Whole-body synthesis-secretion rates of long-chain n-3 PUFAs from circulating unesterified α-linolenic acid in unanesthetized rats

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Post-publication record

Nature

Retraction

Reason

Falsification/Fabrication of Data;Investigation by Company/Institution;Misconduct - Official Investigation(s) and/or Finding(s);Misconduct by Author;Removed;

Date

5/1/2014 0:00

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Yes

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Abstract

Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), long-chain n-3 PUFAs important for brain and heart function, can be obtained from dietary fish products or by liver synthesis from α-linolenic acid (α-LNA). Their daily human dietary requirements are not clear, and their liver synthesis rates in humans and nonhumans are unknown. We estimated whole-body (presumably liver) synthesis rates in unanesthetized rats by infusing [U-13C]α-LNA intravenously for 2 h and measuring labeled and unlabeled n-3 PUFA in arterial plasma using negative chemical ionization GC-MS. Newly synthesized esterified [13C]DHA, [13C]EPA, and [13C]docosapentaenoic acid (DPA) appeared in arterial plasma after 60 min of infusion, then their concentrations rose in an S-shaped manner. Esterified concentration × plasma volume data were fit with a sigmoidal equation, whose peak first derivatives provided synthesis rates of unlabeled EPA, DPA, and DHA equal to 8.40, 6.27, and 9.84 μmol/day, respectively. The DHA synthesis rate exceeded the published daily rat brain DHA consumption rate by 30-fold, suggesting that liver synthesis from α-LNA could maintain brain DHA homeostasis were DHA absent from the diet. This stable isotope infusion method could be used to quantify whole-body DHA synthesis rates in human subjects. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), long-chain n-3 PUFAs important for brain and heart function, can be obtained from dietary fish products or by liver synthesis from α-linolenic acid (α-LNA). Their daily human dietary requirements are not clear, and their liver synthesis rates in humans and nonhumans are unknown. We estimated whole-body (presumably liver) synthesis rates in unanesthetized rats by infusing [U-13C]α-LNA intravenously for 2 h and measuring labeled and unlabeled n-3 PUFA in arterial plasma using negative chemical ionization GC-MS. Newly synthesized esterified [13C]DHA, [13C]EPA, and [13C]docosapentaenoic acid (DPA) appeared in arterial plasma after 60 min of infusion, then their concentrations rose in an S-shaped manner. Esterified concentration × plasma volume data were fit with a sigmoidal equation, whose peak first derivatives provided synthesis rates of unlabeled EPA, DPA, and DHA equal to 8.40, 6.27, and 9.84 μmol/day, respectively. The DHA synthesis rate exceeded the published daily rat brain DHA consumption rate by 30-fold, suggesting that liver synthesis from α-LNA could maintain brain DHA homeostasis were DHA absent from the diet. This stable isotope infusion method could be used to quantify whole-body DHA synthesis rates in human subjects. WithdrawalsJournal of Lipid ResearchVol. 55Issue 5PreviewThe following three articles were withdrawn by Dr. Stanley Rapoport after an investigation by the National Institute of Health found that Dr. Fei Gao engaged in research misconduct by fabricating and/or falsifying data in this article. Please note that none of the other authors were implicated in any way. Full-Text PDF Open Access The long-chain n-3 polyunsaturated fatty acids (PUFAs) docosahexaenoic acid (DHA, 22:6n-3) and eicosapentaenoic acid (EPA, 20:5n-3), are found in fish and fish products and are considered important for maintaining nervous system and cardiac integrity (1Contreras M.A. Rapoport S.I. Recent studies on interactions between n-3 and n-6 polyunsaturated fatty acids in brain and other tissues.Curr. Opin. Lipidol. 