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PLoS Biol . 2018 Aug 3;16(8):e2006443. doi: 10.1371/journal.pbio.2006443. eCollection 2018 Aug.

The lysolipid transporter Mfsd2a regulates lipogenesis in the developing brain

August 3, 2018
Jia Pei Chan 1, Bernice H Wong 1, Cheen Fei Chin 1, Dwight L A Galam 1, Juat Chin Foo 2, Loo Chin Wong 1, Sujoy Ghosh 3, Markus R Wenk 2, Amaury Cazenave-Gassiot 2, David L Silver 1

1Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, Singapore.

2Department of Biochemistry, National University of Singapore, Singapore, Singapore.

3Centre for Computational Biology, Duke-NUS Medical School, Singapore, Singapore.

Abstract

Brain development requires a massive increase in brain lipogenesis and accretion of the essential omega-3 fatty acid docosahexaenoic acid (DHA). Brain acquisition of DHA is primarily mediated by the transporter Major Facilitator Superfamily Domain containing 2a (Mfsd2a) expressed in the endothelium of the blood-brain barrier (BBB) and other abundant cell types within the brain. Mfsd2a transports DHA and other polyunsaturated fatty acids (PUFAs) esterified to lysophosphatidylcholine (LPC-DHA). However, the function of Mfsd2a and DHA in brain development is incompletely understood. Here, we demonstrate, using vascular endothelial-specific and inducible vascular endothelial-specific deletion of Mfsd2a in mice, that Mfsd2a is uniquely required postnatally at the BBB for normal brain growth and DHA accretion, with DHA deficiency preceding the onset of microcephaly. In Mfsd2a-deficient mouse models, a lipidomic signature was identified that is indicative of increased de novo lipogenesis of PUFAs. Gene expression profiling analysis of these DHA-deficient brains indicated that sterol regulatory-element binding protein (Srebp)-1 and Srebp-2 pathways were highly elevated. Mechanistically, LPC-DHA treatment of primary neural stem cells down-regulated Srebp processing and activation in a Mfsd2a-dependent fashion, resulting in profound effects on phospholipid membrane saturation. In addition, Srebp regulated the expression of Mfsd2a. These data identify LPC-DHA transported by Mfsd2a as a physiological regulator of membrane phospholipid saturation acting in a feedback loop on Srebp activity during brain development.

Keywords
Blood-brain barrier
Major facilitator superfamily domain containing 2a (Mfsd2a)
Lifespan
Early life
Brain
DHA
LPC
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