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MFSD7c在血脑屏障中发挥胆碱转运体的功能
作者:小柯机器人 发布时间:2024/2/8 21:28:58

新加坡国立大学Long N. Nguyen研究小组发现,MFSD7c在血脑屏障中发挥胆碱转运体的功能。相关论文于2024年2月2日在线发表在《细胞研究》杂志上。

研究人员利用Mfsd7c基因敲除(Mfsd7c-/-)小鼠和基于细胞的试验揭示出MFSD7c是血脑屏障(BBB)上的胆碱转运体。研究人员进行了全面的代谢组学分析,发现了Mfsd7c-/-胚胎大脑和肝脏中代谢物的不同变化。特别是,研究人员发现胆碱相关代谢物在Mfsd7c-/-胚胎的大脑中发生了变化,而在肝脏中则没有。因此,研究人员推测MFSD7c可调节大脑中胆碱的水平。事实上,在细胞中表达人类MFSD7c能显著增加胆碱的吸收。有趣的是,研究人员发现胆碱代谢酶会大大增加MFSD7c对胆碱的摄取,从而证明MFSD7c是胆碱的促进性转运体。此外,单细胞膜片钳分析表明,MFSD7c对胆碱的输入是致电性的。

研究结果表明,MFSD7c的胆碱转运功能在脊椎动物中是保守的,但在酵母菌中并不保守。研究人员证明人类MFSD7c是酵母胆碱转入蛋白HNM1的功能直系同源物。研究人员还发现,在福勒综合征患者中发现的几种错义突变会导致胆碱转运活性丧失或降低。在中枢神经系统内皮细胞中缺乏Mfsd7c的小鼠抑制了从血液中输入外源胆碱,但却意外地增加了大脑中的胆碱水平。稳定同位素追踪研究发现,MFSD7c是脑内输出溶血磷脂酰胆碱衍生胆碱所需的。总之,这些工作确定了MFSD7c是胆碱在BBB的输出者,为今后揭示福勒综合征的疾病机制奠定了基础。

研究人员表示,孤儿转运体 MFSD7c(又称Flvcr2)的突变与福勒综合征有关。

附:英文原文

Title: MFSD7c functions as a transporter of choline at the blood–brain barrier

Author: Nguyen, Xuan Thi Anh, Le, Thanh Nha Uyen, Nguyen, Toan Q., Thi Thuy Ha, Hoa, Artati, Anna, Leong, Nancy C. P., Nguyen, Dat T., Lim, Pei Yen, Susanto, Adelia Vicanatalita, Huang, Qianhui, Fam, Ling, Leong, Lo Ngah, Bonne, Isabelle, Lee, Angela, Granadillo, Jorge L., Gooch, Catherine, Yu, Dejie, Huang, Hua, Soong, Tuck Wah, Chang, Matthew Wook, Wenk, Markus R., Adamski, Jerzy, Cazenave-Gassiot, Amaury, Nguyen, Long N.

Issue&Volume: 2024-02-02

Abstract: Mutations in the orphan transporter MFSD7c (also known as Flvcr2), are linked to Fowler syndrome. Here, we used Mfsd7c knockout (Mfsd7c–/–) mice and cell-based assays to reveal that MFSD7c is a choline transporter at the blood–brain barrier (BBB). We performed comprehensive metabolomics analysis and detected differential changes of metabolites in the brains and livers of Mfsd7c–/–embryos. Particularly, we found that choline-related metabolites were altered in the brains but not in the livers of Mfsd7c–/– embryos. Thus, we hypothesized that MFSD7c regulates the level of choline in the brain. Indeed, expression of human MFSD7c in cells significantly increased choline uptake. Interestingly, we showed that choline uptake by MFSD7c is greatly increased by choline-metabolizing enzymes, leading us to demonstrate that MFSD7c is a facilitative transporter of choline. Furthermore, single-cell patch clamp analysis showed that the import of choline by MFSD7c is electrogenic. Choline transport function of MFSD7c was shown to be conserved in vertebrates, but not in yeasts. We demonstrated that human MFSD7c is a functional ortholog of HNM1, the yeast choline importer. We also showed that several missense mutations identified in patients exhibiting Fowler syndrome had abolished or reduced choline transport activity. Mice lacking Mfsd7c in endothelial cells of the central nervous system suppressed the import of exogenous choline from blood but unexpectedly had increased choline levels in the brain. Stable-isotope tracing study revealed that MFSD7c was required for exporting choline derived from lysophosphatidylcholine in the brain. Collectively, our work identifies MFSD7c as a choline exporter at the BBB and provides a foundation for future work to reveal the disease mechanisms of Fowler syndrome.

DOI: 10.1038/s41422-023-00923-y

Source: https://www.nature.com/articles/s41422-023-00923-y

期刊信息

Cell Research:《细胞研究》,创刊于1990年。隶属于施普林格·自然出版集团,最新IF:20.057
官方网址:https://www.nature.com/cr/
投稿链接:https://mts-cr.nature.com/cgi-bin/main.plex