2002; 13: 267-272Crossref PubMed Scopus (73) Google Scholar, 2Salem Jr., N. Litman B. Kim H.Y. Gawrisch K. Mechanisms of action of docosahexaenoic acid in the nervous system.Lipids. 2001; 36: 945-959Crossref PubMed Scopus (766) Google Scholar–3Uauy R. Dangour A.D. Nutrition in brain development and aging: role of essential fatty acids.Nutr. Rev. 2006; 64: S24-S33Crossref PubMed Scopus (337) Google Scholar). Controversy exists regarding daily nutritional requirements for EPA and DHA, with expert recommendations ranging from 0.1 to 1.6 g/day (4Board F.N. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients). National Academies Press, Washington, DC2005Google Scholar, 5Committee S.R. Minister of National Health and Welfare, Ottawa, Canada1990Google Scholar, 6Foundation B.N. Unsaturated Fatty Acids Nutritional and Physiological Significance: The Report of the British Nutrition Foundation's Task Force. Chapman and Hall, New York1992Crossref Google Scholar–7Simopoulos A.P. Human requirement for N-3 polyunsaturated fatty acids.Poult. Sci. 2000; 79: 961-970Crossref PubMed Scopus (563) Google Scholar). One reason for this controversy may be that the liver synthesis rate of DHA from α-linolenic acid (α-LNA, 18:3 n-3), which is obtained from dietary plant oils, is uncertain. Estimated whole-body conversion fractions of ingested α-LNA to DHA range from 0.2% to 9%, and some clinical studies have been interpreted to mean that whole-body conversion is insufficient to maintain adequate brain and heart DHA homeostasis (8Burdge G.C. Calder P.C. Conversion of alpha-linolenic acid to longer-chain polyunsaturated fatty acids in human adults.Reprod. Nutr. Dev. 2005; 45: 581-597Crossref PubMed Scopus (687) Google Scholar, 9Burdge G.C. Finnegan Y.E. Minihane A.M. Williams C.M. Wootton S.A. Effect of altered dietary n-3 fatty acid intake upon plasma lipid fatty acid composition, conversion of [13C]alpha-linolenic acid to longer-chain fatty acids and partitioning towards beta-oxidation in older men.Br. J. Nutr. 2003; 90: 311-321Crossref PubMed Scopus (185) Google Scholar, 10Burdge G.C. Jones A.E. Wootton S.A. Eicosapentaenoic and docosapentaenoic acids are the principal products of alpha-linolenic acid metabolism in young men.Br. J. Nutr. 2002; 88: 355-363Crossref PubMed Google Scholar, 11Kris-Etherton P.M. Harris W.S. Appel L.J. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease.Circulation. 2002; 106: 2747-2757Crossref PubMed Scopus (2890) Google Scholar, 12Kris-Etherton P.M. Hill A.M. N-3 fatty acids: food or supplements?.J. Am. Diet. Assoc. 2008; 108: 1125-1130Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar–13Youdim fatty acids and the J. Dev. 2000; PubMed Scopus Google Scholar). The liver is the for DHA from and DHA Jr., K. Rapoport S.I. Docosahexaenoic acid synthesis from alpha-linolenic acid by rat brain is by dietary n-3 PUFA Lipid Full Text Full Text PDF PubMed Scopus Google Scholar, Jr., K. Rapoport S.I. liver conversion of alpha-linolenic acid to docosahexaenoic acid in rats on a n-3 Lipid Full Text Full Text PDF PubMed Scopus Google Scholar, of New Scholar, is to the brain and by the Sci. PubMed Scopus Google and by Rev. Nutr. PubMed Scopus Google Scholar). the brain and can DHA that synthesis N. J. of and by and Lipid 2002; Full Text Full Text PDF PubMed Google Scholar, B. J. J. and of rat fatty acid Lipid 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). with the rate of brain DHA synthesis in the rat is of