Docosahexaenoic acid#Metabolic synthesis

DHA is the most abundant omega−3 fatty acid in the brain and retina.{{cite journal | last1=Kim | first1=Hee-Yong | last2=Huang | first2=Bill X. | last3=Spector | first3=Arthur A. | title=Phosphatidylserine in the brain: Metabolism and function | journal=Progress in Lipid Research | volume=56 | year=2014 | issn=0163-7827 | doi=10.1016/j.plipres.2014.06.002 | pages=1–18|pmc=4258547|pmid=24992464}} DHA comprises 40% of the polyunsaturated fatty acids (PUFAs) in the brain and 60% of the PUFAs in the retina. Fifty percent of a neuronal plasma membrane is composed of DHA.{{cite journal | last = Singh | first = Meharban | title = Essential fatty acids, DHA and the human brain | journal = Indian Journal of Pediatrics | volume = 72 | issue = 3 | pages = 239–242 | url = http://medind.nic.in/icb/t05/i3/icbt05i3p239.pdf | access-date = October 8, 2007 | date = March 2005 | doi = 10.1007/BF02859265 | pmid = 15812120 | s2cid = 5067744 | archive-date = February 27, 2012 | archive-url = https://web.archive.org/web/20120227115425/http://medind.nic.in/icb/t05/i3/icbt05i3p239.pdf | url-status = dead }} DHA modulates the carrier-mediated transport of choline, glycine, and taurine, the function of delayed rectifier potassium channels, and the response of rhodopsin contained in the synaptic vesicles.{{cite journal | last1=Spector | first1=Arthur A. | last2=Kim | first2=Hee-Yong | title=Discovery of essential fatty acids | journal=Journal of Lipid Research | volume=56 | issue=1 | year=2015 | issn=0022-2275 | pmid=25339684 | pmc=4274059 | doi=10.1194/jlr.r055095 |doi-access=free | pages=11–21}}{{cite journal | last = Spector | first = Arthur A. | title = Essentiality of fatty acids | journal= Lipids | volume= 34 | pages = S1–S3 | year = 1999 | doi= 10.1007/BF02562220 | pmid= 10419080| s2cid = 4061017 }}

Phosphatidylserine (PS) – which contains high DHA content – has roles in neuronal signaling and neurotransmitter synthesis, and DHA deficiency is associated with cognitive decline.{{cite journal

|doi=10.1172/JCI25420

|journal=J Clin Invest |date=October 2005|volume=115|pages=2774–83

|title= A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease

|vauthors= Lukiw WJ, Cui JG, Marcheselli VL, Bodker M, Botkjaer A, Gotlinger K, Serhan CN, Bazan NG

|author-link8= Nicolas Bazan

|issue=10

|pmid=16151530

|pmc=1199531}} DHA levels are reduced in the brain tissue of severely depressed people.{{cite journal

| author=McNamara RK

| title=Selective deficits in the omega-3 fatty acid docosahexaenoic acid in the postmortem orbitofrontal cortex of patients with major depressive disorder

| journal=Biol. Psychiatry

| volume=62

| issue=1

| pages=17–24

| year=2007

| pmid=17188654

| doi=10.1016/j.biopsych.2006.08.026

|name-list-style=vanc| author2=Hahn CG

| author3=Jandacek R

| display-authors=3

| last4=Rider

| first4=Therese

| last5=Tso

| first5=Patrick

| last6=Stanford

| first6=Kevin E.

| last7=Richtand

| first7=Neil M.

| s2cid=32898004

}}{{Cite journal

| pmid = 23759469

| year = 2013

| last1 = McNamara

| first1 = R. K.

| title = Lower docosahexaenoic acid concentrations in the postmortem prefrontal cortex of adult depressed suicide victims compared with controls without cardiovascular disease

| journal = Journal of Psychiatric Research

| volume = 47

| issue = 9

| pages = 1187–91

| last2 = Jandacek

| first2 = R

| last3 = Tso

| first3 = P

| last4 = Dwivedi

| first4 = Y

| last5 = Ren

| first5 = X

| last6 = Pandey

| first6 = G. N.

