美国怀特黑德生物医学研究所Andrew L. Cangelosi团队近期取得重要工作进展，他们研究发现肝脏中Sestrin-mTORC1对亮氨酸的分区感知控制着对膳食亮氨酸的反应
研究人员发现缺乏Sestrin1和Sestrin2的小鼠在饮食中缺乏亮氨酸时不能抑制mTORC1，并且会迅速丧失白色脂肪组织（WAT）和肌肉。WAT损失是由肝脏中异常的mTORC1活性和成纤维细胞生长因子21（FGF21）产生所驱动的。肝小叶中的Sestrin表达是分区的，说明了亮氨酸对mTORC1活性和FGF21诱导的区域特异性调节。这些结果将哺乳动物Sestrins确立为生理亮氨酸传感器，并揭示了mTORC1通路对营养物质感知的空间组织。
据介绍，雷帕霉素复合物1（mTORC1）激酶的机制靶点控制生长对营养物质的反应，包括氨基酸亮氨酸。在培养细胞中，mTORC1通过与亮氨酸结合的Sestrin蛋白感知亮氨酸，但Sestrin介导的亮氨酸感知在哺乳动物中的生理功能和分布尚不清楚。
附：英文原文
Title: Zonated leucine sensing by Sestrin-mTORC1 in the liver controls the response to dietary leucine
Author: Andrew L. Cangelosi, Anna M. Puszynska, Justin M. Roberts, Andrea Armani, Thao P. Nguyen, Jessica B. Spinelli, Tenzin Kunchok, Brianna Wang, Sze Ham Chan, Caroline A. Lewis, William C. Comb, George W. Bell, Aharon Helman, David M. Sabatini
Issue&Volume: 2022-07-01
Abstract: The mechanistic target of rapamycin complex 1 (mTORC1) kinase controls growth in response to nutrients, including the amino acid leucine. In cultured cells, mTORC1 senses leucine through the leucine-binding Sestrin proteins, but the physiological functions and distribution of Sestrin-mediated leucine sensing in mammals are unknown. We find that mice lacking Sestrin1 and Sestrin2 cannot inhibit mTORC1 upon dietary leucine deprivation and suffer a rapid loss of white adipose tissue (WAT) and muscle. The WAT loss is driven by aberrant mTORC1 activity and fibroblast growth factor 21 (FGF21) production in the liver. Sestrin expression in the liver lobule is zonated, accounting for zone-specific regulation of mTORC1 activity and FGF21 induction by leucine. These results establish the mammalian Sestrins as physiological leucine sensors and reveal a spatial organization to nutrient sensing by the mTORC1 pathway.
DOI: abi9547
Source: https://www.science.org/doi/10.1126/science.abi9547