American Journal of Clinical Nutrition, Vol. 88, No. 2, 282-288,
August 2008
© 2008 American Society for Nutrition
ORIGINAL RESEARCH COMMUNICATION |
Inclusion of 10% fish oil in mixed medium-chain triacylglycerol–long-chain triacylglycerol emulsions increases plasma triacylglycerol clearance and induces rapid eicosapentaenoic acid (20:5n–3) incorporation into blood cell phospholipids1,2,3
Christian M Simoens1,
Richard J Deckelbaum1,
Jacques J Massaut1 and
Yvon A Carpentier1
1 From the L Deloyers Laboratory for Experimental Surgery, Université Libre de Bruxelles, Brussels, Belgium (CMS and YAC); the Department of Gastrointestinal Surgery (CMS) and the Intensive Care Unit (JJM), CHU Brugmann, Université Libre de Bruxelles, Brussels, Belgium; and the Institute of Human Nutrition, Columbia University, New York, NY (RJD)
2 Supported by grants from the Belgian "Fonds de la Recherche Scientifique Médicale" (grant 3.4620.01) to YAC and the NIH (grant HL40404) to RJD.
3 Reprints not available. Address correspondence to YA Carpentier, L Deloyers Laboratory for Experimental Surgery, Université Libre de Bruxelles, 40 Avenue Wybran, B-1070 Brussels, Belgium. E-mail: nutrisub{at}ulb.ac.be.
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ABSTRACT
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Background:Lipolysis of a fish oil (FO) emulsion is much slower than that of a soybean [long-chain triacylglycerol (LCT)] emulsion; in contrast, emulsions containing medium-chain triacylglycerol (MCT) are efficiently hydrolyzed by lipoprotein lipase.
Objectives:We questioned whether incorporating 10% FO in a mixed MCT-LCT emulsion would affect plasma triacylglycerol clearance and provide efficient delivery of n–3 polyunsaturated fatty acids to cells and tissues.
Design:This prospective crossover study was conducted in 8 normolipidemic subjects with the use of the hypertriglyceridemic clamp model and compared plasma triacylglycerol clearance of a lipid emulsion (5:4:1) made of 50% MCT, 40% LCT, and 10% FO (wt:wt:wt) to a control (5:5) preparation with 50% MCT and 50% LCT. Subjects were daily infused for 5 h, over 4 consecutive days. Fatty acyl pattern was daily measured in plasma phospholipids as well as in leukocyte and platelet phospholipids.
Results:Inclusion of 10% FO in mixed emulsion particles enhanced plasma clearance of infused triacylglycerols (18%; P < 0.0001). The faster elimination of the 5:4:1 emulsion appears related to an enhanced uptake of remnant particles rather than to faster intravascular lipolysis. Each infusion of 5:4:1 raised the eicosapentaenoic acid (C20:5n–3) concentration in blood cell phospholipids to reach a 7-fold enrichment in platelets and a >2-fold enrichment in leukocytes after 4 infusions. In contrast, the docosahexaenoic acid (C22:6n–3) concentration remained unchanged in blood cell phospholipids.
Conclusions:Infusion of a mixed emulsion with MCTs, soy LCTs, and FO is associated with efficient plasma triacylglycerol clearance and results in rapid incorporation of C20:5n–3 but not C22:6n–3 in leukocyte and platelet phospholipids.
