Many cellular processes produce reactive oxygen species, which can produce cellular damage. Therefore, antioxidants are essential for cells to survive. Many diseases seem to be connected to impaired antioxidant functions. However, the impact of the most abundant antioxidant in the body, glutathione (GSH), across all tissues in adult animals is unknown, as knocking out GCLC, the enzyme that controls GSH production, is embryonically lethal in mice. A study in Nature Communications reports the development of mouse models with conditional Gclc deletion and demonstrates the role of GSH in adult mice. Loss of GSH in the mice increases the activity of the transcription factor NRF2, responsible for cell homeostasis during oxidative stress, and represses the expression of lipogenic genes. Gclc KO mice also showed lower body weight and depleted triglycerides compared to control animals. Mechanistically, the study shows that GSH supports lipid abundance and the supply of triglycerides into circulation by repressing NRF2 activation. These results hint that GSH is a central component in the liver’s balance of redox buffering and triglyceride production.

Original reference: Asantewaa, G. et al. Nat. Commun. 15, 6152 (2024)

许多细胞过程都会产生活性氧，这会造成细胞损伤。因此，抗氧化剂对于细胞的生存至关重要。许多疾病似乎与抗氧化功能受损有关。然而，体内最丰富的抗氧化剂谷胱甘肽 (GSH) 对成年动物所有组织的影响尚不清楚，因为敲除 GCLC（控制 GSH 产生的酶）对小鼠来说是胚胎致命的。 Nature Communications的一项研究报道了条件性Gclc缺失的小鼠模型的开发，并证明了 GSH 在成年小鼠中的作用。小鼠体内 GSH 的缺失会增加转录因子 NRF2 的活性，该因子负责氧化应激期间的细胞稳态，并抑制脂肪生成基因的表达。与对照动物相比，Gclc KO 小鼠还表现出较低的体重和较低的甘油三酯。从机制上讲，研究表明 GSH 通过抑制 NRF2 激活来支持脂质丰度和甘油三酯进入循环系统的供应。这些结果表明，GSH 是肝脏氧化还原缓冲和甘油三酯生成平衡的核心成分。

原始参考文献： Asantewaa, G. et al.纳特。交流。 15、6152 (2024)