RESUMO
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.
Assuntos
Glutamato-Cisteína Ligase , Glutationa , Fígado , Fator 2 Relacionado a NF-E2 , Triglicerídeos , Animais , Glutationa/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fígado/metabolismo , Glutamato-Cisteína Ligase/metabolismo , Glutamato-Cisteína Ligase/genética , Camundongos , Triglicerídeos/metabolismo , Estresse Oxidativo , Masculino , Metabolismo dos Lipídeos , Camundongos Knockout , Camundongos Endogâmicos C57BL , Oxirredução , Lipogênese/genéticaRESUMO
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 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 reported to be highest in liver tissue, which is also a hub for lipid production. While the loss of GSH did not cause liver failure, it decreased lipogenic enzyme expression, circulating triglyceride levels, and fat stores. Mechanistically, we found 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.
RESUMO
Buffering oxidative stress is as a crucial requirement for tumorigenesis. Antioxidant is a term reserved for molecules that quench reactive oxygen species (ROS) and alleviate oxidative stress. The details regarding antioxidant synthesis, their utilization to eliminate ROS, and their ability to promote different stages of tumorigenesis are unclear. Here, we focus on glutathione (GSH), the most abundant antioxidant in the cell, and its precursor amino acids (cysteine, glutamate, and glycine). Even though GSH was discovered more than a century ago, continued research into this antioxidant has provided answers to longstanding questions while also posing new ones.