The brain is highly enriched with fatty acids. These include the polyunsaturated fatty acids (PUFAs) arachidonic acid and docosahexaenoic acid, which are largely esterified to the phospholipid cell ...membrane. Once PUFAs are released from the membrane, they can participate in signal transduction, either directly or after enzymatic conversion to a variety of bioactive derivatives ('mediators'). PUFAs and their mediators regulate several processes within the brain, such as neurotransmission, cell survival and neuroinflammation, and thereby mood and cognition. PUFA levels and the signalling pathways that they regulate are altered in various neurological disorders, including Alzheimer's disease and major depression. Diet and drugs targeting PUFAs may lead to novel therapeutic approaches for the prevention and treatment of brain disorders.
N-3 polyunsaturated fatty acids (PUFA) and the numerous families of lipid mediators derived from them collectively regulate numerous biological processes. The mechanisms by which n-3 PUFA regulate ...biological processes begins with an understanding of the n-3 biosynthetic pathway that starts with alpha-linolenic acid (18:3n-3) and is commonly thought to end with the production of docosahexaenoic acid (DHA, 22:6n-3). However, our understanding of this pathway is not as complete as previously believed. In the current review we provide a background of the evidence supporting the pathway as currently understood and provide updates from recent studies challenging three central dogma of n-3 PUFA metabolism. By building on nearly three decades of research primarily in cell culture and oral dosing studies, recent evidence presented focuses on in vivo kinetic modelling and compound-specific isotope abundance studies in rodents and humans that have been instrumental in expanding our knowledge of the pathway. Specifically, we highlight three main updates to the n-3 PUFA biosynthesis pathway: (1) DHA synthesis rates cannot be as low as previously believed, (2) DHA is both a product and a precursor to tetracosahexaenoic acid (24:6n-3) and (3) increases in EPA in response to DHA supplementation are not the result of increased retroconversion.
•Recent meta-analyses suggest that EPA is protective in major depression.•While EPA levels are low in the brain, it rapidly enters and is metabolised in the brain.•A better understanding of EPA ...metabolism in the brain could lead to new treatments for depression.
The results of several meta-analyses suggest that eicosapentaenoic acid (EPA) supplementation is therapeutic in managing the symptoms of major depression. It was previously assumed that because EPA is extremely low in the brain it did not cross the blood-brain barrier and any therapeutic effects it exerted would be via the periphery. However, more recent studies have established that EPA does enter the brain, but is rapidly metabolised following entry. While EPA does not accumulate within the brain, it is present in microglia and homeostatic mechanisms may regulate its esterification to phospholipids that serve important roles in cell signaling. Furthermore, a variety of signaling molecules from EPA have been described in the periphery and they have the potential to exert effects within the brain. If EPA is confirmed to be therapeutic in major depression as a result of adequately powered randomized clinical trials, future research on brain EPA metabolism could lead to the discovery of novel targets for treating or preventing major depression.
Docosahexaenoic acid (DHA) is an essential, omega-3, long-chain polyunsaturated fatty acid that is a key component of cell membranes and plays a vital role in vertebrate brain function. The capacity ...to synthesize DHA is limited in mammals, despite its critical role in neurological development and health. For humans, DHA is most commonly obtained by eating fish. Global warming is predicted to reduce the de novo synthesis of DHA by algae, at the base of aquatic food chains, and which is expected to reduce DHA transferred to fish. We estimated the global quantity of DHA (total and per capita) currently available from commercial (wild caught and aquaculture) and recreational fisheries. The potential decrease in the amount of DHA available from fish for human consumption was modeled using the predicted effect of established global warming scenarios on algal DHA production and ensuing transfer to fish. We conclude that an increase in water temperature could result, depending on the climate scenario and location, in a ~ 10 to 58% loss of globally available DHA by 2100, potentially limiting the availability of this critical nutrient to humans. Inland waters show the greatest potential for climate-warming-induced decreases in DHA available for human consumption. The projected decrease in DHA availability as a result of global warming would disproportionately affect vulnerable populations (e.g., fetuses, infants), especially in inland Africa (due to low reported per capita DHA availability). We estimated, in the worst-case scenario, that DHA availability could decline to levels where 96% of the global population may not have access to sufficient DHA.
ACSL6 is critical for maintaining brain DHA levels Chouinard-Watkins, Raphaël; Bazinet, Richard P.
Proceedings of the National Academy of Sciences - PNAS,
12/2018, Volume:
115, Issue:
49
Journal Article
Peer reviewed
Open access
The importance of DHA in the brain has led to many nutritional studies examining the role of diet in regulating its levels; however, mechanistic details regarding its uptake into the brain have been ...relatively scarce. While it is clear that plasma unesterified DHA can enter the brain, the molecular mechanisms regulating this process are not clear. In PNAS, Fernandez et al find that a member of the long-chain acyl-CoA synthetase (ACSL) family, ACSL6, is essential for enriching the brain with DHA.
