Glutathione synthesis in the mouse liver supports lipid abundance through NRF2 repression PMID: 39034312

ADC Targets in Oncology

2026-04-10

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

Nat Commun. 2024 Jul 21;15(1):6152. doi: 10.1038/s41467-024-50454-2.

Gloria Asantewaa ¹ ² ³ , Emily T Tuttle ² ³ , Nathan P Ward ⁴ , Yun Pyo Kang ⁴ , Yumi Kim ⁴ , Madeline E Kavanagh ⁵ ⁶ , Nomeda Girnius ⁷ , Ying Chen ⁸ , Katherine Rodriguez ² ³ , Fabio Hecht ² ³ , Marco Zocchi ² ³ , Leonid Smorodintsev-Schiller ² ³ , TashJaé Q Scales ² ³ , Kira Taylor ² ³ , Fatemeh Alimohammadi ³ ⁹ , Renae P Duncan ¹⁰ ¹¹ , Zachary R Sechrist ³ ¹⁰ ¹¹ , Diana Agostini-Vulaj ¹¹ , Xenia L Schafer ¹ , Hayley Chang ² ³ , Zachary R Smith ² ³ , Thomas N O'Connor ² ⁹ , Sarah Whelan ¹² , Laura M Selfors ⁷ , Jett Crowdis ⁷ , G Kenneth Gray ⁷ , Roderick T Bronson ⁷ , Dirk Brenner ¹³ ¹⁴ ¹⁵ , Alessandro Rufini ¹² ¹⁶ , Robert T Dirksen ⁹ , Aram F Hezel ² ³ , Aaron R Huber ¹¹ , Joshua Munger ¹ ³ , Benjamin F Cravatt ⁵ , Vasilis Vasiliou ⁸ , Calvin L Cole ³ ¹⁰ , Gina M DeNicola ⁴ , Isaac S Harris ¹⁷ ¹⁸ ¹⁹

Affiliations

1. Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY, USA.
2. Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA.
3. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.
4. Department of Metabolism and Physiology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
5. Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA.
6. Leiden Institute of Chemistry, Leiden University, Leiden, the Netherlands.
7. Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
8. Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA.
9. Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY, USA.
10. Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.
11. Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
12. Leicester Cancer Research Centre, University of Leicester, Leicester, UK.
13. Experimental and Molecular Immunology, Dept. of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg.
14. Immunology & Genetics, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg.
15. Odense Research Center for Anaphylaxis (ORCA), Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, Denmark.
16. Dipartimento di Bioscienze, Università degli Studi di Milano, Milan, Italy.
17. Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA. [email protected].
18. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA. [email protected].
19. Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY, USA. [email protected].

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.