| doi = 10.1016/j.jpsychires.2013.05.007

| pmc = 3710518

}}

Aerobic eukaryotes, specifically microalgae, mosses, fungi, and some animals, perform biosynthesis of DHA as a series of desaturation and elongation reactions, catalyzed by the sequential action of desaturase and elongase enzymes. This pathway, originally identified in Thraustochytrium, applies to these groups:{{Cite journal|date=2003-02-01|last=Qiu |first=Xiao |title=Biosynthesis of docosahexaenoic acid (DHA, 22:6-4, 7,10,13,16,19): two distinct pathways|journal=Prostaglandins, Leukotrienes and Essential Fatty Acids |volume=68|issue=2|pages=181–186|doi=10.1016/S0952-3278(02)00268-5|issn=0952-3278|pmid=12538082}}

1. a desaturation at the sixth carbon of alpha-linolenic acid by a delta 6 desaturase to produce stearidonic acid (SDA, 18:4 ω-3),
2. elongation of the stearidonic acid by a delta 6 elongase to produce eicosatetraenoic acid (ETA, 20:4 ω-3),
3. desaturation at the fifth carbon of eicosatetraenoic acid by a delta 5 desaturase to produce eicosapentaenoic acid (EPA, 20:5 ω-3),
4. elongation of eicosapentaenoic acid by a delta 5 elongase to produce docosapentaenoic acid (DPA, 22:5 ω-3), and
5. desaturation at the fourth carbon of docosapentaenoic acid by a delta 4 desaturase to produce DHA.

In humans, DHA is either obtained from the diet or may be converted in small amounts from eicosapentaenoic acid (EPA, 20:5, ω-3). With the identification of FADS2 as a human Δ4-desaturase in 2015, it is now known that humans follow the same synthesis pathway as aerobic eukaryotes, involving Δ5-elongation to DPA and Δ4-desaturation to DHA.{{cite journal |last1=Park |first1=HG |last2=Park |first2=WJ |last3=Kothapalli |first3=KS |last4=Brenna |first4=JT |title=The fatty acid desaturase 2 (FADS2) gene product catalyzes Δ4 desaturation to yield n-3 docosahexaenoic acid and n-6 docosapentaenoic acid in human cells. |journal=FASEB Journal |date=September 2015 |volume=29 |issue=9 |pages=3911–9 |doi=10.1096/fj.15-271783 |doi-access=free |pmid=26065859|pmc=4550368 }}

A "Sprecher's shunt" hypothesis, proposed in 1991, postulates that EPA is twice elongated to 24:5 ω-3, then desaturated to 24:6 ω-3 (via delta 6 desaturase) in the mitochondria, then shortened to DHA (22:6 ω-3) via beta oxidation in the peroxisome. The hypothesis was accepted in the absence of an identified Δ4-desaturase in mammals prior to 2015.{{cite journal |author1=De Caterina, R |author2=Basta, G|title= n-3 Fatty acids and the inflammatory response – biological background |date=June 2001| journal= European Heart Journal Supplements |volume= 3 |issue= Supplement D |pages= D42–D49 |doi= 10.1016/S1520-765X(01)90118-X |doi-access= free }}{{cite journal|title=The metabolism of 7,10,13,16,19-docosapentaenoic acid to 4,7,10,13,16,19-docosahexaenoic acid in rat liver is independent of a 4-desaturase|author1=A Voss |author2=M Reinhart |author3=S Sankarappa |author4=H Sprecher |url=http://www.jbc.org/content/266/30/19995.full.pdf+html |access-date= January 2, 2011 |date=October 1991| journal=The Journal of Biological Chemistry |volume= 266 |issue= 30 |pages= 19995–20000 |doi=10.1016/S0021-9258(18)54882-1 |pmid= 1834642 |doi-access=free }} The shunt model does not match clinical data, specifically that patients with beta oxidation defects do not display issues in DHA synthesis. With the identification of a Δ4-desaturase, it is considered outdated.