alpha-linolenic acid in brain and liver development and in the PubMed Scopus Google Scholar, Jr., K. Rapoport S.I. acid not to docosahexaenoic acid brain of rats a in docosahexaenoic 2005; PubMed Scopus Google S.I. metabolism of essential polyunsaturated fatty acids on the and the Fatty Full Text Full Text PDF PubMed Scopus Google and the rat heart a DHA synthesis a 2 B. J. J. and of rat fatty acid Lipid 2005; Full Text Full Text PDF PubMed Scopus Google Scholar, K. Rapoport S.I. heart docosahexaenoic acid from alpha-linolenic acid Lipid 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). We have estimated the liver synthesis rate of DHA from α-LNA in unanesthetized rats that been a DHA of fatty acids for after The liver rate of DHA from of labeled and unlabeled liver lipid concentrations following a min infusion of Jr., K. Rapoport S.I. Docosahexaenoic acid synthesis from alpha-linolenic acid by rat brain is by dietary n-3 PUFA Lipid Full Text Full Text PDF PubMed Scopus Google Scholar, Jr., K. Rapoport S.I. liver conversion of alpha-linolenic acid to docosahexaenoic acid in rats on a n-3 Lipid Full Text Full Text PDF PubMed Scopus Google Scholar, Jr., K. Rapoport S.I. acid not to docosahexaenoic acid brain of rats a in docosahexaenoic 2005; PubMed Scopus Google Scholar, S.I. metabolism of essential polyunsaturated fatty acids on the and the Fatty Full Text Full Text PDF PubMed Scopus Google Scholar, Jr., K. Rapoport S.I. of acid is a of the in brain of 2006; PubMed Scopus Google Scholar, K. Rapoport S.I. Jr., liver conversion rate of alpha-linolenic to docosahexaenoic acid in rats on a Lipid 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). published data that for the labeled PUFAs were not in the liver the min infusion is to the brain and by the Sci. PubMed Scopus Google Scholar, of fatty acids by the rat PubMed Scopus Google Scholar, Rapoport for of esterified acid from plasma brain of Lipid Full Text PDF PubMed Google and could not be in plasma the of the infusion K. Rapoport S.I. Jr., liver conversion rate of alpha-linolenic to docosahexaenoic acid in rats on a Lipid 2006; Full Text Full Text PDF PubMed Scopus Google the of is an in the unanesthetized rats intravenously with [U-13C]α-LNA for 2 which a plasma α-LNA infusion, esterified and arterial plasma concentrations of [13C]EPA, [13C]docosapentaenoic acid and were using negative chemical ionization concentrations of synthesized esterified labeled n-3 PUFAs to in an S-shaped after 60 min of infusion, suggesting that a by rates of EPA, DPA, and DHA were estimated by plasma esterified concentration × plasma volume data infusion for labeled then the PUFA data with a sigmoidal and of the first derivatives of the rates of the PUFAs were by rates by unlabeled esterified from which plasma were [U-13C]α-LNA from [U-13C]α-LNA by with × by and the concentration of [U-13C]α-LNA by acid n-3 PUFA EPA, DPA, and DHA, for and were from were and were from or and were from or The by the and of the National Institute of Health and Human and the National of Health for the and of rats were from and in an with and and a h The rats to and which and and by whose been Jr., K. Rapoport S.I. acid not to docosahexaenoic acid brain of rats a in docosahexaenoic 2005; PubMed Scopus Google Scholar, K. Rapoport S.I. Jr., liver conversion rate of alpha-linolenic to docosahexaenoic acid in rats on a Lipid 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). and to and of the n-3 PUFAs EPA, and DHA and and the n-6 PUFAs acid and acid were and respectively. The acid to α-LNA concentration is the for synthesis of acid and DHA, Jr., K. Rapoport S.I. acid not to docosahexaenoic acid brain of rats a in docosahexaenoic 2005; PubMed Scopus Google Scholar). The dietary DHA by on a daily The of dietary alpha-linolenic acid on the of of to and of in Nutr. PubMed Scopus Google Scholar, Controversy in fatty acid J. PubMed Scopus Google Scholar). The rats were for were provided food the to the of were with and with were in the and K. Rapoport S.I. 