A natural form of Docosahexaenoic Acid (DHA) made by the liver called Lyso-Phosphatidyl-Choline (LPC-DHA), is critical for normal foetal and infant brain development, research from Duke-NUS indicates. The researchers also found that primarily only one form of DHA can reach the brain through a specific “transporter.”

It is commonly accepted that DHA is important for brain development, but the reason for this has not been known. These findings are expected to lead to innovations in clinical and nutritional products that can bolster the brain’s DHA levels.

“Our latest study shows that LPC-DHA or simply ‘activated-DHA’ is crucial for normal brain development after birth. It also shows for the first time that activated DHA controls crucial processes in the brain that regulate the growth of new membranes in neurons and other cell types during the time after the baby is born when the brain is rapidly growing. Other forms of DHA are not able to enter the brain because of the blood-brain barrier (BBB) that guards against the free flow of substances into this vital organ,"

Prof David Silver of Duke-NUS' Cardiovascular and Metabolic Disorders programme said.

Activated DHA

Due to the presence of this barrier to the brain, there exist many specialised chemical “transporters” in our body that are inherently designed to carry nutrients and other substances in and out of the BBB. In the case of DHA, the designated transporter is known as Mfsd2a.

“DHA can only enter the brain if it can be transported by Mfsd2a in the form of activated DHA. All other ingested forms of DHA cannot efficiently be transported into the brain,"

Said Prof Silver.

The validated research clearly shows that two vital components are needed for DHA to reach the developing brain in sufficient quantities for health growth: the presence of functional Mfsd2a, and the abundance of activated DHA. Prof Silver and his collaborators have identified four families with mutations in Mfsd2a that have severe microcephaly and intellectual disabilities.

[caption id=“attachment_96972” align=“aligncenter” width=“680”]Mfsd2a is required at the BBB for postnatal brain growth. Mfsd2a is required at the BBB for postnatal brain growth.
Credit: Chan JP, et al. CC-BY[/caption]

While there is no clear-cut genetic evidence for a crucial role of DHA in brain development, these human genetic studies prove that Mfs2da and “activated DHA” or LPC-DHA are critical for such development.

“DHA ingested through diet does not reach the brain unless it is in the modified LPC form. As such, LPC-DHA can be introduced into the diet in order provide sufficient DHA levels for healthy brain development and to improve brain development in at-risk populations,"

lead author Dr. Bernice Wong said.

Brain Development

This finding could lead to improvements in worldwide nutrition programmes and in food industries. Clinical benefits from the findings could help address neonatal as well as adult neurological diseases that result from low DHA levels in the brain or issues with postnatal brain development.

The brain is one of the most lipid-rich organs in the body, consisting mostly of glycerophospholipids, cholesterol, and sphingolipids.

Prenatal brain development is a complex developmental process that involves the coordinated establishment of hundreds of specialized cell types and the building of synaptic connectivity, together with a functioning blood-brain barrier. Postnatal brain growth involves proliferation of astrocytes and oligodendrocytes, myelination of axons, and expansion of neuron dendrites.

An essential requirement common to both prenatal and postnatal brain development is the biosynthesis of a huge amount of membrane phospholipid, the origin of which was believed to be exclusively derived from de novo biosynthesis within cells of the brain, and acquisition of essential fatty acids from the periphery into the developing brain.

This work provides genetic and biochemical evidence that Mfsd2a is required at the BBB during postnatal life to mediate normal brain growth and that DHA deficiency precedes the onset of microcephaly. Also, using an unbiased gene-profiling approach, the researchers determined that a major function of DHA during brain development is to regulate Srebp-1 and Srebp-2 activity resulting in major changes in phospholipid saturation.

Funding for the study came from the National Research Foundation, Singapore.

Chan JP, Wong BH, Chin CF, Galam DLA, Foo JC, Wong LC, et al. The lysolipid transporter Mfsd2a regulates lipogenesis in the developing brain PLoS Biol 16(8): e2006443. https://doi.org/10.1371/journal.pbio.2006443

Top Image: Model for physiological role of LPC-DHA in regulating membrane phospholipid homeostasis and brain growth. In the developing brain, de novo lipogenesis mediated by Srebp-1 and Srebp-2 and accretion of DHA in the form of lysophosphatidylcholine (LPC-DHA) uptake at the BBB by Mfsd2a are essential for brain development. Credit: Chan JP, et al. CC-BY

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