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INTRODUCTION
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Lipid emulsions are an important component of parenteral nutrition, both as a source of energy substrate and a supplier of essential fatty acids. Classical lipid emulsions are made of soybean oil and provide large amounts of polyunsaturated fatty acids (PUFAs), mainly linoleic acid (C18:2n–6). Prolonged infusions of these emulsions increase C18:2n–6 concentrations in cell membranes (1). Concerns were raised about such changes in the fatty acyl pattern, namely in acutely ill patients who often have severe inflammatory reactions, impaired endothelial function, and ectopic fat deposition. Indeed, inflammatory and thrombotic reactions may be exacerbated by eicosanoids derived from arachidonic acid (C20:4n–6) (2). In contrast, n–3 long-chain PUFAs and eicosanoids derived from eicosapentaenoic acid (C20:5n–3) may protect against excessive inflammatory reactions (3), improve endothelial function (4), and reduce ectopic fat deposition (5). Because both n–3 and n–6 PUFAs compete for the same enzymatic pathways, formation of end-product eicosanoids depends on the ratio between n–6 and n–3 PUFA concentrations in membrane phospholipids. Oral administration of fish oil (FO) induces incorporation of n–3 PUFAs in cell membranes, but only after 2–3 d of supplementation (6). This suggests an interest for supplying n–3 PUFAs by intravenous route in the setting of patients with acute illness (7) and in patients receiving long-term parenteral nutrition. With regard to the latter, conventional emulsions made of soybean oil do not reduce the ratio of n–6 to n–3 fatty acids because they provide substantially more n–6 (52–54% C18:2n–6) than n–3 [7–9% 
-linolenic acid (C18:3n–3)] fatty acids. In such conditions, C18:3n–3 conversion into C20:5n–3 is low (<5% in men and <10% in women), and that into docosahexaenoic acid (C22:6n–3) is negligible (8, 9). Infusions of pure FO emulsions may represent an attractive option. However, hydrolysis of FO triacylglycerols by lipoprotein lipase (LPL) is not efficient and results in a limited release of C20:5n–3 and C22:6n–3 (10); as a consequence, emulsions made of pure FO must be infused at low rates. In contrast, the intravascular clearance of emulsions containing a mixture of medium-chain triacylglycerols (MCTs) and soybean-derived long-chain triacylglycerols (LCTs) is faster than that of LCT emulsions (11). MCTs are efficiently hydrolyzed from the mixture (11), which leads to the rapid formation of small-sized remnant particles readily taken up by the liver and other tissues (12). Hence, we questioned whether mixing the same particle in a 50% proportion of MCTs together with 10% FO and 40% soy LCTs would counteract the slow elimination of FO and whether this limited proportion of FO would result in n–3 PUFA incorporation in cell membranes. This was tested with the use of the hypertriglyceridemic clamp technique in a group of normolipidemic volunteers (13). A MCT-LCT (50:50; wt:wt) emulsion used in Europe for >20 y was selected as the control preparation.
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SUBJECTS AND METHODS
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Subjects and infusion protocol
Eight healthy male volunteers [age ( 
± SD: 23 ± 3 y) were selected according to the following criteria: normal physical examination, normal range for hepatic and renal function, fasting plasma triacylglycerols < 1.14 mmol/L (100 mg/dL), cholesterol < 5.18 mmol/L (200 mg/dL), phospholipids < 2.58 mmol/L (200 mg/dL), and glucose < 6.11 mmol/L (110 mg/dL).
Each subject received 2 series of 4 consecutive daily infusions of lipid emulsions with the use of the hypertriglyceridemic clamp technique. To avoid a carry over effect of n–3 PUFAs on triacylglycerol elimination, the MCT-LCT emulsion was administered during the first series of infusions in all subjects, and the 5:4:1 emulsion was given during the second series of infusions. An interval of 6 wk separated both series of experiments.
We used a hypertriglyceridemic clamp infusion protocol. The principle of the hypertriglyceridemic clamp is to maintain a stable value of triacylglycerols at the predetermined concentration during a period of time sufficient to stabilize triacylglycerol exchanges between compartments. In steady conditions and assuming constant VLDL secretion, plasma elimination of exogenous triacylglycerols is equal to infusion rate.
Each infusion was performed after an overnight fast, and the subjects were requested to eat a standard meal (with a limited fat intake and no alcohol) on the previous evening. An intravenous line was inserted in each arm, one for infusing the substrates and the other for drawing blood samples. Intravenous lines were kept patent by a slow infusion of saline. No heparin was used. The concentration of plasma substrates was stabilized by a combined infusion of glucose and amino acids as previously reported (14). In brief, glucose (glucose 10%; B Braun AG, Melsungen, Germany) was infused at 0.25 g · kg body wt–1 · h–1 and amino acids (Aminoplasmal; B Braun AG) at 0.05 g · kg body wt–1 · h–1 during the first hour. Thereafter, glucose and amino acid infusion rates were kept constant at 0.16 and 0.05 g · kg–1 · h–1, respectively, for the rest of the test. After 2.5 h (–2.5 h to 0 h) of combined glucose and amino acid infusion, lipids were added for the next 5 h. On the basis of data from previous similar triacylglycerol clamps, a priming dose (1 g triacylglycerols · kg–1 · h–1) was infused over 5 min to rapidly increase plasma triacylglycerol concentration by 
3mmol/L. The rate of lipid infusion was then abruptly reduced to 0.2 g triacylglycerols·kg–1·h–1 and, thereafter, regularly adjusted to maintain plasma triacylglycerol concentration at values as close as possible to 3 mmol/L above the concentration at 0 h(13). To guide selection of infusion rates, plasma triacylglycerol concentrations were determined at 15-min intervals with the use of the fast analyzer Reflotron (Boehringer, Mannheim, Germany). Lipid and glucose-amino acid infusions were stopped after 5 h.
