Conversion de l’ALA en DHA

La question des acides gras semble fondamentale dans l’histoire de l’évolution humaine. L’humanité semble avoir dû sa formidable capacité à accroître la taille de son cerveau à sa capacité à accéder à des quantités importantes d’acides gras, et spécialement à l’un de ceux-ci, l’acide docosahexaénoïque (DHA), de la famille des oméga 3. Or, cette molécule n’existe (pratiquement) que dans le règne animal. On retrouve bien des oméga 3 dans le règne végétal, mais sous une autre forme, plus simple, l’acide alpha-linolénique (ALA), qui nécessite d’être convertie en DHA.

Une question scientifique majeure est donc de déterminer si les humains sont capables de convertir efficacement l’ALA en DHA ou non. Si la réponse est oui, alors les humains ont probablement pu accroitre leur volume cérébral à partir de sources végétales. Mais si la réponse est non, alors il a fallu que nos ancêtres trouvent du DHA déjà formé de source animale en quantités importantes.

Les études menées depuis une vingtaine d’années suggèrent majoritairement que cette conversion est très limitée.


Conversion des acides gras polyinsaturés

Effect of supplementation with flaxseed oil and different doses of fish oil for 2 weeks on plasma phosphatidylcholine fatty acids in young women
Lean Hodson et al.
European Journal of Clinical Nutrition, 2018
https://www.nature.com/articles/s41430-018-0174-2

Flaxseed oil supplementation for 14 day resulted in significant (P < 0.01) increases in ALA, EPA and DPA, whilst DHA remained unchanged.

 

Ici, le taux de conversion diminue avec le temps si on tente une complémentation avec de fortes doses d’ALA :

Effect of 1‐ and 2‐Month High‐Dose Alpha‐Linolenic Acid Treatment on 13C‐Labeled Alpha‐Linolenic Acid Incorporation and Conversion in Healthy Subjects
Marc Pignitter et al., 2018
https://onlinelibrary.wiley.com/doi/full/10.1002/mnfr.201800271

One of the more widely accepted hypotheses is that long‐term high intake of ALA might inhibit its conversion to EPA.13 This hypothesis could be confirmed by the results obtained from the current study.[…]
previous studies reported rather low conversion of ALA to DHA in plasma and erythrocytes, ranging from 0 to 3.8% […]
This decrease in 13C‐DHA concentration after long‐term consumption of high amounts of ALA might be attributed to competitive substrate inhibition.49 It is well known that Δ6‐desaturase catalyzes the conversion of ALA to stearidonic acid, but also the desaturation of tetracosapentaenoic to tetracosahexaenoic acid.44 Both reactions yield DHA. The competition between ALA and tetracosapentaenoic acid for Δ6‐desaturase activity might explain the reduced DHA formation under conditions of ALA excess.

Même avec une alimentation avec un ratio très élevé en ALA/LA, le DHA ne s’améliore pas, seul l’EPA s’améliore :

Effects of a low and a high dietary LA/ALA ratio on long-chain PUFA concentrations in red blood cells.
Greupner T. et al.
Food and function, 2018
https://www.ncbi.nlm.nih.gov/pubmed/30101962
https://www.researchgate.net/publication/326994574_Effects_of_a_low_and_a_high_dietary_LAALA_ratio_on_long-chain_PUFA_concentrations_in_red_blood_cells

In the course of the loLA/hiALA diet ALA and EPA concentrations and relative amounts of ∑EPA + DHA increased, whereas LA concentrations decreased. The DHA concentration was unaffected. […] Compared to our previous study, where we simply increased the ALA intake, our results show that ALA supplementation combined with a reduced LA intake (loLA/hiALA diet) more efficiently enhanced EPA blood concentrations.

Metabolism and functional effects of plant-derived omega-3 fatty acids in humans.
Baker EJ et al.
Progress in lipids research, 2016
https://www.ncbi.nlm.nih.gov/pubmed/27496755
https://www.sciencedirect.com/science/article/pii/S0163782716300303

Although it is generally considered that humans have limited capacity for conversion of ALA to EPA and DHA, sex differences in conversion to DHA have been identified. If conversion of ALA to EPA and DHA is limited, then ALA may have a smaller health benefit than EPA and DHA. SDA is more readily converted to EPA and appears to offer better potential for health improvement than ALA. However, conversion of both ALA and SDA to DHA is limited in most humans.

