The lysolipid transporter Mfsd2a regulates lipogenesis in the developing brain

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

doi:10.1371/journal.pbio.2006443

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.

Highlights

The brain is one of the most lipid-rich organs in the body, consisting mostly of glycerophospholipids, cholesterol, and sphingolipids [1]
De novo synthesis of fatty acids is mediated by sterol regulatory-element binding protein (Srebp) transcription factors, whereas acquisition of essential fatty acids via uptake of plasma-derived lysophosphatidylcholine containing the essential omega-3 fatty acid docosahexaenoic acid (LPC-DHA) is mediated by the transporter Major Facilitator Superfamily Domain containing 2a (Mfsd2a) in the cells
We previously found that the brain sizes of conventional gene-targeted Mfsd2a knockout mice (2aKO) at embryonic day 18.5 (e18.5), a stage equivalent to late third trimester in human development, were similar to wild-type (WT) littermates, and the brains were DHA deficient [23]

Summary

Introduction

The brain is one of the most lipid-rich organs in the body, consisting mostly of glycerophospholipids, cholesterol, and sphingolipids [1]. De novo lipogenesis is driven by sterol regulatory-element binding proteins (SREBPs), identified by Brown and Goldstein to be transcription factors that are important for the regulation of genes that maintain cellular lipid homeostasis. In the presence of cholesterol or oxysterols, the precursor form of Srebp (about 130 kDa), in complex with its chaperone protein sterol cleavage-activating protein (Scap), is retained in the endoplasmic reticulum (ER) bound to insulin-induced gene 1 (Insig-1) [7]. At the Golgi, the Srebp precursor is cleaved by Site-1 and Site-2 proteases, releasing the N-terminal basic helix-loop-helix leucine zipper transcription factor domain (about 60–70 kDa) that enters the nucleus and activates target genes by binding to sterol regulatory elements (SREs) [9]. Underscoring the importance of de novo lipogenesis for brain development, targeted deletion of Scap in brain resulted in perinatal lethality [10]

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