Subjects were allowed to eat a standard meal and to drink water in the evening before infusions. The hypertriglyceridemic clamp was performed for 4 consecutive days with the same lipid preparation.
For fatty acid analysis in blood cell and plasma phospholipids, samples were collected before starting any infusion on days 1, 2, 3, and 4. Another sample was also taken in the fasting condition on day 5.
The study protocol was approved by the Ethical Committee of the Faculty of Medicine, Université Libre de Bruxelles (Brussels, Belgium). Each volunteer received complete information on the potential risks of the infusions and signed an informed consent before his admission in the study.
Lipid emulsions
Both emulsions used in the present study had a triacylglycerol concentration of 20 g/100 mL and were manufactured by B Braun AG. Their composition is shown in Table 1
. The MCT-LCT (5:5) emulsion contained an equal (1:1; wt:wt) proportion of MCTs and of LCTs. The 5:4:1 emulsion contained MCTs, LCTs, and FO in a wt:wt:wt ratio of 5:4:1. Both emulsions contained 1.2 g/dL of the same egg yolk phospholipid emulsifier and 2.5 g/dL of glycerol. Thus, the only difference between the emulsions was in the composition of triacylglycerol fatty acids with the 5:4:1 emulsion containing 10% FO (ie, a total of 2.6% C20:5n–3 and 1.3% C22:6n–3, wt:wt, of total triacylglycerol fatty acids).
Clinical status and vital signs
Vital signs (body temperature, heart rate, blood pressure) were monitored hourly during the tests. Adverse events (defined as any illness or other unfavorable change in the clinical status, whether considered as related to the study) were recorded from the beginning of the first infusion until completion of follow-up.
Sample collection and processing
Blood samples were drawn into glass tubes containing EDTA (1 mg/mL blood) that were immediately put in iced water. Plasma was quickly separated by low speed centrifugation (1000 x g) at 4 °C for 10 min with the use of a refrigerated centrifuge (J2-21; Beckman Instruments Inc, Fullerton, CA). Plasma samples were then divided into aliquots and stored for future analyses.
Isolation from blood of red cells, leukocytes, and platelets was performed with the use of a dextran extraction method (15). Cells were directly isolated from fresh blood, and separation of phospholipids was immediately started with the use of thin-layer chromatography.
Plasma lipoprotein fractions were isolated by sequential ultracentrifugation at 4 °C with the use of a TL 100 ultracentrifuge (Beckman Instruments Inc) with a TLA 100.2 fixed angle rotor (Beckman Instruments Inc) (16). The fractions were collected in the following order: at d < 1.006 g/mL, the triacylglycerol-rich particle fraction containing endogenous VLDLs together with the majority of exogenous emulsion particles; at 1.006 < d < 1.063 g/mL, the LDL fraction; and at 1.063 < d < 1.21 g/mL, the HDL fraction. Lipid analyses were performed in all lipoprotein fractions as soon as they were obtained. Plasma samples for triacylglycerols, total cholesterol, free cholesterol, nonesterified fatty acids (NEFAs), phospholipid, and apolipoprotein measurements were frozen at –20 °C until analyses that were performed within 4 wk. Plasma samples for measurement of fatty acyl pattern in selected lipid components were stored at –70 °C in glass tubes until analysis that was performed within 4 wk.
Analytic procedures
Analyses of plasma triacylglycerols were performed enzymatically within 24 h with the use of the "Test-Combination" (triacylglycerols without free glycerol) kit (Boehringer Mannheim GmbH, Mannheim, Germany). In addition, rapid evaluations (<15 min) of plasma triacylglycerol concentrations were performed during lipid infusion by the enzymatic method with the use of the Reflotron analyzer (Boehringer Mannheim GmbH).
Concentrations of total and free cholesterol were measured enzymatically with Monotest cholesterol CHOD-PAP high-performance and Test-Combination free cholesterol (Boehringer Mannheim GmbH) kits, respectively. Plasma NEFA concentration was measured enzymatically with the use of the NEFA quick BMY (Boehringer Mannheim and Yamanouchi KK, Tokyo, Japan) kits. Phospholipid concentration was measured colorimetrically according to Bartlett (17).