Marine bacteria and the microalgae Schizochytrium use an anerobic polyketide synthase pathway to synthesize DHA.

DHA can be metabolized into DHA-derived specialized pro-resolving mediators (SPMs), DHA epoxides, electrophilic oxo-derivatives (EFOX) of DHA, neuroprostanes, ethanolamines, acylglycerols, docosahexaenoyl amides of amino acids or neurotransmitters, and branched DHA esters of hydroxy fatty acids, among others.{{cite journal|last1=Kuda|first1=Ondrej|title=Bioactive metabolites of docosahexaenoic acid|journal=Biochimie|date=2017|doi=10.1016/j.biochi.2017.01.002|volume=136|pages=12–20|pmid=28087294}}

The enzyme CYP2C9 metabolizes DHA to epoxydocosapentaenoic acids (EDPs; primarily 19,20-epoxy-eicosapentaenoic acid isomers [i.e. 10,11-EDPs]).{{cite journal | vauthors = Westphal C, Konkel A, Schunck WH | title = CYP-eicosanoids--a new link between omega-3 fatty acids and cardiac disease? | journal = Prostaglandins & Other Lipid Mediators | volume = 96 | issue = 1–4 | pages = 99–108 | date = Nov 2011 | pmid = 21945326 | doi = 10.1016/j.prostaglandins.2011.09.001 | doi-access = free }}

{{See also|Omega-3 fatty acid#Health effects of omega−3 supplementation}}

Though mixed and plagued by methodological inconsistencies, there is now convincing evidence from ecological, RCTs, meta-analyses and animal trials that shows a benefit for omega−3 dietary intake for cardiovascular health. Of the n−3 FAs, DHA has been argued to be the most beneficial due to its preferential uptake in the myocardium, its strongly anti-inflammatory activity and its metabolism toward neuroprotectins and resolvins, the latter of which directly contribute to cardiac function.{{cite journal |last1=Mclennan |first1=Peter |title=Cardiac physiology and clinical efficacy of dietary fish oil clarified through cellular mechanisms of omega-3 polyunsaturated fatty acids. |journal=European Journal of Applied Physiology |date=2014 |volume=114 |issue=7 |pages=1333–1356|doi=10.1007/s00421-014-2876-z |pmid=24699892 |s2cid=959967 |url=https://ro.uow.edu.au/cgi/viewcontent.cgi?article=2605&context=smhpapers |url-access=subscription }}

DHA is associated with its role in cardiovascular protection and lowering the risk of coronary artery disease. DHA supplementation has been shown to improve high-density lipoprotein (‘good cholesterol’), and lower total cholesterol as well as blood pressure levels.{{Cite journal |last1=Horrocks |first1=L. A. |last2=Yeo |first2=Y. K. |date= 1999|title=Health benefits of docosahexaenoic acid (DHA) |url=https://pubmed.ncbi.nlm.nih.gov/10479465/ |journal=Pharmacological Research |volume=40 |issue=3 |pages=211–225 |doi=10.1006/phrs.1999.0495 |issn=1043-6618 |pmid=10479465}}