Metabolism and functional effects of plant-derived omega-3 fatty acids in humans
Ella J. Baker et al.
Progress in lipid research, 2016
https://www.sciencedirect.com/science/article/pii/S0163782716300303

However, conversion of both ALA and SDA to DHA is limited in most humans.

 

Docosahexaenoic Acid
Calder PC.
Annals of nutrition and metabolism, 2016
https://www.ncbi.nlm.nih.gov/pubmed/27842299
https://www.karger.com/Article/FullText/448262

DHA is metabolically related to other n-3 fatty acids: it can be synthesised from the plant essential fatty acid α-linolenic acid (ALA). However, this pathway does not appear to be very efficient in many individuals, although the conversion of ALA to DHA is much better in young women than in young men. Furthermore, young infants may be more efficient converters of ALA to DHA than many adults, although the conversion rate is variable among infants. Many factors have been identified that affect the rate of conversion. The implication of poor conversion is that preformed DHA needs to be consumed.

Past and Present Insights on Alpha-linolenic Acid and the Omega-3 Fatty Acid Family
Aliza H. Stark et al., 2015
https://www.tandfonline.com/doi/abs/10.1080/10408398.2013.828678?casa_token=YehE6gKCJ4gAAAAA:rofWbXRDuZfsD-b37XhVeRBW_LddGQXNJrQXm_pWUpghtILZ77hreoGWgIRSsCMs98jczMcJTR2M

Alpha-linolenic acid (ALA) is the parent essential fatty acid of the omega-3 family. This family includes docosahexaenoic acid (DHA), which has been conserved in neural signaling systems in the cephalopods, fish, amphibian, reptiles, birds, mammals, primates, and humans. This extreme conservation, in spite of wide genomic changes of over 500 million years, testifies to the uniqueness of this molecule in the brain and affirms the importance of omega-3 fatty acids.[…]
Unlike humans, rats and mice can readily convert ALA to EPA and DHA

Des résultats intéressants mais transitoires et un peu étonnants au vu de la faible augmentation de l’EPA avec de l’huile de chia :
Modification of Docosahexaenoic Acid Composition of Milk from Nursing Women Who Received Alpha Linolenic Acid from Chia Oil during Gestation and Nursing
Rodrigo Valenzuela et al., 2015
The chia group, compared to the control group, showed (i) a significant increase in ALA ingestion and a significant reduction of linoleic acid (LA) ingestion, no showing modification of arachidonic acid (AA), eicosapentaenoic acid (EPA) and DHA; (ii) a significant increase of erythrocyte ALA and EPA and a reduction of LA. AA and DHA were not modified; (iii) a increased milk content of ALA during the six months of nursing, whereas LA showed a decrease. AA and EPA were not modified, however DHA increased only during the first three months of nursing. Consumption of chia oil during the last trimester of pregnancy and the first three months of nursing transiently increases the milk content of DHA.

Bioavailability and potential uses of vegetarian sources of omega-3 fatty acids: a review of the literature.
Lane K. et al.
Critical reviews in food science and nutrition, 2014

Presently alpha-linolenic acid (ALA) is the most widely used vegetarian LC3PUFA, but only marginal amounts are converted into eicosapentaenoic (EPA) and docosahexaenoic acid (DHA)

Supplementation of Milled Chia Seeds Increases Plasma ALA and EPA in Postmenopausal Women
Fuxia Jin et al., 2012
https://link.springer.com/article/10.1007/s11130-012-0286-0

ingestion of 25 g/day milled chia seeds for seven weeks by postmenopausal women resulted in significant increases in plasma ALA and EPA but not DPA and DHA.

a-Linolenic acid supplementation and conversion to n-3 long-chain
polyunsaturated fatty acids in humans