Fatty acyl pattern was determined by gas liquid chromatography in plasma lipid components (triacylglycerols, cholesteryl esters, phospholipids, NEFAs) and in blood cell phospholipids previously separated by thin-layer chromatography (18). Concentrations of apolipoproteins A-1, A-2, B, C-I, C-II, C-III, and E were measured by sandwich enzyme-linked immunoabsorbent assay (19).
Statistical analyses
Results are expressed as mean values ± SDs. Data were analyzed with a 2-factor repeated-measures analysis of variance with interaction (triacylglycerol elimination, fatty acyl pattern) or with a 3-factor analysis of variance for comparison of lipoprotein and apolipoprotein values (STATA 8.2 for UNIX, StataCorp, College Station, TX).
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RESULTS
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Clinical side effects
No serious adverse effects were observed with either emulsion. All volunteers completed the trial.
Clearance of injected triacylglycerols
To closely maintain plasma triacylglycerol concentration at values of 3 mmol/L above concentrations at 0 h, infusion rates were regularly adjusted in relation to plasma triacylglycerol concentrations measured with the Reflotron method. Triacylglycerol concentrations were stable over the last 2 h (hour 3 to hour 5) of infusions. Substantial differences of triacylglycerol elimination were observed between persons, as indicated by the wide range of infusion rates applied during the last 2 h of lipid infusion: 98–203mg triacylglycerols · kg–1 · h–1 with the 5:5 emulsion and 134–278 mg triacylglycerols/ · kg–1 · h–1 with the 5:4:1 emulsion. It was the same subjects who rapidly cleared both emulsions (and vice versa), and the clearance of an emulsion remained fairly constant for any given subject over the 4 consecutive daily infusions.
The average infusion rate over the last 2 h (hour 3 to hour 5) was higher with the 5:4:1 emulsion (204 ± 38 mg · kg–1 · h–1) than with the 5:5 emulsion (164 ± 58 mg · kg–1 · h–1; P < 0.0001), indicating a higher rate of plasma triacylglycerol elimination (Figure 1). We also used an alternate connotative calculation of elimination rate (in mmol/h) with the use of the equation: total amount (in mmol) of infused triacylglycerol over 5 h –(triacylglycerol concentration at 3–5 h – triacylglycerol concentration at 0 h) x plasma volume. Data calculated with this model confirms a higher elimination rate for the 5:4:1 emulsion (351 ± 56 mmol/h or 193 ± 33 mg · kg–1 · h–1) compared with the 5:5 emulsion (298 ± 66 mmol/h or 164 ± 36 mg·kg–1 · h–1; P < 0.0001). Lipid infusions were associated with rises of plasma NEFA concentration. Substantial differences were observed between subjects, but no significant differences were noted between the emulsions (data not shown).
Fatty acyl composition of plasma phospholipids
No major modification of fatty acyl pattern was observed in plasma phospholipids after the 5:5 infusions. In contrast, the relative content of 20:5n–3 was markedly increased on days 3, 4, and 5, ie, after 
2 infusions of the 5:4:1 emulsion (Table 2).
Fatty acyl composition of blood cell phospholipids
Platelets
Fatty acyl profiles remained stable in platelet phospholipids during repeated infusions of the 5:5 emulsion, except for a mild (<10%; P < 0.01) and progressive increase of 18:2n–6 relative concentration. With the 5:4:1 emulsion, 18:2n–6 concentration remained unchanged, whereas 20:4n–6 slightly decreased. The relative concentration of 20:5n–3 was markedly increased from day 2 on, whereas that of 22:6n–3 remained unchanged (Figure 2).
White blood cells
No substantial modification of the fatty acyl profile was found in white blood cell phospholipids after the 5:5 infusions. In contrast, a progressive increase of 20:5n–3 concentration was observed after 2 infusions of the 5:4:1 infusion; 22:6n–3 remained unchanged (Figure 3).
Red blood cells
Fatty acyl composition remained stable in red blood cell phospholipids after 4 consecutive infusions of the 5:5 emulsion. A modest increase of the 20:5n–3 relative concentration (from 0.7 ± 0.2% to 1.0 ± 0.3%; P < 0.05) was observed on day 5, ie, after 4 infusions of the 5:4:1 emulsion.
