FUNCTION OF THE LYSOLIPID TRANSPORTER Mfsd2a IN EYE AND BRAIN

Abstract

Brain and eye development require a large supply of lipid and essential fatty acids like docosahexaenoic acid (DHA). Although highly enriched in both brain and eye, DHA is not synthesized efficiently and must be transported into these tissues from plasma. Our laboratory discovered the lysophosphatidylcholine (LPC) transporter, Major Facilitator Superfamily Domain containing 2a (Mfsd2a) to be highly expressed at the blood-brain barrier and responsible for DHA accretion into brain. Mechanisms for DHA uptake in eye are not known. This thesis aimed to determine if Mfsd2a is required for DHA accretion in eye and to determine biochemical functions of DHA in the developing brain and eye. We made four fundamental discoveries: 1) Mfsd2a is highly expressed at the retinal pigment epithelium of the blood-eye barrier and constitutes the major pathway for DHA accretion, 2) Mfsd2a at the BBB is required for postnatal brain growth, 3) Mfsd2a is required both pre- and postnatally for brain DHA accretion, and DHA deficiency in Mfsd2a KO mice precedes the onset of microcephaly and 4) a major function of DHA in brain and eye is to regulate lipogenesis and membrane phospholipid composition by negatively regulating Srebp activity.