J. Thomas Brenna et al.

With no other changes in diet, improvement of blood DHA status can be achieved with dietary supplements of preformed DHA, but not with supplementation of ALA, EPA, or other precursors.
Flaxseed oil and fish-oil capsule consumption alters human red blood cell n–3 fatty acid composition: a multiple-dosing trial comparing 2 sources of n–3 fatty acid
Gwendolyn Barcelo-Coblijn et al., 2008.
Problème avec le lien de l’étude complète. Lien de l’abstract : https://www.ncbi.nlm.nih.gov/pubmed/18779299
Seulement 6mg de DHA dans le groupe huile de poisson. Les résultats ne donnent pas d’élévation des taux de DHA dans le groupe végétal, une élévation sensiblement moindre d’EPA que dans le groupe poisson, mais l’étude conclut quand même que la conversion se fait bien.
Conversion of a-linolenic acid in humans is influenced by the
absolute amounts of a-linolenic acid and linoleic acid in the diet and
not by their ratio
Compared with the control group, ALA incorporation into phospholipids increased by 3.6% in the low-LA group (P=0.012) and decreased by 8.0% in the high-ALA group (P=
0.001). In absolute amounts, it increased by 34.3 mg (P=0.020) in the low-LA group but hardly changed in the high-ALA group. Nearly all ALA from the plasma phospholipid pool was converted into eicosapentaenoic acid. Conversion of eicosapentaenoic acid into docosapentaenoic acid and docosahexaenoic acid hardly changed in the 3 groups and was 0.1% of dietary ALA.

Distribution, interconversion, and dose response of n−3 fatty acids in humans
Linda M Arterburn,
Eileen Bailey Hall, Harry Oken, 2006
https://academic.oup.com/ajcn/article/83/6/1467S/4633217

Limited storage of the n−3 fatty acids in adipose tissue suggests that a continued dietary supply is needed. A large proportion of dietary α-linolenic acid (ALA) is oxidized, and because of limited interconversion of n−3 fatty acids in humans, ALA supplementation does not result in appreciable accumulation of long-chain n−3 fatty acids in plasma. Eicosapentaenoic acid (EPA) but not DHA concentrations in plasma increase in response to dietary EPA. Dietary DHA results in a dose-dependent, saturable increase in plasma DHA concentrations and modest increases in EPA concentrations. Plasma DHA concentrations equilibrate in approximately 1 mo and then remain at steady state throughout supplementation. DHA doses of ≈2 g/d result in a near maximal plasma response. Both dietary DHA and EPA reduce plasma arachidonic acid concentrations. Tissue contents of DHA and EPA also increase in response to supplementation with these fatty acids. Human milk contents of DHA are dependent on diet, and infant DHA concentrations are determined by their dietary intake of this fatty acid. We conclude that the most predictable way to increase a specific long-chain n−3 fatty acid in plasma, tissues, or human milk is to supplement with the fatty acid of interest.

Une supplémentation en huile de lin détériore ici le ratio Acide Arachidonique / EPA :

Effect of randomized supplementation with high dose olive, flax or fish oil on serum phospholipid fatty acid levels in adults with attention deficit hyperactivity disorder.
Young, GS et al., 2005
https://hal.archives-ouvertes.fr/hal-00900582/file/hal-00900582.pdf

Flax oil supplementation resulted in an increase in alpha-LNA and a slight decrease in the ratio of AA/EPA, while fish oil supplementation resulted in increases in EPA, DHA and total omega-3 fatty acids and a decrease in the AA/EPA ratio to values seen in the Japanese population.