Plasma lipoproteins
Plasma lipoproteins were separated from samples taken before (0 h) and at the end (5 h) of lipid infusions on days 1 and 4. The content of lipids and of selected apolipoproteins was measured in the different fractions.
As expected, most of the triacylglycerol increase measured in plasma at the end of infusions was found in the d < 1.006 g/mL fraction, which contained a majority of infused emulsion particles together with endogenous VLDL. As noted for total plasma, triacylglycerol content in the d < 1.006 g/mL fraction increased to higher concentrations with the 5:4:1 emulsion than with the 5:5 emulsion. Hypertriglyceridemia induced by the infusion of either emulsion resulted in a marked enrichment of LDL and HDL with triacylglycerols on days 1 and 4. Triacylglycerol enrichment in LDL was higher with the 5:4:1 emulsion than with the 5:5 emulsion on day 4 only (P = 0.009), whereas triacylglycerol enrichment in HDL was higher with the 5:4:1 emulsion than with the 5:5 emulsion on both days 1 and 4 (P = 0.004) (Table 3).
A marked increase of cholesteryl ester concentration was observed in the triacylglycerol-rich particle fraction, presumably in emulsion particles (from 0.07 ± 0.04 mmol/L to 0.16 ± 0.06 mmol/L with the 5:5 emulsion and from 0.05 ± 0.04 mmol/L to 0.21 ± 0.09 mmol/L with the 5:4:1 emulsion). Cholesteryl ester concentration tended to decrease in LDL and HDL during either lipid infusion (data not shown).
Plasma concentration of apolipoproteins A-1, A-2, B, C-I, C-II, and C-III was not significantly modified by the infusion of either lipid emulsion. However, an increase of the ratio of apolipoprotein E to apolipoprotein C-I (apo E:apoC-I) was observed at the end of lipid infusions on days 1 and 4 (P < 0.001) and was more marked with the 5:4:1 emulsion than with the 5:5 emulsion on day 4 (P = 0.015) (Table 4).
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DISCUSSION
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In this crossover study, 8 healthy volunteers with a normal lipid profile underwent 2 series of 4 consecutive daily intravenous triacylglycerol clamp tests, a first series with the control MCT-LCT (5:5) mixture and another one, 6 wk later, with the test preparation (5:4:1) that contained 10% FO. The order of administration was not randomized to avoid a possible carry over effect of n–3 fatty acid enrichment on plasma triacylglycerol clearance. The triacylglycerol clamps were performed on a background infusion of glucose and amino acids to stabilize at low concentrations endogenous lipolysis in adipose tissues and to substantially reduce the contribution of endogenous fatty acid to plasma lipid changes. This also reproduced conditions met in patients receiving glucose and lipid infusions as part of parenteral nutrition. For the triacylglycerol clamps, the increase of plasma triacylglycerol concentration above the values at 0 h was set at 3 mmol/L. Plasma triacylglycerol concentrations were stable over the last 2 h (hour 3 to hour 5) of lipid infusion and allowed us to evaluate the elimination rate of exogenous lipids. Data obtained with 2 models of calculation indicate a higher plasma elimination of the 5:4:1 emulsion than of the 5:5 emulsion, suggesting that the presence of 10% FO in the mixture does not impair but instead enhances the clearance of infused triacylglycerols. This was unexpected because previous studies had shown pure FO triacylglycerols to be resistant to LPL hydrolysis (10). Emulsion clearance involves not only the intravascular hydrolysis of a part of particle triacylglycerols by LPL (which leads to the formation of remnant particles) but also the removal of remnants by receptor-mediated and nonreceptor endocytosis in the liver and in extrahepatic tissues. The latter pathway may occur at an early stage of emulsion metabolism by comparison to chylomicrons (20). We can only speculate on which of these steps contribute to the higher elimination rate of the 5:4:1 emulsion. Because the plasma NEFA concentration rose to similar concentrations during the infusion of either preparation suggests no difference in LPL activity; this was not unexpected because both emulsions contained the same fraction (50%) of MCTs which are promptly hydrolyzed by LPL (11, 21). This also indicates that LPL activity was not substantially inhibited by the presence of 10% FO in the 5:4:1 mixture. Data obtained after injection of labeled FO-containing emulsions in mice suggests that the presence of n–3 PUFAs enhances triacylglycerol elimination by an enhanced tissue uptake of emulsion particles distinct from changes in blood lipolysis (22–24). During the triacylglycerol clamp procedure, an increase of endogenous VLDL production is likely to occur in the liver, which is assumed not to differ between both preparations. Indeed, although marine n–3 fatty acid supplementation can reduce VLDL secretion, this effect is not immediate and seems to require n–3 PUFA incorporation in cell membranes (25).