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This used to in the infusion to which of infusion for of esterified n-3 PUFAs in rat infusion The by by are fit the data and to for synthesized [13C]EPA, and [13C]DHA, the esterified to the infusion of the sigmoidal in The of the were estimated for esterified labeled n-3 and for the are in the plasma concentration of not to the min infusion not or for for of n-3 PUFAs from α-LNA in rat are mean Open in a are mean The mean of were used to rates by for EPA, DPA, and DHA and for the three to 8.40, 6.27, and 9.84 rates were used to plasma rates equal to and and plasma equal to and for esterified EPA, DPA, and DHA, this estimated whole-body rates of EPA, DPA, and DHA from α-LNA in unanesthetized rats a diet. intravenously for and arterial plasma concentrations of esterified EPA, DPA, and DHA were a of infusion were concentrations of the labeled Esterified appeared in plasma after min of infusion, labeled esterified PUFA products appeared after 60 then rose and appeared to concentration × plasma volume data for labeled EPA, DPA, and DHA, not for were fit by with a sigmoidal The of the that labeled esterified n-3 PUFAs the (presumably and that rates were by 60 min of labeled EPA, DPA, and DHA could not be in arterial plasma any This is not plasma of PUFAs are min in the rat Rapoport S.I. of to brain lipid metabolism in unanesthetized PubMed Scopus Google Scholar). and of α-LNA can in N. J. of and by and Lipid 2002; Full Text Full Text PDF PubMed Google Scholar, B. J. J. and of rat fatty acid Lipid 2005; Full Text Full Text PDF PubMed Scopus Google Scholar, of alpha-linolenic acid in brain and liver development and in the PubMed Scopus Google Scholar, Jr., K. Rapoport S.I. acid not to docosahexaenoic acid brain of rats a in docosahexaenoic 2005; PubMed Scopus Google Scholar, S.I. metabolism of essential polyunsaturated fatty acids on the and the Fatty Full Text Full Text PDF PubMed Scopus Google K. Rapoport S.I. heart docosahexaenoic acid from alpha-linolenic acid Lipid 2008; Full Text Full Text PDF PubMed Scopus Google the that could esterified products in plasma that whole-body not their liver metabolism and of New Scholar, and by Rev. Nutr. PubMed Scopus Google Scholar). the whole-body be considered to liver rates of esterified EPA, DPA, and rates of esterified EPA, DPA, and DHA from estimated from the first derivatives of 2 to infusion and 8.40, 6.27, and 9.84 μmol/day, respectively. in rats an and intravenously for min with the DHA synthesis rate S.I. metabolism of essential polyunsaturated fatty acids on the and the Fatty Full Text Full Text PDF PubMed Scopus Google Scholar, K. Rapoport S.I. Jr., liver conversion rate of alpha-linolenic to docosahexaenoic acid in rats on a Lipid 2006; Full Text Full Text PDF PubMed Scopus Google of the rate in this The min infusion rate is an this and studies that rat and rates are not min Jr., K. Rapoport S.I. liver conversion of alpha-linolenic acid to docosahexaenoic acid in rats on a n-3 Lipid Full Text Full Text PDF PubMed Scopus Google Scholar, is to the brain and by the Sci. PubMed Scopus Google Scholar, and by Rev. Nutr. PubMed Scopus Google Scholar, Jr., K. Rapoport S.I. acid not to docosahexaenoic acid brain of rats a in docosahexaenoic 2005; PubMed Scopus Google Scholar, K. Rapoport S.I. Jr., liver conversion rate of alpha-linolenic