Nature Communications (Jul 2024)
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,
- Isaac S. Harris
Affiliations
- Gloria Asantewaa
- Department of Biochemistry and Biophysics, University of Rochester Medical Center
- Emily T. Tuttle
- Department of Biomedical Genetics, University of Rochester Medical Center
- Nathan P. Ward
- Department of Metabolism and Physiology, Moffitt Cancer Center and Research Institute
- Yun Pyo Kang
- Department of Metabolism and Physiology, Moffitt Cancer Center and Research Institute
- Yumi Kim
- Department of Metabolism and Physiology, Moffitt Cancer Center and Research Institute
- Madeline E. Kavanagh
- Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute
- Nomeda Girnius
- Department of Cell Biology, Harvard Medical School
- Ying Chen
- Department of Environmental Health Sciences, Yale School of Public Health
- Katherine Rodriguez
- Department of Biomedical Genetics, University of Rochester Medical Center
- Fabio Hecht
- Department of Biomedical Genetics, University of Rochester Medical Center
- Marco Zocchi
- Department of Biomedical Genetics, University of Rochester Medical Center
- Leonid Smorodintsev-Schiller
- Department of Biomedical Genetics, University of Rochester Medical Center
- TashJaé Q. Scales
- Department of Biomedical Genetics, University of Rochester Medical Center
- Kira Taylor
- Department of Biomedical Genetics, University of Rochester Medical Center
- Fatemeh Alimohammadi
- Wilmot Cancer Institute, University of Rochester Medical Center
- Renae P. Duncan
- Center for Musculoskeletal Research, University of Rochester Medical Center
- Zachary R. Sechrist
- Wilmot Cancer Institute, University of Rochester Medical Center
- Diana Agostini-Vulaj
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center
- Xenia L. Schafer
- Department of Biochemistry and Biophysics, University of Rochester Medical Center
- Hayley Chang
- Department of Biomedical Genetics, University of Rochester Medical Center
- Zachary R. Smith
- Department of Biomedical Genetics, University of Rochester Medical Center
- Thomas N. O’Connor
- Department of Biomedical Genetics, University of Rochester Medical Center
- Sarah Whelan
- Leicester Cancer Research Centre, University of Leicester
- Laura M. Selfors
- Department of Cell Biology, Harvard Medical School
- Jett Crowdis
- Department of Cell Biology, Harvard Medical School
- G. Kenneth Gray
- Department of Cell Biology, Harvard Medical School
- Roderick T. Bronson
- Department of Cell Biology, Harvard Medical School
- Dirk Brenner
- Experimental and Molecular Immunology, Dept. of Infection and Immunity (DII), Luxembourg Institute of Health
- Alessandro Rufini
- Leicester Cancer Research Centre, University of Leicester
- Robert T. Dirksen
- Department of Pharmacology and Physiology, University of Rochester Medical Center
- Aram F. Hezel
- Department of Biomedical Genetics, University of Rochester Medical Center
- Aaron R. Huber
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center
- Joshua Munger
- Department of Biochemistry and Biophysics, University of Rochester Medical Center
- Benjamin F. Cravatt
- Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute
- Vasilis Vasiliou
- Department of Environmental Health Sciences, Yale School of Public Health
- Calvin L. Cole
- Wilmot Cancer Institute, University of Rochester Medical Center
- Gina M. DeNicola
- Department of Metabolism and Physiology, Moffitt Cancer Center and Research Institute
- Isaac S. Harris
- Department of Biomedical Genetics, University of Rochester Medical Center
- DOI
- https://doi.org/10.1038/s41467-024-50454-2
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 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.
