SCIENCE & SOLUTIONS

SCIENCE

Essential Fatty Acids and the Brain

Essential Fatty Acids (EFAs) and long-chain polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA) are lipids critical for brain growth, development and function.

However, the brain’s protective blood brain barrier (BBB) is impermeable to free circulating EFAs or those bound to triglycerides and most phospholipids1,2. How the brain acquires its lipids during development and throughout life has remained a puzzle to scientist for years.

 

The Discovery of MFSD2a and LPL-EFAs

  • To enter the brain, EFAs must be transported by a specific protein found on the BBB; the Major Facilitator Superfamily Domain–Containing 2a (MFSD2a)3-6
  • MFSD2a specifically transports EFAs and PUFAs attached to a Lysophospholipid (LPL), of which Lysophosphatidylcholines (LPCs) are the most abundant circulating form5.
  • Patients with genetic mutations in MFSD2a that disrupt LPC-EFA transport suffer from severe microcephaly (small brains) and cognitive defects3,4.

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These findings demonstrate that MFSD2a is the major transporter of EFAs to the brain during development and throughout life. In addition, LPLs are a previously under-appreciated pool of EFAs critical to brain growth and function in humans.

 

Vanteres’ preclinical and clinical research if focused on:

  • Identifying populations or conditions in which deficiencies or dysregulation of LPLs contribute to poor health and/or disease.
  • The development of specific ATLs as therapeutics for the treatment of these conditions.

 


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SOLUTIONS

MFSD2a and ATLs – the Larger Opportunity  

MFSD2a transports LPL-unsaturated fatty acids, such as LPC-DHA, more efficiently than the more abundant LPL-saturated fatty acids5,6. At the level of the BBB and retinal-blood barrier (REB), this is consistent with MFSD2a preferential delivery of DHA to the brain and eye.

However, MFSD2a is also expressed in several tissues and cell types where EFA uptake does not require MFSD2a transport i.e. liver and brown adipose tissue5,6.

Emerging science indicates that MFSD2a transport of LPL-EFAs can act as a intracellular signal to regulate cellular function, and that dysregulation of LPL-EFA metabolism, transport and/or signalling may contribute to disease.


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REFERENCES

  1. Betsholtz, C. Lipid transport and human brain development. Nat Genet 47, 699-701, doi:10.1038/ng.3348 (2015).
  2. Mitchell, R. W. & Hatch, G. M. Fatty acid transport into the brain: of fatty acid fables and lipid tails. Prostaglandins Leukot Essent Fatty Acids 85, 293-302, doi:10.1016/j.plefa.2011.04.007 (2011).
  3. Alakbarzade, V. et al. A partially inactivating mutation in the sodium-dependent lysophosphatidylcholine transporter MFSD2A causes a non-lethal microcephaly syndrome. Nat Genet 47, 814-817, doi:10.1038/ng.3313 (2015).
  4. Guemez-Gamboa, A. et al. Inactivating mutations in MFSD2A, required for omega-3 fatty acid transport in brain, cause a lethal microcephaly syndrome. Nat Genet 47, 809-813, doi:10.1038/ng.3311 (2015).
  5. Nguyen, L. N. et al. Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid. Nature 509, 503-506, doi:10.1038/nature13241 (2014).
  6. Quek, D. Q., Nguyen, L. N., Fan, H. & Silver, D. L. Structural Insights into the Transport Mechanism of the Human Sodium-dependent Lysophosphatidylcholine Transporter MFSD2A. J Biol Chem 291, 9383-9394, doi:10.1074/jbc.M116.721035 (2016).
  7. Angers, M., Uldry, M., Kong, D., Gimble, J. M. & Jetten, A. M. Mfsd2a encodes a novel major facilitator superfamily domain-containing protein highly induced in brown adipose tissue during fasting and adaptive thermogenesis. Biochem J 416, 347-355, doi:10.1042/bj20080165 (2008).
  8. Berger, M. M. et al. Fish oil after abdominal aorta aneurysm surgery. Eur J Clin Nutr 62, 1116-1122, doi:10.1038/sj.ejcn.1602817 (2008).
  9. Del Bas, J. M. et al. Impairment of lysophospholipid metabolism in obesity: altered plasma profile and desensitization to the modulatory properties of n-3 polyunsaturated fatty acids in a randomized controlled trial. Am J Clin Nutr 104, 266-279, doi:10.3945/ajcn.116.130872 (2016).
  10. ulipani, S. et al. Biomarkers of Morbid Obesity and Prediabetes by Metabolomic Profiling of Human Discordant Phenotypes. Clinica chimica acta; international journal of clinical chemistry 463, 53-61, doi:10.1016/j.cca.2016.10.005 (2016).
  11. Barber, M. N. et al. Plasma lysophosphatidylcholine levels are reduced in obesity and type 2 diabetes. PLoS One 7, e41456, doi:10.1371/journal.pone.0041456 (2012).