1. Glutathione synthesis in the mouse liver supports lipid abundance through NRF2 repression.
- Author
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Asantewaa G, Tuttle ET, Ward NP, Kang YP, Kim Y, Kavanagh ME, Girnius N, Chen Y, Rodriguez K, Hecht F, Zocchi M, Smorodintsev-Schiller L, Scales TQ, Taylor K, Alimohammadi F, Duncan RP, Sechrist ZR, Agostini-Vulaj D, Schafer XL, Chang H, Smith ZR, O'Connor TN, Whelan S, Selfors LM, Crowdis J, Gray GK, Bronson RT, Brenner D, Rufini A, Dirksen RT, Hezel AF, Huber AR, Munger J, Cravatt BF, Vasiliou V, Cole CL, DeNicola GM, and Harris IS
- Subjects
- Animals, Mice, Oxidative Stress, Male, Lipid Metabolism, Mice, Knockout, Mice, Inbred C57BL, Oxidation-Reduction, Lipogenesis genetics, Glutathione metabolism, NF-E2-Related Factor 2 metabolism, NF-E2-Related Factor 2 genetics, Liver metabolism, Glutamate-Cysteine Ligase metabolism, Glutamate-Cysteine Ligase genetics, Triglycerides metabolism
- 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., (© 2024. The Author(s).)
- Published
- 2024
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