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

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 ChangMarkus R. Wenk, Jerzy Adamski, Amaury Cazenave-Gassiot, Long N. Nguyen

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish
Pages (from-to)245-257
Number of pages13
JournalCell Research
Volume34
Issue number3
DOIs
StatePublished - Mar 2024

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