Conversion of α-linolenic acid to longer-chain polyunsaturated fatty acids in human adults
Graham C. BURDGE, Philip C. CALDER, 2005
https://hal.archives-ouvertes.fr/hal-00900584/document
Increasing αLNA intake for a period of weeks to months results in an increase in the proportion of eicosapentaenoic acid (EPA; 20:5n-3) in plasma lipids, in erythrocytes, leukocytes, platelets and in breast milk but there is no increase in docosahexaenoic acid (DHA;22:6n-3), which may even decline in some pools at high α LNA intakes.
Long-chain conversion of [13C] linoleic acid and alpha-linolenic acid in response to marked changes in their dietary intake in men
Our finding of a substantial increase in EPA but no change in DHA in membrane phospholipids is consistent with most (11, 14, 48, 49) but not all (50, 51) previous re-
ports of ALA supplementation in adults. The highest levels of enrichment of EPA are usually achieved at the lower intakes of FXO (48), suggesting that high levels of ALA inhibit its conversion to EPA. Indeed, the inverse relationship between dietary ALA and the DHA content of membrane phospholipids (42) suggests that increased ALA
and/or EPA may displace DHA. In a recent 6 month study with 9.5 g of ALA per day, although EPA increased in peripheral blood mononuclear cells, DHA concentration decreased (49). The ALA/LA ratio rather than the absolute amount of ALA has been suggested to regulate the conversion to EPA (52), consistent with the report that dou-
bling the intake of ALA at a constant dietary ALA/LA value had no additional influence on platelet EPA content
Méta-analyse très intéressante, on a des taux très variables, mais toujours faibles, selon les méthodes utilisées :
a-Linolenic acid metabolism in men and women: nutritional and
biological implications
Overall, the capacity for conversion of a-LNA to DHA differs markedly between men and women. This has important implications for their nutritional requirements
for n-3 PUFAs. It is possible that demands for DHA by individual tissues in men are relatively modest, possibly due to efficient recycling, and can be met by the diet or
the low level of a-LNA conversion. Nevertheless, men with a poor DHA intake together with higher partition-ing of fatty acids towards b-oxidation would be at greater risk of marginal DHA status than women. There is evidence which suggests oestrogen-mediated upregulation of conversion of a-LNA to DHA in women

Alpha-linolenic acid supplementation during human pregnancy

does not effect cognitive functioning
ALA supplementation hardly affected the maternal DHA status and no significant differences were found in cognitive
performance between the two groups. This indicates that ALA supplementation during pregnancy does not affect cognitive
performance during and 32 weeks after gestation.

Efficiency of conversion of alpha-linolenic acid to long chain n-3 fatty acids in man.
Brenna JT., 2002
https://www.ncbi.nlm.nih.gov/pubmed/11844977

Studies generally agree that whole body conversion of 18:3n-3 to 22:6n-3 is below 5% in humans, and depends on the concentration of n-6 fatty acids and long chain polyunsaturated fatty acids in the diet. Complete oxidation of dietary 18:3n-3 to CO2 accounts for about 25% of 18:3n-3 in the first 24 h, reaching 60% by 7 days. Much of the remaining 18:3n-3 serves as a source of acetate for synthesis of saturates and monounsaturates, with very little stored as 18:3n-3. In term and preterm infants, studies show wide variability in the plasma kinetics of 13C n-3 long chain polyunsaturated fatty acids after 13C-18:3n-3 dosing, suggesting wide variability among human infants in the development of biosynthetic capability to convert 18:3n-3 to 22:6n3. Tracer studies show that humans of all ages can perform the conversion of 18:3n-3 to 22:6n3. Further studies are required to establish quantitatively the partitioning of dietary 18:3n-3 among metabolic pathways and the influence of other dietary components and of physiological states on these processes.

Les femmes semblent convertir mieux que les hommes, mais l’étude souligne aussi les différences interpersonnelles :

Conversion of α-linolenic acid to eicosapentaenoic, docosapentaenoic and docosahexaenoic acids in young women
Graham C. Burge, Stephen A. Wootton, 2002.
https://www.cambridge.org/core/journals/british-journal-of-nutrition/article/conversion-of-linolenic-acid-to-eicosapentaenoic-docosapentaenoic-and-docosahexaenoic-acids-in-young-women/2B640958BD4A0061593384DF076DBC74

Estimated net fractional ALNA inter-conversion was EPA 21 %, DPA 6 % and DHA 9 %. […] Comparison with previous studies suggests that women may possess a greater capacity for ALNA conversion than men. Such metabolic capacity may be important for meeting the demands of the fetus and neonate for DHA during pregnancy and lactation. Differences in DHA status between women both in the non-pregnant state and in pregnancy may reflect variations in metabolic capacity for DHA synthesis.