A central goal in the study of long chain n-3 polyunsaturated fatty acids (PUFA) is to translate findings from the basic sciences to the population level to improve human health and prevent chronic ...diseases. A tenet of this vision is to think in terms of precision medicine and nutrition, that is, stratification of individuals into differing groups that will have different needs across the lifespan for n-3 PUFAs. Therefore, there is a critical need to identify the sources of heterogeneity in the human population in the dietary response to n-3 PUFA intervention.
We briefly review key sources of heterogeneity in the response to intake of long chain n-3 PUFAs. These include background diet, host genome, composition of the gut microbiome, and sex. We also discuss the need to integrate data from newer rodent models (e.g. population-based approaches), multi -omics, and analyses of big data using machine learning and data-driven cluster analyses.
Accounting for vast heterogeneity in the human population, particularly with the use of big data integrated with preclinical evidence, will drive the next generation of precision nutrition studies and randomized clinical trials with long-chain n-3 PUFAs.
Brain docosahexaenoic acid uptake and metabolism Lacombe, R.J.Scott; Chouinard-Watkins, Raphaël; Bazinet, Richard P.
Molecular aspects of medicine,
December 2018, 2018-12-00, 20181201, Volume:
64
Journal Article
Peer reviewed
Open access
Docosahexaenoic acid (DHA) is the most abundant n-3 polyunsaturated fatty acid in the brain where it serves to regulate several important processes and, in addition, serves as a precursor to ...bioactive mediators. Given that the capacity of the brain to synthesize DHA locally is appreciably low, the uptake of DHA from circulating lipid pools is essential to maintaining homeostatic levels. Although, several plasma pools have been proposed to supply the brain with DHA, recent evidence suggests non-esterified-DHA and lysophosphatidylcholine-DHA are the primary sources. The uptake of DHA into the brain appears to be regulated by a number of complementary pathways associated with the activation and metabolism of DHA, and may provide mechanisms for enrichment of DHA within the brain. Following entry into the brain, DHA is esterified into and recycled amongst membrane phospholipids contributing the distribution of DHA in brain phospholipids. During neurotransmission and following brain injury, DHA is released from membrane phospholipids and converted to bioactive mediators which regulate signaling pathways important to synaptogenesis, cell survival, and neuroinflammation, and may be relevant to treating neurological diseases. In the present review, we provide a comprehensive overview of brain DHA metabolism, encompassing many of the pathways and key enzymatic regulators governing brain DHA uptake and metabolism. In addition, we focus on the release of non-esterified DHA and subsequent production of bioactive mediators and the evidence of their proposed activity within the brain. We also provide a brief review of the evidence from post-mortem brain analyses investigating DHA levels in the context of neurological disease and mood disorder, highlighting the current disparities within the field.
Docosahexaenoic acid (DHA) is important for brain function, and can be obtained directly from the diet or synthesized in the body from α-linolenic acid (ALA). Debate exists as to whether DHA ...synthesized from ALA can provide sufficient DHA for the adult brain, as measures of DHA synthesis from ingested ALA are typically <1% of the oral ALA dose. However, the primary fate of orally administered ALA is β-oxidation and long-term storage in adipose tissue, suggesting that DHA synthesis measures involving oral ALA tracer ingestion may underestimate total DHA synthesis. There is also evidence that DHA synthesized from ALA can meet brain DHA requirements, as animals fed ALA-only diets have brain DHA concentrations similar to DHA-fed animals, and the brain DHA requirement is estimated to be only 2.4–3.8mg/day in humans. This review summarizes evidence that DHA synthesis from ALA can provide sufficient DHA for the adult brain by examining work in humans and animals involving estimates of DHA synthesis and brain DHA requirements. Also, an update on methods to measure DHA synthesis in humans is presented highlighting a novel approach involving steady-state infusion of stable isotope-labeled ALA that bypasses several limitations of oral tracer ingestion. It is shown that this method produces estimates of DHA synthesis that are at least 3-fold higher than brain uptake rates in rats.
•A growing body of literature is bringing forward new peripheral biomarkers to diagnose Alzheimer's disease.•Peripheral fatty acids have been proposed as putative biomarkers of AD, however discrepant ...results are reported in the literature.•To improve the predictive potential of these biomarkers further studies to validate and standardize the methods are recommended.
Alzheimer's disease (AD) is a complex and heterogeneous neurodegenerative disease. A wide range of techniques have been proposed to facilitate early diagnosis of AD, including biomarkers from the cerebrospinal fluid and blood. Although phosphorylated tau and amyloid beta are amongst the most promising biomarkers of AD, other peripheral biomarkers have been identified and in this review we synthesize the current knowledge on circulating fatty acids. Fatty acids are involved in different biological process including neurotransmission and inflammation. Interestingly, some fatty acids appear to be modulated during disease progression, including long chain saturated fatty acids, and polyunsaturated fatty acids, such as docosahexaenoic acid . However, discrepant results have been reported in the literature and there is the need for further validation and method standardization. Nonetheless, our literature review suggests that fatty acid analyses could potentially provide a valuable source of data to further inform the pathology and progression of AD.
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