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Short-Term Carnitine Supplementation Does Not Augment LCP3 Status of Vegans and Lacto-Ovo-Vegetarians

Department of Pathology and Laboratory Medicine, Groningen University Hospital (M.R.F., H.M.v.R., E.N.S., F.A.J.M.)
Sigma-Tau Ethifarma BV, Assen (O.J.B.), THE NETHERLANDS

Address reprint requests to: Dr. M.R. Fokkema, Pathology and Laboratory Medicine, University Hospital Groningen, CMC-V, room Y1.165, P.O. Box 30.001, NL-9700 RB Groningen, THE NETHERLANDS. E-mail: m.r.fokkema{at}path.azg.nl

	ABSTRACT

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Objective: Long-chain polyunsaturated omega-3 fatty acids (LCP3) synthesis, notably that of docosahexaenoic acid (DHA), from the precursor alpha-linolenic acid (ALA) proceeds with difficulty. We investigated whether carnitine supplementation augments the LCP3 status of apparently healthy vegans and lacto-ovo-vegetarians, who are expected to have low carnitine status.

Methods: Group A (n = 11) took 990 mg/day l-carnitine from weeks 1–4, and 990 mg/day l-carnitine + 4 mL/day linseed oil from weeks 5–8. Group B (n = 9) took 4 mL/day linseed oil from weeks 1–4, and 4 mL/day linseed oil + 990 mg/day l-carnitine from weeks 5–8. Fatty acid compositions of red blood cells, platelets, plasma cholesterol esters and plasma triglycerides were measured in the fasting state at baseline, and after 4 and 8 weeks.

Results: Carnitine supplementation increased plasma free and total carnitine concentrations with 30 and 25%, respectively, but did not affect eicosapentaenoic acid (EPA) and DHA contents of any of the investigated compartments. EPA and DHA changes were negatively related to initial carnitine status.

Conclusions: Our results suggest that carnitine is not an important limiting factor, if any, for LCP3 synthesis in vegans and lacto-ovo-vegetarians. This conclusion is also likely to apply to omnivores. The most efficient means to augment EPA and particularly DHA status remains consumption of LCP3 from e.g. fish or supplements.

Key words: carnitine, alpha-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, vegans, vegetarians

	INTRODUCTION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Consumption of fatty acids (FA) of the 3-series (FA3) is associated with lower risk of cardiovascular disease (CVD), cancer, and inflammatory and autoimmune disease [1]. Augmented FA3 intake may also be beneficial for patients with neuropsychiatric disorders such as dementia, schizophrenia and mood disorders [2]. Intakes of long chain polyunsaturated FA3 (LCP3; from e.g. fish) are more effective in reducing CVD risk factors than intakes of the LCP3 precursor alpha-linolenic acid (ALA; from vegetables oils such as linseed oil) [3]. The principal LCP3, i.e. eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are held responsible for the beneficial effects. The difference in CVD risk factor reduction observed with LCP3 and ALA is assumed to derive from the low efficacy by which ALA augments EPA and DHA status [3,4]. Many investigators have shown that the synthesis of EPA and particularly DHA from ALA proceeds with difficulty in humans [5]. ALA is rapidly oxidized in the liver and it has also been suggested that a sizeable amount is incorporated into the skin [6]. In addition, ALA competes with its more abundant 6-counterpart linoleic acid (LA) for conversion to LCP. Dietary 6/3 ratio’s have increased within the past 100 years from about 2.4:1 to about 12:1 [1], and it is therefore likely that our chain elongation and desaturation enzymes are particularly engaged with FA6. Negative feedback inhibition by the highly abundant LCP6 (notably arachidonic acid; AA, from meat) in contemporary omnivorous diets may also account for the poor conversion. In a previous study, we investigated the effects of ALA supplementation in vegans, who do not, or to a low extent, consume LCP and have low LCP3 status [7]. We found that ALA supplementation augmented LCP3 status at least as poor in vegans as in omnivores, suggesting that either their high 6 status or high dietary LA/ALA ratio might have precluded LCP3 synthesis.

