Volume 34, No 3, Mar 2024

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 34 Issue 3, March 2024: 245-257   |  Open Access

ORIGINAL ARTICLES

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

Xuan Thi Anh Nguyen^1,† , Thanh Nha Uyen Le^1,17,† , Toan Q. Nguyen¹ , Hoa Thi Thuy Ha¹ , Anna Artati² , Nancy C. P. Leong¹ , Dat T. Nguyen¹ , Pei Yen Lim^1,3 , Adelia Vicanatalita Susanto^1,4,5 , Qianhui Huang¹ , Ling Fam¹ , Lo Ngah Leong⁶ , Isabelle Bonne^6,7,8 , Angela Lee⁹ , Jorge L. Granadillo⁹ , Catherine Gooch⁹ , Dejie Yu¹⁰ , Hua Huang^10,11,12,13 , Tuck Wah Soong^10,11,12,13 , Matthew Wook Chang^1,4,5 , Markus R. Wenk^1,3 , Jerzy Adamski^1,14,15 , Amaury Cazenave-Gassiot^1,3 , Long N. Nguyen^{1,3,8,13,16,*}

¹Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
²Metabolomics and Proteomics Core, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
³Singapore Lipidomics Incubator (SLING), Life Sciences Institute, National University of Singapore, Singapore, Singapore
⁴NUS Synthetic Biology for Clinical and Technological Innovation (SynCTI), National University of Singapore, Singapore, Singapore
⁵Synthetic Biology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
⁶Electron Microscopy Unit, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
⁷Department of Microbiology and Immunology, Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
⁸Life Sciences Institute, Immunology Programme, National University of Singapore, Singapore, Singapore
⁹Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University in St Louis, Saint Louis, MO, USA
¹⁰Electrophysiology Core Facility, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
¹¹Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
¹²Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
¹³Cardiovascular Diseases Program, National University of Singapore, Singapore, Singapore
¹⁴Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
¹⁵Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
¹⁶Immunology Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
¹⁷Present address: Hudson Institute of Medical Research, Clayton, VIC, Australia
^†These authors contributed equally: Xuan Thi Anh Nguyen, Thanh Nha Uyen Le
Correspondence: Long N. Nguyen(bchnnl@nus.edu.sg)

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.

https://doi.org/10.1038/s41422-023-00923-y

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