Can adults adequately convert alpha-linolenic acid (18:3n-3) to eicosapentaenoic acid (20:5n-3) and docosahexaenoic acid (22:6n-3)?
Gester H., 1998
https://www.ncbi.nlm.nih.gov/pubmed/9637947

The use of ALA labelled with radioisotopes suggested that with a background diet high in saturated fat conversion to long-chain metabolites is approximately 6% for EPA and 3.8% for DHA. With a diet rich in n-6 PUFA, conversion is reduced by 40 to 50%. It is thus reasonable to observe an n-6/n-3 PUFA ratio not exceeding 4-6.

Ne concerne pas la conversion de l’ALA, mais étude intéressante par son ancienneté.

Supplementation with an algae source of docosahexaenoic acid increases (n-3) fatty acid status and alters selected risk factors for heart disease in vegetarian subjects.
Conquer JA1, Holub BJ. (1996)

Healthy vegetarians (12 male, 12 female) consumed nine capsules daily of either DHA (1.62 g/d) or corn oil for 6 wk. Consumption of DHA capsules increased DHA levels in serum phospholipid by 246% (from 2.4 to 8.3 g/100 g fatty acids) and in platelet phospholipid by 225% (from 1.2 to 3.9 g/100 g fatty acids). EPA levels increased in serum phospholipid by 117% (from 0.57 to 1.3 g/100 g fatty acids) and in platelet phospholipid by 176% (0.21 to 0.58 g/100 g fatty acids) via metabolic retroconversion; the estimated extent of DHA retroconversion to EPA was 11.3 and 12.0%, based on the serum and platelet analyses, respectively. Arachidonic acid [AA; 20:4(n-6)] levels in serum and platelet phospholipids decreased moderately during the trial period (DHA group) as did both docosapentaenoic acids [22:5(n-6) and 22:5(n-3)].


Aspects génétiques

Parmi les enzymes impliquées dans la conversion de l’ALA se trouvent deux désaturases, la delta5 et la delta6. Les gènes codant pour ces deux enzymes sont respectivement le gène FADS1 et le gène FADS2. La delta6 désaturase intervenant deux fois dans la conversion ALA vers DHA, elle est, ainsi que le gène FADS2, d’une importance relative plus grande que la delta5 et le gène FADS1.

Sur le gène FADS2 :
Positive Selection on a Regulatory Insertion–Deletion Polymorphism in FADS2 Influences Apparent Endogenous Synthesis of Arachidonic Acid
Kumar S. D. Kothapalli et al., 2016
https://academic.oup.com/mbe/article/33/7/1726/2578764

Analysis using 1000 Genomes Project data confirmed our observation, revealing a global I/I genotype of 70% in South Asians, 53% in Africans, 29% in East Asians, and 17% in Europeans. Tests based on population divergence, site frequency spectrum, and long-range haplotype consistently point to positive selection encompassing rs66698963 in South Asian, African, and some East Asian populations. Basal plasma phospholipid arachidonic acid (ARA) status was 8% greater in I/I compared with D/D individuals. The biochemical pathway product–precursor difference, ARA minus linoleic acid, was 31% and 13% greater for I/I and I/D compared with D/D, respectively. This study is consistent with previous in vitro data suggesting that the insertion allele enhances n-6 LCPUFA synthesis and may confer an adaptive advantage in South Asians because of the traditional plant-based diet practice.

Dietary adaptation of FADS genes in Europe varied across time and geography
Kaixiong Ye et al.
Nature ecology and evolution, 2017
https://www.biorxiv.org/content/biorxiv/early/2017/03/09/111229.full.pdf

Specifically, in pre-Neolithic hunter–gatherers subsisting on animal-
based diets with a substantial aquatic contribution, LCPUFAssynthesis-
diminishing alleles were adaptive. In recent European
farmers subsisting on plant-heavy diets, LCPUFA-synthesisenhancing
alleles were adaptive.

 


Modélisation de la molécule de DHA (Wikimedia commons, auteur : Ben Mills).

Molécule de DHA.png

Processus de conversion des acides gras (Wikimedia Commons, Créé par David R. Throop, vectorisé par Fvasconcellos).
Attention, chez l’humain, c’est une delta6 désaturase, et non une delta4, qui assurent la conversion finale vers le DHA. Il manque aussi la liste des cofacteurs nutritionnels impliqués dans les processus.

conversion des éicosanoïdes