From 1991, it is assumed that LCP3 and LCP6 synthesis proceeds in a competitive manner via a series of alternating desaturations and chain elongations in the endoplasmic reticulum, followed by a final ß-oxidation step in peroxisomes [8]. Since then, this so-called Voss-pathway has become generally accepted. In 1997, Infante et al. [9] proposed a different pathway for LCP synthesis. They hypothesized that LCP3 and LCP6 synthesis take place in a non-competitive manner in the outer mitochondrial membrane via a channeled carnitine-dependent pathway that includes a final 4-desaturation step catalyzed by a 4-desaturase. In addition they suggested that AA and EPA, but not DHA, can also be synthesized in the endoplasmic reticulum via a so-called ‘escape route’. A comparison of the Voss-pathway and the major Infante-pathway for LCP3 synthesis from ALA is depicted in Table 1. One of the major differences of the Voss and Infante LCP-synthetic pathways lies in the dependence of LCP synthesis, and particularly that of DHA, on adequate free carnitine pools in the Infante-pathway [10]. Vegans and lacto-ovo-vegetarians are expected to have low carnitine status, since they do not consume food products that are rich in carnitine, such as meat [11]. According to the Infante-pathway, their apparently low conversion rate of ALA to DHA may consequently derive from their low carnitine status.

View this table: [in this window] [in a new window]   Table 1. Proposed Pathways for Conversion of ALA to LCP3

	SUBJECTS AND METHODS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Study Design
Apparently healthy subjects who reported not to eat meat or fish (vegans and lacto-ovo-vegetarians) or to use drugs that are known to interfere with carnitine metabolism (phenobarbital, valproic acid, phenytoin, carbamazepine, pivampicillin and pentylenetetrazol) were eligible to participate in this study. They were recruited by advertisement in periodicals of the Dutch Vegan Society, in local health-food stores and vegetarian restaurants. The protocol was approved by the medical ethics committee of the Groningen University Hospital and was in agreement with the Helsinki declaration of 1975 as revised in 1996.

The participants were divided into two groups. They were assigned to one of the groups by us. Subjects in group A took carnitine (0.99 g/day) for 4 weeks (weeks 1–4) and carnitine together with linseed oil (4 mL/day) during the next four weeks (weeks 5–8). Group B took the same linseed oil dose from weeks 1–4 and linseed oil together with carnitine from weeks 5–8. Self-reported anthropometric data were recorded at baseline and blood was taken after a 10h fast from all subjects at baseline, and after 4 and 8 weeks. They were asked to consume their regular diets during the study period. Carnitine was taken daily at breakfast in 3 tablets containing 330 mg levocarnitine each (Carnitene, Sigma Tau, Rome, Italy), corresponding to a median [range] dose of 14.9 [11.0–19.4] mg/kg bodyweight. The linseed oil dose (Lijnzaadolie ‘De Nieuwe Band’ Spack, Oostvoorne, The Netherlands) was divided among breakfast (1 mL), lunch (1 mL) and dinner (2 mL), and was taken via a dose-syringe from a dark bottle. The FA contents of the linseed oil per 100 mL, as determined by gas chromatography, were 8.3 g saturated FA, 15.0 g monounsaturated FA (14.4 g 18:19) and 63.4 g polyunsaturated FA (13.0 g LA and 50.3 g ALA). From this it was calculated that the daily linseed oil dose contained 2.01 g ALA at an LA/ALA ratio of 0.26 g/g. In our previous study, this supplement decreased mean ± SD dietary LA/ALA ratio’s from 13.7 ± 4.0 to 6.8 ± 1.9 g/g [7].

Blood Sampling and Analytical Methods
Ten mL EDTA-anticoagulated blood was collected in the fasting state by puncture of the cubital vein at baseline, and after 4 and 8 weeks. EDTA-anticoagulated blood was separated by centrifugation into EDTA-plasma, and RBC and PLT pellets. Free (reference values, 22.3–54.8 µmol/L) and total (26.6–73.7 µmol/L) carnitine concentrations were determined in plasma with electrospray tandem mass spectrometry [12]. CE and TG were isolated from plasma by solid-phase extraction according to our previously described method [13]. RBC and PLT pellets were washed with physiological saline. FA in RBC, PLT, CE and TG were transmethylated to FA methyl esters in methanol/6N HCl (5:1, by vol.), extracted in hexane and subsequently determined by capillary gas chromatography with flame ionization detection [13]. FA compositions were expressed in mol%.