Foods high in omega−3 fatty acids may be recommended to women who want to become pregnant or when nursing.{{cite web|url=http://www.hsph.harvard.edu/nutritionsource/omega-3-fats/|title=Omega-3 Fatty Acids: An Essential Contribution|author=Harvard School Of Public Health|date=18 September 2012|access-date=12 June 2015}} A working group from the International Society for the Study of Fatty Acids and Lipids recommended 300 mg/day of DHA for pregnant and lactating women, whereas the average consumption was between 45 mg and 115 mg per day of the women in the study, similar to a Canadian study.{{cite journal |vauthors=Denomme J, Stark KD, Holub BJ |title=Directly quantitated dietary (n-3) fatty acid intakes of pregnant Canadian women are lower than current dietary recommendations |journal=The Journal of Nutrition |volume=135 |issue=2 |pages=206–11 |year=2005 |doi=10.1093/jn/135.2.206|pmid=15671214 |url=http://jn.nutrition.org/cgi/pmidlookup?view=long&pmid=15671214|doi-access=free }}

A major structural component of the mammalian central nervous system, DHA is the most abundant omega−3 fatty acid in the brain and retina.{{cite journal | vauthors = Hüppi PS | title = Nutrition for the brain: commentary on the article by Isaacs et al. on page 308 | journal = Pediatric Research | volume = 63 | issue = 3 | pages = 229–31 | date = March 2008 | pmid = 18287959 | doi = 10.1203/pdr.0b013e318168c6d1 | s2cid = 6564743 | url = http://surfer.nmr.mgh.harvard.edu/ftp/articles/caudatecomm.pdf | doi-access = free }} Brain and retinal function rely on dietary intake of DHA to support a broad range of cell membrane and cell signaling properties, particularly in grey matter and retinal photoreceptor cell outer segments, which are rich in membranes.{{cite journal | vauthors = Harris WS, Baack ML | title = Beyond building better brains: bridging the docosahexaenoic acid (DHA) gap of prematurity | journal = Journal of Perinatology | volume = 35 | issue = 1 | pages = 1–7 | date = January 2015 | pmid = 25357095 | pmc = 4281288 | doi = 10.1038/jp.2014.195 }}{{cite journal | vauthors = SanGiovanni JP, Chew EY | title = The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina | journal = Progress in Retinal and Eye Research | volume = 24 | issue = 1 | pages = 87–138 | date = January 2005 | pmid = 15555528 | doi = 10.1016/j.preteyeres.2004.06.002 | s2cid = 13757616 }}

A systematic review found that DHA had no significant benefits in improving visual field in individuals with retinitis pigmentosa.{{Cite journal|last1=Schwartz|first1=Stephen G.|last2=Wang|first2=Xue|last3=Chavis|first3=Pamela|last4=Kuriyan|first4=Ajay E.|last5=Abariga|first5=Samuel A.|date=18 June 2020|title=Vitamin A and fish oils for preventing the progression of retinitis pigmentosa|journal=The Cochrane Database of Systematic Reviews|volume=2020|issue=6|pages=CD008428|doi=10.1002/14651858.CD008428.pub3|issn=1469-493X|pmid=32573764|pmc=7388842}} Animal research shows effect of oral intake of deuterium-reinforced DHA (D-DHA) for prevention of macular degeneration.{{Cite journal |last=Dunaief |first=Joshua L. |date=2022 |title=Heavy lipids protect against heavy metals |journal=Aging |volume=14 |issue=12 |pages=4933–4934 |doi=10.18632/aging.204143 |pmc=9271310 |pmid=35748784}}

Omega−3 PUFAs such as DHA and eicosapentaenoic acid (EPA) are effective in the prevention and treatment of asthma and allergic diseases.{{Cite journal |last1=Miyata |first1=Jun |last2=Arita |first2=Makoto |date= 2015|title=Role of omega-3 fatty acids and their metabolites in asthma and allergic diseases |journal=Allergology International|volume=64 |issue=1 |pages=27–34 |doi=10.1016/j.alit.2014.08.003 |issn=1440-1592 |pmid=25572556|doi-access=free }}

File:DHA pills.jpg

Ordinary types of cooked salmon contain 500–1500 mg DHA and 300–1000 mg EPA per 100 grams.{{cite web|url=http://www.health.gov/dietaryguidelines/dga2005/report/html/table_g2_adda2.htm|title=EPA and DHA Content of Fish Species. Appendix G2|publisher=US Department of Agriculture|date=2005|access-date=15 September 2013|archive-date=6 October 2013|archive-url=https://web.archive.org/web/20131006020346/http://www.health.gov/dietaryguidelines/dga2005/report/html/table_g2_adda2.htm|url-status=dead}} Additional rich seafood sources of DHA include caviar (3400 mg per 100 grams), anchovies (1292 mg per 100 grams), mackerel (1195 mg per 100 grams), and cooked herring (1105 mg per 100 grams).

