1. Glutathione synthesis in the mouse liver supports lipid abundance through NRF2 repression
- Author
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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
- Subjects
Science - 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.
- Published
- 2024
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