Data Processing and Statistics
Data were processed with SPSS 10 (Microsoft, USA). Between-group differences in anthropometrics and FA compositions at baseline were tested with the Mann-Whitney U test for continuous and with the chi-square test for binomial variables, using p < 0.05. FA composition and carnitine changes from weeks 1–4 and from weeks 5–8 were tested for groups A and B separately, using Wilcoxon tests at p < 0.025, i.e. after correction for type 1 errors according to Bonferroni. Correlations between EPA and DHA changes, and carnitine concentrations or changes were investigated with the Spearman rank correlation test at p < 0.05 for groups A and B separately.

	RESULTS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Baseline Characteristics
The study group comprised 22 participants, of whom 13 were assigned to group A (carnitine, carnitine + ALA) and 9 to group B (ALA, ALA + carnitine). Two vegans (1 male and 1 female) in group A dropped out for personal reasons. Baseline anthropometrics, plasma carnitine concentrations and RBC fatty acid contents of the total study population and as stratified for study groups are depicted in Table 2. There were no significant differences between groups A and B. Group A tended to have lower 3 status compared with group B, ALA and DHA were significantly lower in TG only (p < 0.05). These differences may be due to the non-significantly higher percentage vegans in group A.

Group B.
Mean ± SD plasma free and total carnitine did not change from baseline (31.3 ± 9.4 and 38.1 ± 10.3 µmol/L, respectively) to week 4 (30.9 ± 8.6 and 37.7 ± 9.7 µmol/L), and increased upon supplementation to week 8 (40.7 ± 11.0, p = 0.008 and 47.9 ± 12.8 µmol/L, p = 0.008).

Fatty Acid Changes
The Fig. 1 shows the ALA, EPA and DHA compositions of RBC, PLT, CE and TG at baseline, and after 4 and 8 weeks for groups A and B separately.

View larger version (21K): [in this window] [in a new window]   Fig. 1. 3-fatty acid changes in various compartments for groups A and B. Bars represent mean ± SEM for fatty acids (mol%) in red blood cells, platelets, plasma cholesterol esters and plasma triglycerides for n = 11 in group A and n = 9 (n = 8 for platelets) in group B. Group A took 990 mg/day l-carnitine from weeks 1–4, and 990 mg/day l-carnitine + 4 mL/day linseed oil from weeks 5–8. Subjects took 4 mL/day linseed oil from weeks 1–4, and 4 mL/day linseed oil + 990 mg/day l-carnitine from weeks 5–8. Asterisks indicate significant changes (p < 0.025), compared with previous sampling. ALA; alpha-linolenic acid, EPA; eicosapentaenoic acid, DHA; docosahexaenoic acid.

Group B.
ALA (RBC,PLT,TG) and EPA (PLT,CE,TG) increased from weeks 1–4 (p < 0.025). DHA increased in CE (p = 0.008), and decreased (p = 0.018) in PLT during this period. ALA and DHA increased (p < 0.025) in RBC from weeks 5–8. Of the FA6, only 22:56 decreased (p = 0.021) in CE from weeks 1–4.

Correlations with EPA and DHA Changes during the Study
Table 3 illustrates the relations between EPA and DHA changes on the one hand, and carnitine status or carnitine changes on the other hand. EPA and DHA changes from weeks 1–4 in various compartments proved inversely related with free and total carnitine status at baseline for both groups. DHA changes (PLT) from weeks 5–8 were also negatively related to free carnitine at week 4 for group B. Taken together these data suggest that subjects with the lowest initial carnitine status exhibited the highest EPA and DHA increases upon carnitine supplementation. Opposed to this suggestion was the positive relation in group A between DHA changes in RBC from weeks 5–8 and free and total carnitine at week 4. This relation was due to two outliers exhibiting a DHA decrease at low carnitine status. The significance of this relation disappeared after their omission.

