Yehoshua Noa, Khamaysi Ahlam, Shimshilashvili Liana, Keshet Aharon, Taha Mahmoud, Fremder Moran, Eini-Rider Hadar, Ohana Ehud
The Dept. of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel.
The Dept. of Physiology and Cell Biology, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel.
Nat Commun. 2025 Jul 24;16(1):6819. doi: 10.1038/s41467-025-62103-3.
The composition of tricarboxylic acid cycle metabolites in the external environment of cells determines vital physiological functions, including nutrient and mineral absorption, inflammation, and cellular energy management. Here, we study how the transport of external metabolites into the cells functions as an independent metabolic pathway that controls cellular energy. We show that liver cells orchestrate simultaneous fluxes of glucose and the omnipotent metabolite citrate across the cell membrane, acting as a first line metabolic pathway that responds to nutrient availability. Using functional mapping and gene silencing, we delineate the underlying molecular mechanism showing that the liver citrate transporter (NaCT) interacts with glucose transporters (Glut) and the anion transporters. The interaction is mediated by a specific region of the NaCT protein to reciprocally regulate the transport functions. Our findings describe an independent mechanism that coordinates external metabolites and glucose balance, thus driving key energy management processes in response to nutrient availability in the liver.
细胞外部环境中三羧酸循环代谢物的组成决定了重要的生理功能，包括营养物质和矿物质吸收、炎症以及细胞能量管理。在此，我们研究细胞外代谢物进入细胞的转运如何作为一种控制细胞能量的独立代谢途径发挥作用。我们发现肝细胞协调葡萄糖和全能代谢物柠檬酸同时穿过细胞膜的通量，作为对营养物质可用性作出反应的一线代谢途径。通过功能图谱和基因沉默，我们阐明了潜在的分子机制，表明肝脏柠檬酸转运体（NaCT）与葡萄糖转运体（Glut）及阴离子转运体相互作用。这种相互作用由NaCT蛋白的特定区域介导，以相互调节转运功能。我们的研究结果描述了一种协调细胞外代谢物与葡萄糖平衡的独立机制，从而在肝脏中响应营养物质可用性驱动关键的能量管理过程。