to docosahexaenoic acid in rats on a Lipid 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, of fatty acids by the rat PubMed Scopus Google Rapoport for of esterified acid from plasma brain of Lipid Full Text PDF PubMed Google Scholar). This of is for the and to a with to of New Scholar, and by Rev. Nutr. PubMed Scopus Google Scholar, A.M. A.M. and of PubMed Scopus Google Scholar, and of J. PubMed Scopus Google Scholar, K. the 2005; PubMed Scopus Google of n-3 and n-6 fatty 2000; PubMed Scopus Google Scholar). by some n-3 PUFAs could be to the liver or could be in by to their and then of New Scholar, A.M. A.M. and of PubMed Scopus Google Scholar, and of J. PubMed Scopus Google Scholar). the rate of of DHA from α-LNA may the of the rates in for EPA, DPA, and DHA, of liver by unlabeled esterified α-LNA from stable liver or of New Scholar, the of to Sci. 88: PubMed Scopus Google Scholar, of by in Sci. PubMed Scopus Google Scholar, Fatty acid of Opin. Lipidol. PubMed Scopus Google N. J. from by and Lipid Full Text PDF PubMed Google may be Jr., K. Rapoport S.I. Docosahexaenoic acid synthesis from alpha-linolenic acid by rat brain is by dietary n-3 PUFA Lipid Full Text Full Text PDF PubMed Scopus Google Scholar, Jr., K. Rapoport S.I. liver conversion of alpha-linolenic acid to docosahexaenoic acid in rats on a n-3 Lipid Full Text Full Text PDF PubMed Scopus Google Scholar, K. Rapoport S.I. Dietary n-3 PUFA for and in rat liver not Lipid Full Text Full Text PDF PubMed Scopus Google which that the liver DHA synthesis rate is The plasma rates and of the synthesized n-3 PUFAs in unanesthetized in can be with obtained using in humans human for EPA, DPA, and DHA and Jr., N. Physiological of alpha-linolenic acid metabolism in Lipid 2001; Full Text Full Text PDF PubMed Google with the of and min in this rat of may rates of and lipid metabolism in rats in humans between and metabolism in the nervous PubMed Scopus Google Scholar, A.D. Rapoport S.I. consumption by metabolism in of and New Scopus Google and the that the rat of the esterified n-3 DHA conversion from α-LNA is considered DHA for maintaining DHA G.C. Jones A.E. Wootton S.A. Eicosapentaenoic and docosapentaenoic acids are the principal products of alpha-linolenic acid metabolism in young men.Br. J. Nutr. 2002; 88: 355-363Crossref PubMed Google Scholar, Jr., N. Physiological of alpha-linolenic acid metabolism in Lipid 2001; Full Text Full Text PDF PubMed Google Scholar, of conversion of alpha-linolenic acid to n-3 fatty acids in Opin. Nutr. 2002; PubMed Scopus Google measuring conversion not a rate of DHA synthesis the method in this of ingested α-LNA to DHA in humans and range from 0.2% to (8Burdge G.C. Calder P.C. Conversion of alpha-linolenic acid to longer-chain polyunsaturated fatty acids in human adults.Reprod. Nutr. Dev. 2005; 45: 581-597Crossref PubMed Scopus (687) Google Scholar, 10Burdge G.C. Jones A.E. Wootton S.A. Eicosapentaenoic and docosapentaenoic acids are the principal products of alpha-linolenic acid metabolism in young men.Br. J. Nutr. 2002; 88: 355-363Crossref PubMed Google Scholar, Jr., N. Physiological of alpha-linolenic acid metabolism in Lipid 2001; Full Text Full Text PDF PubMed Google Scholar, G.C. Wootton S.A. Conversion of alpha-linolenic acid to docosapentaenoic and docosahexaenoic acids in young J. Nutr. 2002; 88: PubMed Google Scholar, M.A. is a in metabolism of and Fatty Full Text PDF PubMed Scopus Google Scholar, Jr., N. the brain docosahexaenoic of dietary alpha-linolenic docosahexaenoic and in the 2005; PubMed Scopus Google of dietary alpha-linolenic acid on the conversion and of 2000; PubMed Scopus Google suggesting for any that whose plasma DHA are of have