An early step in the metabolism of artificial emulsions after their infusion in the circulation consists of the acquisition of selected apolipoproteins (mainly apo Cs and apo E) by transfer from HDL. Apo C-II plays an important role in facilitating particle binding to the LPL receptor site and in activating triacylglycerol hydrolysis by the enzyme; in contrast, apo C-III tends to inhibit LPL-mediated lipolysis. At a later stage of particle metabolism, apo E and apo C-I have opposing effects in modulating cellular uptake of remnant particles, with apo E facilitating their disposal. In the present study, an increase of plasma apo E:apo C-I was observed at the end of lipid infusions, which was higher with the 5:4:1 emulsion than with the 5:5 emulsion on day 4; this may contribute to an increased cellular endocytosis of 5:4:1 particles.
The large variability of plasma triacylglycerol clearance between individual subjects contrasts with the narrow range of fasting plasma triacylglycerol concentrations in the studied subjects. However, the elimination rate for a given person remained remarkably stable over the 4 consecutive infusions with a given preparation, suggesting no activation or inhibition of clearance induced by previous infusions.
The infusion of the FO-containing (5:4:1) emulsion resulted in a rapid and substantial incorporation of C20:5n–3 in membrane phospholipids of platelets and leukocytes. A marked enrichment (2–3-fold) was already observed after the first infusion and remained largely present on day 2 (0 h), ie, after 16 h of lipid-free interval. The C20:5n–3 content was increased 7-fold in platelets and >2-fold in leukocytes after 4 consecutive infusions of the 5:4:1 emulsion. In contrast, the C22:6n–3 content was not raised in blood cell membrane phospholipids, even after 4 consecutive infusions. Although the C22:6n–3 concentration in FO (13%) was half that of C20:5n–3 (26%), one would expect a proportional C22:6n–3 enrichment in platelet and white blood cell phospholipids if the uptake and cellular metabolism of both PUFAs were similar. The present data suggest different organ uptake or metabolic pathways for C20:5n–3 and C22:6n–3 that warrant further investigation. To our knowledge, there is no indication that C22:6n–3 is particularly susceptible to β oxidation, as reported for linolenate (26). Differences of incorporation in blood cell phospholipids between both n–3 PUFAs may also indicate a preferential uptake of C22:6n–3 in specific tissues such as brain and retina.
In summary, the presence of 10% FO in emulsion particles together with soybean LCTs and MCTs does not reduce, but rather enhances, the clearance of infused triacylglycerols, and this difference may not be related to a higher rate of hydrolysis but to a more efficient uptake of remnant particles. C20:5n–3, but not C22:6n–3, is efficiently and rapidly incorporated into blood cell membrane phospholipids, suggesting differences between both these n–3 PUFAs with respect to specific tissue uptake and metabolic pathways.
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ACKNOWLEDGMENTS
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The author's responsibilities were as follows—YAC: was responsible for the design of the study; CMS and RJD: collected, analyzed, and interpreted data; JJM: was in charge of the statistical analysis. All authors contributed to the writing of the manuscript. YAC reports having received consulting and lecture fees from B Braun, Melsungen (Germany). The other authors had no personal or financial conflict of interest.
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Received for publication December 10, 2007.
Accepted for publication April 30, 2008.
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ABSTRACT
INTRODUCTION
) emulsion than for the control 5:5 (
) emulsion. Two-factor repeated-measures ANOVA with interaction showed a significant emulsion effect (P < 0.0001) without day effect (P = 0.88) or interaction effect (P = 0.81).
, C22:6n–3; 
, C20:4n–6) measured in platelet phospholipids with the 5:4:1 (closed symbols) or 5:5 (open symbols) emulsions. Samples were collected before starting infusion on days 1, 2, 3, and 4, and an additional sample was taken in fasting conditions on day 5. The C20:4n–6 relative concentration decreased with the 5:4:1 emulsion; a 2-factor repeated-measures ANOVA indicated a significant emulsion effect (P < 0.0001) as well as a day effect (P = 0.044) but no interaction effect (P = 0.126). For C20:5n–3, statistical analysis indicated an emulsion effect (P < 0.0001) as well as a day effect (P = 0.00045) and interaction effect (P = 0.0033). C22:6n–3 remained unchanged.