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

Asantewaa, Gloria; Tuttle, Emily T.; Ward, Nathan P.; Kang, Yun Pyo; Kim, Yumi; Kavanagh, Madeline E.; Girnius, Nomeda; Chen, Ying; Rodriguez, Katherine; Hecht, Fabio; Zocchi, Marco; Smorodintsev-Schiller, Leonid; Scales, TashJaé Q.; Taylor, Kira; Alimohammadi, Fatemeh; Duncan, Renae P.; Sechrist, Zachary R.; Agostini-Vulaj, Diana; Schafer, Xenia L.; Chang, Hayley; Smith, Zachary R.; O’Connor, Thomas N.; Whelan, Sarah; Selfors, Laura M.; Crowdis, Jett; Gray, G. Kenneth; Bronson, Roderick T.; Brenner, Dirk; Rufini, Alessandro; Dirksen, Robert T.; Hezel, Aram F.; Huber, Aaron R.; Munger, Joshua; Cravatt, Benjamin F.; Vasiliou, Vasilis; Cole, Calvin L.; DeNicola, Gina M.; Harris, Isaac S.

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

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 Smorodintsev-Schiller, TashJaé Q. Scales, Kira Taylor, Fatemeh Alimohammadi, Renae P. Duncan, Zachary R. Sechrist, Diana Agostini-Vulaj, Xenia L. Schafer, Hayley Chang, Zachary R. Smith, Thomas N. O’Connor, Sarah Whelan, Laura M. Selfors, Jett Crowdis, G. Kenneth Gray, Roderick T. Bronson, Dirk Brenner, Alessandro Rufini, Robert T. Dirksen, Aram F. Hezel, Aaron R. Huber, Joshua Munger, Benjamin F. Cravatt, Vasilis Vasiliou, Calvin L. Cole, Gina M. DeNicola and Isaac S. Harris ()
Additional contact information
Gloria Asantewaa: University of Rochester Medical Center
Emily T. Tuttle: 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
Nomeda Girnius: Harvard Medical School
Ying Chen: Yale School of Public Health
Katherine Rodriguez: University of Rochester Medical Center
Fabio Hecht: University of Rochester Medical Center
Marco Zocchi: University of Rochester Medical Center
Leonid Smorodintsev-Schiller: University of Rochester Medical Center
TashJaé Q. Scales: University of Rochester Medical Center
Kira Taylor: University of Rochester Medical Center
Fatemeh Alimohammadi: University of Rochester Medical Center
Renae P. Duncan: University of Rochester Medical Center
Zachary R. Sechrist: 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
Zachary R. Smith: University of Rochester Medical Center
Thomas N. O’Connor: 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
Alessandro Rufini: University of Leicester
Robert T. Dirksen: University of Rochester Medical Center
Aram F. Hezel: University of Rochester Medical Center
Aaron R. Huber: University of Rochester Medical Center
Joshua Munger: 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
Gina M. DeNicola: Moffitt Cancer Center and Research Institute
Isaac S. Harris: University of Rochester Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50454-2

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