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

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

机构地区：[1]Department of Biochemistry,Yong Loo Lin School of Medicine,National University of Singapore,Singapore,Singapore [2]Metabolomics and Proteomics Core,Helmholtz Center Munich,German Research Center for Environmental Health,Neuherberg,Germany [3]Singapore Lipidomics Incubator(SLING),Life Sciences Institute,National University of Singapore,Singapore,Singapore [4]NUS Synthetic Biology for Clinical and Technological Innovation(SynCT),National University of Singapore,Singapore,Singapore [5]Synthetic Biology Translational Research Programme,Yong Loo Lin School of Medicine,National University of Singapore,Singapore,Singapore [6]Electron Microscopy Unit,Yong Loo Lin School of Medicine,National University of Singapore,Singapore,Singapore [7]Department of Microbiology and Immunology,Immunology Translational Research Programme,Yong Loo Lin School of Medicine,National University of Singapore,Singapore,Singapore [8]Life Sciences Institute,Immunology Programme,National University of Singapore,Singapore,Singapore [9]Division of Genetics and Genomic Medicine,Department of Pediatrics,Washington University in St Louis,Saint Louis,MO,USA [10]Electrophysiology Core Facility,Yong Loo Lin School of Medicine,National University of Singapore,Singapore,Singapore [11]Department of Physiology,Yong Loo Lin School of Medicine,National University of Singapore,Singapore,Singapore [12]Healthy Longevity Translational Research Program,Yong Loo Lin School of Medicine,National University of Singapore,Singapore,Singapore [13]Cardiovascular Diseases Program,National University of Singapore,Singapore,Singapore [14]Institute of Experimental Genetics,Helmholtz Zentrum Munchen,German Research Center for Environmental Health,Neuherberg,Germany [15]Institute of Biochemistry,Faculty of Medicine,University of Ljubljana,Ljubljana,Slovenia [16]Immunology Translational Research Program,Yong Loo Lin School of Medicine,National University of Singapore,Singapore,Singapore [17]Hudson Institute of Medical Research,Clayton,VIC,Australia

出　　处：《Cell Research》2024年第3期245-257,共13页细胞研究（英文版）

基　　金：supported in part by Singapore Ministry of Health's National Research Council NMRC/OFIRG/0066/20,Singapore Ministry of Education grants (T2EP30221-0012,T2EP30123-0014,and NUHSRO/2022/067/T1 (to L.N.N.));the Synthetic Biology Translational Research Programme of the Yong Loo Lin School of Medicine of the National University of Singapore (NUHSRO/2020/077/MSC/02/SB to M.W.C.).

摘　　要：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.

关 键 词：MFS BARRIER sized 

分 类 号：R651.15[医药卫生—外科学]