Brains from mammals taken as food are also a good direct source. Beef brain, for example, contains approximately 855 mg of DHA per 100 grams in a serving.{{cite web|title=Beef, variety meats and by-products, brain, cooked, simmered|url=http://nutritiondata.self.com/facts/beef-products/3463/2|access-date=2011-10-27}} While DHA may be the primary fatty acid found in certain specialized tissues, these tissues, aside from the brain, are typically small in size, such as the seminiferous tubules and the retina. As a result, animal-based foods, excluding the brain, generally offer minimal amounts of preformed DHA.{{cite journal | url=https://doi.org/10.1016/j.jhevol.2014.02.017 | doi=10.1016/j.jhevol.2014.02.017 | title=Docosahexaenoic acid and human brain development: Evidence that a dietary supply is needed for optimal development | date=2014 | last1=Brenna | first1=J. Thomas | last2=Carlson | first2=Susan E. | journal=Journal of Human Evolution | volume=77 | pages=99–106 | pmid=24780861 | bibcode=2014JHumE..77...99B | url-access=subscription }}

In the early 1980s, NASA sponsored scientific research on a plant-based food source that could generate oxygen and nutrition on long-duration space flights. Certain species of marine algae produced rich nutrients, leading to the development of an algae-based, vegetable-like oil that contains two polyunsaturated fatty acids, DHA and arachidonic acid.{{cite web|last=Jones|first=John|title=Nutritional Products from Space Research|url=http://www.sti.nasa.gov/tto/spinoff1996/42.html|archive-url=https://web.archive.org/web/19970618060909/http://www.sti.nasa.gov/tto/spinoff1996/42.html|url-status=dead|archive-date=1997-06-18|work=May 1st, 2001|publisher=NASA}}

DHA is widely used as a food supplement. It was first used primarily in infant formulas.{{cite web|title=FDA: Why is there interest in adding DHA and ARA to infant formulas?|url=https://www.fda.gov/Food/FoodSafety/Product-SpecificInformation/InfantFormula/ConsumerInformationAboutInfantFormula/ucm108558.htm|archive-url=https://web.archive.org/web/20090708235014/http://www.fda.gov/Food/FoodSafety/Product-SpecificInformation/InfantFormula/ConsumerInformationAboutInfantFormula/ucm108558.htm|url-status=dead|archive-date=July 8, 2009|publisher=US Food & Drug Administration|access-date=1 July 2002}} In 2019, the US Food and Drug Administration published qualified health claims for DHA.{{cite web|title=FDA Announces New Qualified Health Claims for EPA and DHA Omega-3 Consumption and the Risk of Hypertension and Coronary Heart Disease|url=https://www.fda.gov/food/cfsan-constituent-updates/fda-announces-new-qualified-health-claims-epa-and-dha-omega-3-consumption-and-risk-hypertension-and|archive-url=https://web.archive.org/web/20190910201925/https://www.fda.gov/food/cfsan-constituent-updates/fda-announces-new-qualified-health-claims-epa-and-dha-omega-3-consumption-and-risk-hypertension-and|url-status=dead|archive-date=September 10, 2019|publisher=US Food and Drug Administration|date=19 June 2019|access-date=30 August 2019}}