the rates of and of from in British and from J. Nutr. 2003; Google Scholar, n-3 polyunsaturated fatty acids in plasma in British and J. Nutr. 2005; Full Text Full Text PDF PubMed Scopus Google that liver conversion is to maintain DHA in in the of dietary EPA and this with to brain is that brain DHA consumption in rats the of this S.I. metabolism of essential polyunsaturated fatty acids on the and the Fatty Full Text Full Text PDF PubMed Scopus Google Scholar, Jr., K. Rapoport S.I. of acid is a of the in brain of 2006; PubMed Scopus Google Scholar, M.A. Jr., N. Rapoport S.I. Nutritional of alpha-linolenic acid not and of docosahexaenoic acid and in rat 2000; PubMed Scopus Google Scholar, Jr., K. Rapoport S.I. of docosahexaenoic acid in rat brain are by of nutritional of n-3 polyunsaturated fatty PubMed Scopus Google S.I. and of essential PUFAs in Lipid 2001; Full Text Full Text PDF PubMed Google the estimated whole-body conversion rate from α-LNA of and of the brain conversion rate Jr., K. Rapoport S.I. acid not to docosahexaenoic acid brain of rats a in docosahexaenoic 2005; PubMed Scopus Google Scholar). The of the rate of DHA from α-LNA to the rate of brain DHA consumption may This be by DHA from the and dietary α-LNA which in conversion of α-LNA to DHA and and of 2 and and of and Jr., K. Rapoport S.I. liver conversion of alpha-linolenic acid to docosahexaenoic acid in rats on a n-3 Lipid Full Text Full Text PDF PubMed Scopus Google Scholar, K. Rapoport S.I. Dietary n-3 PUFA for and in rat liver not Lipid Full Text Full Text PDF PubMed Scopus Google Scholar). The infusion method of this could be to rates of whole-body synthesis of EPA, DPA, and DHA from or of and DHA from EPA, dietary and in humans rates in humans to a for daily EPA DHA consumption, which on the expert from 0.1 to 1.6 (4Board F.N. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients). National Academies Press, Washington, DC2005Google Scholar, 5Committee S.R. Minister of National Health and Welfare, Ottawa, Canada1990Google Scholar, 6Foundation B.N. Unsaturated Fatty Acids Nutritional and Physiological Significance: The Report of the British Nutrition Foundation's Task Force. Chapman and Hall, New York1992Crossref Google Scholar–7Simopoulos A.P. Human requirement for N-3 polyunsaturated fatty acids.Poult. Sci. 2000; 79: 961-970Crossref PubMed Scopus (563) Google Scholar). and heart and metabolism could be to and liver conversion to PUFA consumption which can be using S.I. metabolism of essential polyunsaturated fatty acids on the and the Fatty Full Text Full Text PDF PubMed Scopus Google Scholar, K. Rapoport S.I. of and in aging: a with 45: Google Scholar, J. K. Rapoport S.I. J. K. N. of docosahexaenoic acid the human brain using Lipid Full Text Full Text PDF PubMed Scopus Google Scholar). whole-body liver of esterified EPA, DPA, and DHA from were by infusing intravenously for 2 h in unanesthetized rats a diet. The DHA synthesis rate in this 9.84 μmol/day, is the rat brain DHA consumption which that liver synthesis could maintain brain DHA The infusion method could be to long-chain n-3 n-6 PUFA rates in human in to and The authors the National of Health and for and Dr. for

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The record

Venue

Journal of Lipid Research

Topic

Fatty Acid Research and Health

Field

Nursing

Canadian institutions

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Funders

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Keywords

ChemistrySecretionEndocrinologyPolyunsaturated fatty acidSecretion rateInternal medicineLinolenic acidBiochemistryFatty acidBiologyMedicineLinoleic acid

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