The lysolipid transporter Mfsd2a regulates lipogenesis in the developing brain

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.

Child Head Circumference and Placental MFSD2a Expression Are Associated to the Level of MFSD2a in Maternal Blood During Pregnancy

“…Altogether, these findings indicate an essential role for lyso-PL in human brain development and function, and provide the first description of diseases associated with aberrant brain lyso-PL transport in humans (18). Moreover, Chan et al, have demonstrated in a mouse model that the adequate presence of MFSD2a at the blood-brain barrier (BBB) is required for normal postnatal brain growth and for maintaining plasma membrane phospholipid composition during brain development (44). Despite there were no changes in infant head circumference among groups, probably due to the low number of subjects to find differences in this clinical variable our current study shows how maternal blood MFSD2a level at third trimester correlate with postnatal infant head circumference of their offspring during the first 6 months of life (Figure 3 and Table 2) which is in agreement with Chan et al (44).…”

“…Moreover, Chan et al, have demonstrated in a mouse model that the adequate presence of MFSD2a at the blood-brain barrier (BBB) is required for normal postnatal brain growth and for maintaining plasma membrane phospholipid composition during brain development (44). Despite there were no changes in infant head circumference among groups, probably due to the low number of subjects to find differences in this clinical variable our current study shows how maternal blood MFSD2a level at third trimester correlate with postnatal infant head circumference of their offspring during the first 6 months of life (Figure 3 and Table 2) which is in agreement with Chan et al (44). This result would suggest that the neurodevelopment of the child could be affected by the reduction of the MFSD2a level in the maternal blood during pregnancy.…”

Dissecting the Genetic and Etiological Causes of Primary Microcephaly

“…Knockdown of COPB2 increases the expression of CDK inhibitors (P16 and P21) and decreases the expression of cyclin A1 and A2, which are responsible for progression through S phase. MFSD2A encodes a fatty acid transporter that acts at the blood-brain barrier (133,134). It is responsible for the uptake of lysophosphatidylcholines (LPCs), such as those derived from docosahexanoic acid (DHA), which are not synthesized within the brain but are essential for neurogenesis.…”

“…Mutations in MFSD2A result in increased plasma levels of LPCs and a corresponding decrease in LPC uptake into the brain; this reduced uptake is associated with both lethal and non-lethal microcephaly in humans and animal models (63,64,133,135). The presence of DHA in the brain suppresses the activity of master transcriptional regulators of sterol and fatty acid synthesis (133). Accordingly, reduced uptake of DHA due to mutations in MFSD2A results in the increased expression of the master transcriptional regulators and their downstream targets.…”

Maternal Docosahexaenoic Acid Status During Pregnancy and Its Impact on Infant Neurodevelopment

“…Once saturated, the phospholipid DHA poolsweaken SREBP activity that leads to a decrease in lipogenesis. Thus, in normal physiology, the activity of MFSD2a is regulated by SREBP to maintain a balance between de novo lipogenesis and exogenous uptake of LPC-DHA[141].…”