	DISCUSSION

An important, but highly unexpected finding was the inverse relation between EPA and DHA changes and initial carnitine status or carnitine changes. These correlations (Table 3) might indicate that the baseline carnitine status of our study population was too high to find any effects of carnitine supplementation on EPA and DHA status. Indeed, we found that merely 2 persons, both vegetarians, had plasma free and total carnitine values below the reference range. A higher carnitine status than expected might be explained by previous observations that (strict) vegetarians have higher carnitine recycling efficiency by increased renal re-absorption [17]. On the basis of these results we can not conclude that carnitine is not a limiting factor of LCP3 synthesis. The inability to find an effect of carnitine on LCP3 status may also relate to some extent to our study design. This becomes e.g. illustrated by the difficulty to assign the DHA increase in RBC from weeks 5–8 (group B, Fig. 1) to either a postponed effect of ALA or to a combined effect of ALA and carnitine. Longer supplementation periods may shed light on this limitation of the present design. Significant effects may theoretically also be found with higher carnitine dosages, although it may be questioned whether these would be relevant, since the present 990 mg/day dosage exceeds the usual carnitine intakes of omnivores (100–300 mg/day; [18]) with more than 330%. Another factor that might have influenced our results is the high dietary LA/ALA ratio. Baseline RBC LA/ALA ratio’s of the present study group were similar (p = 0.574) to those of our previous study [[7] data not shown], in which the subjects had mean baseline dietary LA/ALA ratio’s of 12.8 g/g. Intake of 6-rich, 3-poor, vegetable oils is therefore also likely to be a major determinant of LCP3 synthesis in the present study. Although our results cannot exclude an influence of carnitine, our data do suggest that carnitine is not the limiting factor for the well-known poor conversion of ALA to DHA in apparently healthy vegans and lacto-ovo-vegetarians. This conclusion is even more likely to apply to healthy omnivorous populations, considering their higher carnitine intakes and their probably even more inhibited conversion of ALA to LCP3, because of higher AA and LCP3 intakes.

Unfortunately, our results do not contribute to the discussions on the LCP3 synthesis pathways. On the one hand, our findings that mean EPA and DHA cannot be increased upon carnitine supplementation support the pathway of Voss et al. (Table 1), since carnitine is not necessary for (very) long chain FA transport across the peroxisomal membrane [16]. On the other hand, the presently encountered inverse relations between EPA or DHA changes and initial carnitine levels (see Table 3) do not exclude the Infante-pathway either. The observed increases in AA and 22:46 upon carnitine supplementation (group A), or its combination with ALA, may also be in support of the Infante pathway. The general opinion is currently in favor of the Voss-pathway. Ferdinandusse et al. [15] recently found strong support for this pathway. They showed normal DHA synthesis capacity in fibroblasts of carnitine palmitoyltransferase I deficient patients. These patients are obviously unable to convert activated FA’s into acylcarnitines, which is a necessary step for the import of long chain FA into mitochondria. They would therefore be unable to synthesize DHA via the Infante-pathway [9]. A detailed discussion on the arguments in favor and against both pathways reaches beyond the scope of this publication, but is reviewed elsewhere [4,9,10,15].

The difficulty to synthesize LCP3, in particular DHA, from ALA supports previous results from many other studies [5,7,19]. Overall conversion efficiency to DHA was estimated to be merely 0.047% in 7 days [20], with a highest estimate from AUC’s of 5% in 21 days [21]. DHA conversion may proceed with less difficulty in tissues like the brain and the retina, but is also considered to be limited. The most efficient means to augment EPA and particularly DHA status remains consumption of LCP3 from e.g. fish or fish oil supplements. The relation between LCP3 status and disease risk has as yet only been demonstrated in omnivores. Although it remains to be established whether augmentation of the LCP3 status of (strict) vegetarians reduces their habitually low risk of mortality from all causes, CVD or cancer [22], augmentation may certainly not be harmful. Increased EPA and DHA intakes by vegetarians was shown to reduce their high platelet aggregation [23] and many other beneficial aspects of FA3, such as positive influences on cognitive functions and visual acuity, and immunosuppressive, anti-inflammatory and anti-arrhythmic properties [24], are likely to apply to (strict) vegetarians as well as to omnivores. Augmented ALA intakes may also have positive effects on the cardiovascular system [25], and is probably the easiest manner by which vegans and some vegetarians may increase their (LCP)3 status.

	CONCLUSION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Short-term carnitine, or combined carnitine plus ALA supplementation, does not augment EPA, and particularly DHA, status in healthy vegans and vegetarians regardless of the pathway by which these LCP3 are synthesized from ALA. This conclusion is also likely to apply to omnivores. LCP3 intake from fish or supplements remains the principal means for augmentation of EPA and DHA status for omnivores, whereas the main options for vegans and some vegetarians seems to be the consumption of vegetable oils with high ALA/LA ratios or of EPA and DHA from algae sources.

	ACKNOWLEDGMENTS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
We thank Ingrid A. Martini for her technical assistance with FA analyses and Dr. F.M. Vaz of the laboratory of Genetic Metabolic Diseases of the University of Amsterdam, for performing plasma carnitine analyses.

Received November 25, 2003. Accepted November 25, 2004.

	REFERENCES

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 

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