical Center)

  • Leonid Smorodintsev-Schiller

    (University of Rochester Medical Center
    University of Rochester Medical Center)

  • TashJaé Q. Scales

    (University of Rochester Medical Center
    University of Rochester Medical Center)

  • Kira Taylor

    (University of Rochester Medical Center
    University of Rochester Medical Center)

  • Fatemeh Alimohammadi

    (University of Rochester Medical Center
    University of Rochester Medical Center)

  • Renae P. Duncan

    (University of Rochester Medical Center
    University of Rochester Medical Center)

  • Zachary R. Sechrist

    (University of Rochester Medical Center
    University of Rochester Medical Center
    University of Rochester Medical Center)

  • Diana Agostini-Vulaj

    (University of Rochester Medical Center)

  • Xenia L. Schafer

    (University of Rochester Medical Center)

  • Hayley Chang

    (University of Rochester Medical Center
    University of Rochester Medical Center)

  • Zachary R. Smith

    (University of Rochester Medical Center
    University of Rochester Medical Center)

  • Thomas N. O’Connor

    (University of Rochester Medical Center
    University of Rochester Medical Center)

  • Sarah Whelan

    (University of Leicester)

  • Laura M. Selfors

    (Harvard Medical School)

  • Jett Crowdis

    (Harvard Medical School)

  • G. Kenneth Gray

    (Harvard Medical School)

  • Roderick T. Bronson

    (Harvard Medical School)

  • Dirk Brenner

    (Luxembourg Institute of Health
    University of Luxembourg
    University of Southern Denmark)

  • Alessandro Rufini

    (University of Leicester
    Università degli Studi di Milano)

  • Robert T. Dirksen

    (University of Rochester Medical Center)

  • Aram F. Hezel

    (University of Rochester Medical Center
    University of Rochester Medical Center)

  • Aaron R. Huber

    (University of Rochester Medical Center)

  • Joshua Munger

    (University of Rochester Medical Center
    University of Rochester Medical Center)

  • Benjamin F. Cravatt

    (The Scripps Research Institute)

  • Vasilis Vasiliou

    (Yale School of Public Health)

  • Calvin L. Cole

    (University of Rochester Medical Center
    University of Rochester Medical Center)

  • Gina M. DeNicola

    (Moffitt Cancer Center and Research Institute)

  • Isaac S. Harris

    (University of Rochester Medical Center
    University of Rochester Medical Center
    University of Rochester Medical Center)

Abstract

Cells rely on antioxidants to survive. The most abundant antioxidant is glutathione (GSH). The synthesis of GSH is non-redundantly controlled by the glutamate-cysteine ligase catalytic subunit (GCLC). GSH imbalance is implicated in many diseases, but the requirement for GSH in adult tissues is unclear. To interrogate this, we have developed a series of in vivo models to induce Gclc deletion in adult animals. We find that GSH is essential to lipid abundance in vivo. GSH levels are highest in liver tissue, which is also a hub for lipid production. While the loss of GSH does not cause liver failure, it decreases lipogenic enzyme expression, circulating triglyceride levels, and fat stores. Mechanistically, we find that GSH promotes lipid abundance by repressing NRF2, a transcription factor induced by oxidative stress. These studies identify GSH as a fulcrum in the liver’s balance of redox buffering and triglyceride production.

Suggested Citation

  • Gloria Asantewaa & Emily T. Tuttle & Nathan P. Ward & Yun Pyo Kang & Yumi Kim & Madeline E. Kavanagh & Nomeda Girnius & Ying Chen & Katherine Rodriguez & Fabio Hecht & Marco Zocchi & Leonid Smorodints, 2024. "Glutathione synthesis in the mouse liver supports lipid abundance through NRF2 repression," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50454-2
    DOI: 10.1038/s41467-024-50454-2
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    References listed on IDEAS

    as
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