He Liuqin, Long Jing, Zhou Xihong, Liu Yonghui, Li Tiejun, Wu Xin
Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, China.
Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, College of Life Sciences, Hunan Normal University, Changsha, China.
FASEB J. 2020 Mar;34(3):4702-4717. doi: 10.1096/fj.201902690R. Epub 2020 Feb 6.
Serine has critical roles in maintaining cell growth and redox balance in cancer cells. However, the role of exogenous serine played in oxidative response and proliferation in normal mammalian intestine need to be further elucidated. We used a mouse model and intestinal porcine epithelial cells (IPEC-J2) to reveal that exogenous serine deficiency did not lead to redox imbalance and inhibition of proliferation in the intestine. However, serine deficiency exacerbated oxidative stress, mitochondrial dysfunction, apoptosis, and inhibition of proliferation in IPEC-J2 cells challenged by hydrogen peroxide, while serine supplementation rescued redox imbalance and those proliferation defects. Importantly, serine supplementation restored the glutathione content and decreased the accumulation of reactive oxygen species, while no such effects were observed when glutathione synthesis was inhibited. Additionally, serine supplementation increased nuclear nrf2 expression in IPEC-J2 cells. These results suggested that serine alleviates oxidative stress through supporting glutathione synthesis and activating nrf2 signaling. We further found that serine supplementation activated the mTOR pathway, while inhibition of mTOR diminished the effects of serine on promoting proliferation, suggesting critical roles of the mTOR pathway in this context. Taken together, our study underlines the importance of serine in the maintenance of redox status and proliferation in the intestine and reveals a novel potential mechanism that mediates these effects.
丝氨酸在维持癌细胞的细胞生长和氧化还原平衡中起着关键作用。然而，外源性丝氨酸在正常哺乳动物肠道的氧化应激反应和增殖中所起的作用仍有待进一步阐明。我们使用小鼠模型和猪小肠上皮细胞（IPEC-J2）来揭示外源性丝氨酸缺乏并不会导致肠道氧化还原失衡和增殖抑制。然而，丝氨酸缺乏会加剧过氧化氢刺激的IPEC-J2细胞中的氧化应激、线粒体功能障碍、细胞凋亡以及增殖抑制，而补充丝氨酸则可挽救氧化还原失衡和那些增殖缺陷。重要的是，补充丝氨酸可恢复谷胱甘肽含量并减少活性氧的积累，而在抑制谷胱甘肽合成时未观察到此类效果。此外，补充丝氨酸可增加IPEC-J2细胞中核内nrf2的表达。这些结果表明，丝氨酸通过支持谷胱甘肽合成和激活nrf2信号通路来减轻氧化应激。我们进一步发现，补充丝氨酸可激活mTOR信号通路，而抑制mTOR则会减弱丝氨酸对促进增殖的作用，表明mTOR信号通路在此过程中起着关键作用。综上所述，我们的研究强调了丝氨酸在维持肠道氧化还原状态和增殖中的重要性，并揭示了一种介导这些作用的新潜在机制。
