The lysolipid transporter Mfsd2a regulates lipogenesis in the developing brain

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Brain development necessitates significant lipogenesis and docosahexaenoic acid (DHA) accretion.
• The Major Facilitator Superfamily Domain containing 2a (Mfsd2a) transporter mediates brain uptake of DHA, primarily as lysophosphatidylcholine-DHA (LPC-DHA).
• The precise roles of Mfsd2a and DHA in brain development remain incompletely elucidated.

Purpose of the Study:

• To investigate the essential function of Mfsd2a at the blood-brain barrier (BBB) for postnatal brain growth and DHA accretion.
• To explore the molecular mechanisms by which DHA influences lipogenesis and gene expression during brain development.

Main Methods:

• Utilized vascular endothelial-specific and inducible knockout mouse models to delete Mfsd2a.
• Performed lipidomic analysis and gene expression profiling on Mfsd2a-deficient brains.
• Treated primary neural stem cells with LPC-DHA to assess effects on Srebp activity and phospholipid saturation.

Main Results:

• Mfsd2a is indispensable postnatally at the BBB for normal brain growth and DHA accumulation, with deficiency leading to microcephaly.
• Mfsd2a deficiency induced a lipidomic signature of increased de novo lipogenesis and elevated sterol regulatory-element binding protein (Srebp)-1 and Srebp-2 pathways.
• LPC-DHA uptake via Mfsd2a downregulated Srebp processing and activation, impacting phospholipid saturation and demonstrating a feedback loop where Srebp regulates Mfsd2a expression.

Conclusions:

• Mfsd2a plays a critical, unique role in mediating postnatal brain DHA accretion essential for preventing microcephaly.
• LPC-DHA, transported by Mfsd2a, acts as a key regulator of membrane phospholipid saturation by modulating Srebp activity.
• Identified a novel feedback mechanism between Mfsd2a-mediated DHA transport and Srebp-driven lipogenesis crucial for brain development.