Low liver conversion rate of α-linolenic to docosahexaenoic acid in awake rats on a high-docosahexaenoate-containing diet

Igarashi, Miki; Ma, Kaizong; Chang, Lisa; Bell, Jane M.; Rapoport, Stanley I.; DeMar, James C.

doi:10.1194/jlr.m600030-jlr200

Cited by 51 publications

(68 citation statements)

References 73 publications

(104 reference statements)

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“…In this study, the conversion of ALA into DHA was undetectable, whereas LA conversion into 20:4n-6 reached 13.5%. These results agree with the general observation of a very low biosynthesis of DHA (,1%) in mammalian liver (Igarashi et al, 2006). It is well known that members of the n-6 and n-3 families compete for the elongation-desaturation pathway (Sprecher, 1981), the conversion of LA and ALA into their longer chain homologues being significantly influenced by the composition of dietary fats (Christiansen et al, 1991).…”

Section: Discussionsupporting

confidence: 82%

Distinct metabolism of linoleic and linolenic acids in liver and adipose tissues of finishing Normande cull cows

Gruffat

Gobert

Durand

et al. 2011

Animal

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Feeding strategies based on the addition of plant lipids rich in polyunsaturated fatty acids (PUFAs) in diets of bovines during the finishing period are common to enhance the nutritional value of meat. However, following rumen biohydrogenations, these FAs could still be metabolised in various tissues/organs involved in the FA metabolism such as the liver and adipose tissues (ATs), thus affecting their subsequent deposition in muscles. In this context, the objective of this study was to characterise the various metabolic pathways of linoleic acid (LA) and a-linolenic acid (ALA) in the liver and ATs (subcutaneous (SC) and inter-muscular (IM)) of Normande cull cows fed a diet supplemented (LR) or not (C) with extruded linseeds and rapeseeds, using the ex vivo incubated tissue slice method. Hepatic uptake of both FAs was higher with the LR than with the C diet ( P 5 0.02). For the two diets, ALA uptake was higher than that of LA (146%, P 5 0.04). ALA was much more degraded by b-oxidation (.50% of ALA present in cells) than LA (, 27%) with both diets ( P 5 0.015). Whatever the diet, ALA was not converted into longer and/or more unsaturated FA, whereas about 14% of LA was converted into 20:4n-6. The intensity of the esterification pathway was higher (170%, P 5 0.004) with the LR than with the C diet, for both FAs. Hepatic secretion of ALA as part of the very-low-density lipoprotein particles was lower than that of LA (258% and 223% for C and LR diets respectively, P 5 0.02). In SC and IM ATs, dietary lipid supplementation did not alter metabolic pathways of LA and ALA. They were efficiently taken up by ATs (.68% of FA present in the medium), with uptake being higher for IM than for SC AT (112%, P 5 0.01). Moreover, LA uptake by ATs was higher than ALA uptake (110.7%, P 5 0.027). Both FAs were mainly esterified (.97% of FA present in adipocytes) into neutral lipids (.85% of esterified FA). Around 9.5% of LA was converted into 20:4n-6, whereas only around 1.3% of ALA was converted into 20:5n-3. We concluded that, in our experimental conditions, liver was highly active in ALA catabolism limiting its subsequent deposition in muscles. However, bovine liver and ATs were inefficient at converting ALA into long-chain n-3 PUFA, but actively converted LA into 20:4n-6.

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Section: Discussionsupporting

confidence: 82%

Distinct metabolism of linoleic and linolenic acids in liver and adipose tissues of finishing Normande cull cows

Gruffat

Gobert

Durand

et al. 2011

Animal

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“…The endogenous synthesis of DHA within the brain is low compared with its uptake from dietary and/or liver sources 15, 16. DHA is a well‐known dietary supplement, well tolerated at high dosage and with the ability to cross the blood–brain barrier by passive and active transport 17, 18, 19…”

Section: Discussionmentioning

confidence: 99%

Docosahexaenoic acid is a beneficial replacement treatment for spinocerebellar ataxia 38

Manes

Alberici

Gregorio

et al. 2017

Annals of Neurology

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ObjectiveSpinocerebellar ataxia 38 (SCA38) is caused by mutations in the ELOVL5 gene, which encodes an elongase involved in the synthesis of polyunsaturated fatty acids, including docosahexaenoic acid (DHA). As a consequence, DHA is significantly reduced in the serum of SCA38 subjects. In the present study, we evaluated the safety of DHA supplementation, its efficacy for clinical symptoms, and changes of brain functional imaging in SCA38 patients.MethodsWe enrolled 10 SCA38 patients, and carried out a double‐blind randomized placebo‐controlled study for 16 weeks, followed by an open‐label study with overall 40‐week DHA treatment. At baseline and at follow‐up visit, patients underwent standardized clinical assessment, brain 18‐fluorodeoxyglucose positron emission tomography, electroneurography, and ELOVL5 expression analysis.ResultsAfter 16 weeks, we showed a significant pre–post clinical improvement in the DHA group versus placebo, using the Scale for the Assessment and Rating of Ataxia (SARA; mean difference [MD] = +2.70, 95% confidence interval [CI] = +0.13 to + 5.27, p = 0.042). At 40‐week treatment, clinical improvement was found significant by both SARA (MD = +2.2, 95% CI = +0.93 to + 3.46, p = 0.008) and International Cooperative Ataxia Rating Scale (MD = +3.8, 95% CI = +1.39 to + 6.41, p = 0.02) scores; clinical data were corroborated by significant improvement of cerebellar hypometabolism (statistical parametric mapping analyses, false discovery rate corrected). We also showed a decreased expression of ELOVL5 in patients’ blood at 40 weeks as compared to baseline. No side effect was recorded.InterpretationDHA supplementation is a safe and effective treatment for SCA38, showing an improvement of clinical symptoms and cerebellar hypometabolism. Ann Neurol 2017;82:615–621

