Lipids and Nutraceuticals: Follow up on last month issue.
December 2021
Mike Eyres and Laurence Eyres FNZIFST
Bioactive Lipids and Brain Health
With increased interest in plant-based diets, debate and investigations continue into the bioavailability and conversion rates of 18 carbon omega 3 fatty acids such as DHA and EPA .
The need for a sustainable plant-based source of DHA and EPA is becoming apparent as a result of continued unsustainable pressure on global fisheries and climate change. It has been suggested that global production of DHA from its primary source (marine algae) will reduce in response to warming ocean temperatures. This is an adaptive response by the algae to maintain the correct fluidity of their cell membranes.
Link – https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028814/
New Zealand and Australia are well placed to grow and produce high quality seed crops that yield both edible whole seeds and edible oils high in 18 carbon omega 3’s. Examples include flaxseed, hemp seed, and chia seed. There have been many articles in the past debating whether alpha linolenic acid is a good source of long chain omega 3 EPA and DHA.
This month we are extremely lucky to have a comment from Pofessor Richard Bazinet on this topic and an update on his team’s investigations in the area of bioavailability and metabolism of DHA, with particular respect to the brain.
DHA metabolism: A guest article by Professor Richard Bazinet 
Richard Bazinet joined the University of Toronto in 2006, where he is currently a Professor and Canada Research Chair in Brain Lipid Metabolism. Professor Bazinet is the recipient of several awards, including the Early Career Award from the International Society for the Study of Fatty Acids and Lipids; the Jordi-Folch-Pi Memorial Award from the American Society for Neurochemistry; the Future Leaders Award from the International Life Sciences Institute, the Young Scientist Award for the American Oil Chemists’ Society, the Early Researcher Award from the Canadian Society for Nutrition and a the Ralph Holman life time achievement award from the Oil Chemists’ Society. Richard’s lab is interested in brain lipid metabolism, especially brain docosahexaenoic acid (22:6n-3; DHA) metabolism. We know that the brain is enriched with DHA and that within the brain DHA regulates a lot of important functions either directly or upon conversion to other bioactive molecules, including neuroinflammation, neuronal survival and as a secondary messenger to neurotransmission. While the high level of DHA in the brain suggests that it is important this does not tell us very much about how much dietary DHA we need to consume.
By using kinetic approaches to identify that the plasma unesterified pool of DHA is the major pool supplying the brain, we have extended the interpretation of studies that have imaged unesterified DHA uptake into the brain of adults using position emission tomography and estimated it to be about 4 mg per day. Thus, the adult brain takes up about 4 mg of DHA per day, thus providing a starting point to discuss how much DHA we need to consume to meet this brain “requirement”. DHA can be obtained either (1) directly from the diet from foods such as fish that are high in preformed DHA or (2) DHA can be synthesized from shorter chain precursors. With the increase in popularity of plant-based diets, we have become extremely interested in developing methods to estimate the synthesis rate of DHA from its shorter chain precursors.
It is well established that increasing intake of the 18 carbon precursors to DHA, alpha-linolenic acid (18:3n-3; ALA), stearidonic acid (18:4n-3; SDA) or even the 20-carbon precursor eicosapentaenoic acid (20:5n-3; EPA) do not increase circulating DHA levels in humans. However, this does not mean that these precursors are not converted to DHA. An alternative explanation for their inability to increase circulating DHA is that the synthesis rate of DHA from these precursors approximates the loss rate and thus DHA does not bioaccumulate. While tracer studies with ALA and EPA have led to estimates of fractional conversion, estimates of true conversion and turnover rates are limited in the field. To address the question of ALA conversion to DHA, we have begun working in preclinical models with a technique called compound specific isotope analysis (CSIA) at the natural abundance level using gas chromatography (GC) coupled to high precision isotope ratio mass spectrometry (IRMS). Briefly, this technique can measure the natural variance in carbon 13 content or the signature of molecules. In several preclinical studies, with this powerful technique, we have been able to identify whether tissue DHA was derived from dietary DHA or dietary ALA. Importantly, we conducted a secondary analysis of a randomized controlled clinical trial that supplemented humans with EPA at 3 grams per day for 12 weeks.
As expected from the literature, EPA supplementation did not increase plasma DHA levels, but based on CSIA by GC-IRMS it was apparent that the circulating DHA had taken on the carbon 13 signature of the EPA suggesting that despite not increasing DHA levels, that EPA was readily converted to DHA. Now obviously we need to study the 18 carbon precursors, ALA and SDA, to test if they are also readily converted to DHA without augmenting DHA levels. Collectively this work could have implications for omega-3 recommendations and advance our understanding about DHA synthesis and accumulation. “
The work and concepts described above are covered in more detail in the following 4 papers, or also watch this video on YouTube:
https://www.youtube.com/watch?v=fPkx8U9f-dI
Lacombe RJS, Bazinet RP. Natural abundance carbon isotope ratio analysis and its application in the study of diet and metabolism. Nutr Rev. 2021 Jul 7;79(8):869-888.
Metherel AH, Bazinet RP. Updates to the n-3 polyunsaturated fatty acid biosynthesis pathway: DHA synthesis rates, tetracosahexaenoic acid and (minimal) retroconversion. Prog Lipid Res. 2019 Oct;76:101008
Lacombe RJS, Chouinard-Watkins R, Bazinet RP. Brain docosahexaenoic acid uptake and metabolism.
Mol Aspects Med. 2018 Dec;64:109-134.
Domenichiello AF, Kitson AP, Bazinet RP. Is docosahexaenoic acid synthesis from α-linolenic acid sufficient to supply the adult brain?
Prog Lipid Res. 2015 Jul;59:54-66.