Some manufactured DHA is a vegetarian product extracted from algae, and it competes on the market with fish oil that contains DHA and other omega−3s such as EPA. Both fish oil and DHA are odorless and tasteless after processing as a food additive.{{cite news

|last= Rivlin | first= Gary |work= The New York Times

|title=Magical or Overrated? A Food Additive in a Swirl

| url = https://www.nytimes.com/2007/01/14/business/yourmoney/14omega.html?_r=1

|date=2007-01-14 |access-date=2007-01-15}}

{{Main|Vegetarian nutrition#Omega-3 fatty acids}}

Vegetarian diets typically contain limited amounts of DHA, and vegan diets typically contain no DHA.{{cite journal|pmid=19500961|year=2009|last1=Sanders|first1=T. A.|title=DHA status of vegetarians|journal=Prostaglandins, Leukotrienes and Essential Fatty Acids|volume=81|issue=2–3|pages=137–41|doi=10.1016/j.plefa.2009.05.013}} In preliminary research, algae-based supplements increased DHA levels.{{cite journal|pmid=24261532|year=2014|last1=Lane|first1=K|title=Bioavailability and potential uses of vegetarian sources of omega-3 fatty acids: A review of the literature|journal=Critical Reviews in Food Science and Nutrition|volume=54|issue=5|pages=572–9|last2=Derbyshire|first2=E|last3=Li|first3=W|last4=Brennan|first4=C|doi=10.1080/10408398.2011.596292|s2cid=30307483}} While there is little evidence of adverse health or cognitive effects due to DHA deficiency in adult vegetarians or vegans, breast milk levels remain a concern for supplying adequate DHA to the infant.

Fish oil is widely sold in capsules containing a mixture of omega−3 fatty acids, including EPA and DHA. Oxidized fish oil in supplement capsules may contain lower levels of EPA and DHA.{{cite journal |last1=Albert|first1=Benjamin B|journal=Scientific Reports |date=21 January 2015 |title=Fish oil supplements in New Zealand are highly oxidised and do not meet label content of n-3 PUFA release |doi=10.1038/srep07928 |pmid=25604397 |pmc=4300506 |volume=5 |pages=7928}}{{cite journal|last1=Albert|first1=Benjamin B|last2=Cameron-Smith|first2=David|last3=Hofman|first3=Paul L.|last4=Cutfield|first4=Wayne S.|title=Oxidation of Marine Omega-3 Supplements and Human Health|journal=BioMed Research International|date=2013|volume=2013|pages=464921|doi=10.1155/2013/464921|pmid=23738326|pmc=3657456|doi-access=free}} Light, oxygen exposure, and heat can all contribute to oxidation of fish oil supplements. Buying a quality product that is kept cold in storage and then keeping it in a refrigerator can help minimize oxidation.{{Cite journal|last1=Zargar|first1=Atanaz|last2=Ito|first2=Matthew K.|date=1 August 2011|title=Long chain omega-3 dietary supplements: a review of the National Library of Medicine Herbal Supplement Database|journal=Metabolic Syndrome and Related Disorders|volume=9|issue=4|pages=255–271|doi=10.1089/met.2011.0004|issn=1557-8518|pmid=21787228}}

As optimal DHA level is important for brain development and maturation, there are established daily recommendations for DHA intake in children.{{medical citation needed|date=March 2024}}

The table below shows the daily DHA / DHA + EPA intake recommended for children of different ages:

Experts recommend DHA intake of 10–12 mg/day for children 12–24 months, 100–150 mg/day of DHA+EPA for children 2–4 years old and 150–200 mg/day of DHA+EPA for children 4–6 years old.{{medical citation needed|date=March 2024}}

• DHA-clozapine
• List of omega−3 fatty acids
• Polyunsaturated fatty acids

{{Reflist}}

{{Fatty acids}}

{{Retinoid receptor modulators}}

{{Authority control}}

{{DEFAULTSORT:Docosahexaenoic Acid}}

Category:Fatty acids

Category:Alkenoic acids

Category:Polyenes