MFSD7c identified as a choline “exporter” at the blood–brain barrier, reshaping brain nutrient biology

SINGAPORE — An international team led by researchers from Nguyen Nam Long’s team in LSI SLING reports that MFSD7c (also known as FLVCR2) is a previously unrecognized choline transporter at the blood–brain barrier (BBB)—and, critically, a key route for exporting excess choline out of the brain. The discovery helps explain the vascular–neurological features of the rare neurodevelopmental Fowler syndrome, which is caused by MFSD7c mutations, and reframes long-standing assumptions about how the brain sources and regulates choline.

Choline is essential for phospholipid synthesis and neurotransmitter production, but the molecular machinery that balances its brain levels has been unclear. Using knockout mice, endothelial cell–specific gene deletion, metabolomics, electrophysiology, stable-isotope tracing, and cross-species functional assays, the study shows that MFSD7c facilitates choline transport across endothelial membranes and is conserved across vertebrates. Whole-brain metabolomics in Mfsd7c-deficient embryos revealed brain-specific increases in free choline and related metabolites, without parallel changes in liver, pointing to a BBB-centric mechanism. In cellular systems, human MFSD7c increased choline uptake in a concentration- and time-dependent, electrogenic manner and could functionally replace the yeast choline importer HNM1.

Disease-linked missense variants—several identified in Fowler syndrome patients—abolished or reduced choline transport despite normal protein expression and membrane localization, connecting transport loss to pathogenesis. In vivo, endothelial deletion of Mfsd7c reduced brain entry of exogenous radiolabeled choline at supraphysiological doses, but paradoxically led to higher endogenous brain choline. Stable-isotope tracing resolved this paradox: plasma lysophosphatidylcholine (LPC) is delivered into the brain (via the established Mfsd2a route) and remodelled to liberate choline; MFSD7c is then required to export this LPC-derived choline from the brain parenchyma back across the BBB. When MFSD7c is absent, choline (and acetylcholine) accumulate in the brain, implicating dysregulated choline homeostasis in BBB and neurovascular abnormalities.

By identifying MFSD7c as a facilitative, bidirectional choline transporter whose dominant physiological role at the BBB is export, the work clarifies how the brain avoids choline overload and provides a mechanistic foothold for understanding Fowler syndrome. It also suggests new avenues to probe brain lipid–nutrient flux and to explore whether modulating MFSD7c activity could help restore metabolic balance in neurodevelopmental and vascular conditions such as Alzheimer’s disease and dementia.

Article: MFSD7c functions as a transporter of choline at the blood–brain barrier, Cell Research (2024). DOI: 10.1038/s41422-023-00923-y.