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“…The pups were allowed to nurse until 21 days of age. Lactating rats had free access to water and rodent chow (formulation NIH-31 18-4; Zeigler Bros., Gardner, PA), which contained 4% (wt/wt) crude fat and whose fatty acid composition we previously reported (27,28). a-LNA, EPA, and DHA contributed 5.1%, 2.0%, and 2.3% of total fatty acids, respectively, whereas linoleic acid (LA, 18:2n-6) and arachidonic acid (AA) contributed 47.9% and 0.02%, respectively.…”

Section: Animalsmentioning

confidence: 99%

“…A rat was infused via the femoral vein catheter with 500 mCi/kg [1-14 C]a-LNA (22,27,28). An aliquot of [1-14 C]a-LNA in ethanol was dried under nitrogen, and the residue was dissolved in HEPES buffer (pH 7.4) containing 50 mg/ml fatty acid-free BSA, to a final volume of 1.3 ml.…”

Section: Radiotracer Infusionmentioning

confidence: 99%

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Rat heart cannot synthesize docosahexaenoic acid from circulating α-linolenic acid because it lacks elongase-2

Igarashi

Chang

et al. 2008

Journal of Lipid Research

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The extent to which the heart can convert alinolenic acid (a-LNA, 18:3n-3) to longer chain n-3 PUFAs is not known. Conversion rates can be measured in vivo using radiolabeled a-LNA and a kinetic fatty acid model. [1-14 C]a-LNA was infused intravenously for 5 min in unanesthetized rats that had been fed an n-3 PUFA-adequate [4.6% a-LNA, no docosahexaenoic acid (DHA, 22:6n-3)] or n-3 PUFA-deficient diet (0.2% a-LNA, nor DHA) for 15 weeks after weaning. Arterial plasma was sampled, as was the heart after high-energy microwaving. Rates of conversion of a-LNA to longer chain n-3 PUFAs were low, and DHA was not synthesized at all in the heart. Most a-LNA within the heart had been b-oxidized. In deprived compared with adequate rats, DHA concentrations in plasma and heart were both reduced by .90%, whereas heart and plasma levels of docosapentaenoic acid (DPAn-6, 22:5n-6) were elevated. Dietary deprivation did not affect cardiac mRNA levels of elongase-5 or desaturases D6 and D5, but elongase-2 mRNA could not be detected. In summary, the rat heart does not synthesize DHA from a-LNA, owing to the absence of elongase-2, but must obtain its DHA entirely from plasma. Dietary n-3 PUFA deprivation markedly reduces heart DHA and increases heart DPAn-6, which may make the heart vulnerable to different insults.-Igarashi, M., K. Ma, L. Chang, J. M. Bell, and S. I. Rapoport. Rat heart cannot synthesize docosahexaenoic acid from circulating a-linolenic acid because it lacks elongase-2. J. Lipid Res. 2008Res. . 49: 1735Res. -1745 Supplementary key words diet • heart • deprivation • elongation • synthesis • n-3 polyunsaturated fatty acids Long-chain n-3 PUFAs, particularly eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA,, are reported to be protective against cardiovascular disease (1-8). Thus, a low dietary n-3 PUFA intake and a low plasma DHA concentration are risk factors for cardiac disease (8-10), whereas a high dietary n-3 PUFA content is considered protective (11-13).In some mammalian tissues, EPA and DHA can be converted from shorter chain a-linolenic acid (a-LNA, 18:3n-3), which is enriched in plant oils, by serial steps of desaturation, elongation, and b-oxidation (14-20). Using our kinetic method and model, we showed in unanesthetized rats that rates of conversion of a-LNA to DHA were higher in liver than in brain, and that n-3 dietary deprivation could further increase the liver but not brain rates, in relation to elevated expression of requisite desaturases and elongases (21-23). These enzymes include D5 and D6 desaturases and elongases-2 and -5. They are expressed in the liver and many other rodent tissues, although elongase-2 has not been identified in rat heart (15-17, 24, 25). Thus, the heart may be incapable of synthesizing DHA from a-LNA, consistent with one study on isolated rat cardiomyocytes (26).Because of the importance of n-3 PUFAs to cardiovascular function (see above), and because their kinetics have not been thoroughly examined in vivo, we thought it of interest in this study...

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Low liver conversion rate of α-linolenic to docosahexaenoic acid in awake rats on a high-docosahexaenoate-containing diet

Cited by 51 publications

References 73 publications

Distinct metabolism of linoleic and linolenic acids in liver and adipose tissues of finishing Normande cull cows

Distinct metabolism of linoleic and linolenic acids in liver and adipose tissues of finishing Normande cull cows

Docosahexaenoic acid is a beneficial replacement treatment for spinocerebellar ataxia 38

Rat heart cannot synthesize docosahexaenoic acid from circulating α-linolenic acid because it lacks elongase-2

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