Compartmental modeling to quantify a-linolenic acid conversion after longer term intake of multiple tracer boluses
Compartmental modeling to quantify a-linolenic acid conversion after longer term intake of multiple tracer boluses
Year: 2005
Authors: Goyens, P.L.L. . Spilker, M.E Zock, P.L. Katan, M.B. Mensink, R.P.
Publication Name: Journal of Lipid Research
Publication Details: Volume 46; Pages 1474 – 1483.
Abstract:
To estimate in vivo αlpha-linolenic acid (ALA; C18: 3n-3) conversion, 29 healthy subjects consumed for 28 days a diet providing 7% of energy from linoleic acid (C18:2n-6) and 0.4% from ALA. On day 19, subjects received a single bolus of 30 mg of uniformly labeled [13C]ALA and for the next 8 days 10 mg twice daily. Fasting plasma phospholipid concentrations of 12C- and 13C-labeled ALA, eicosapentaenoic acid (EPA; C20:5n-3), docosapentaenoic acid (DPA; C22:5n-3), and docosahexaenoic acid (DHA; C22:6n-3) were determined on days 19, 21, 23, 26, 27, and 28. To estimate hepatic conversion of n-3 fatty acids, a tracer model was developed based on the averaged 13C data of the participants. A similar trace model was solved using the averaged 12C values, the kinetic parameters derived from the tracer model, and mean ALA consumption. ALA incorporation into plasma phospholipids was estimated by solving both models simultaneously. It was found that nearly 7% of dietary ALA was incorporated into plasma phospholipids. From this pool, 99.8% was converted into EPA and 1% was converted into DPA and subsequently into DHA. The limited incorporation of dietary ALA into the hepatic phospholipid pool contributes to the low hepatic conversion of ALA into EPA. A low conversion of ALA-derived EPA into DPA might be an additional obstacle for DHA synthesis. (Author's abstract)
There is much debate in the literature as to whether ALA is a useful source for EPA and DHA synthesis. Although most results indicate that ALA is converted, these studies only allow a qualitative or semi-quantitative description of n-3 metabolism. In contrast, the use of stable isotopes offers a means to assess quantitatively the in vivo conversion of ALA. Compartmental modeling, however, provides more accurate estimates of the various metabolic parameters underlying the n-3 fatty acid cascade. In this research, compartmental modeling was used to quantify ALA conversion after ingestion of multiple trace amounts of uniformly labeled [13C]ALA ([U-13C]ALA) for 9 days, and enrichments of ALA and its long-chain polyunsaturated fatty acids (LCPUFAs) were measured in plasma phospholipids. The results showed that nearly 7% of daily ALA consumption was incorporated into plasma phospholipids and approximately 99.8% of ALA from this pool was subsequently converted to EPA, whereas only 1% of the EPA plasma phospholipid pool was converted to DPA. Essentially all DPA was used for the synthesis of DHA. Usually, the limiting step within the n-3 cascade is considered to be the Δ -6 desaturation that is necessary for the conversion of ALA to C18:4n-3. However, our study suggests that this is not the limiting step, as nearly all EPA in the plasma phospholipid pool was derived from the ALA plasma phospholipid pool. Thus, entry into the hepatic phospholipid pool is a limiting factor for ALA conversion to DHA. The study found that only CEs produced by the liver itself might reflect hepatic ALA conversion, but, as for TG, plasma CEs are rather poor in n-3 LCPUFAs. The increased mass of the ALA compartment would be reflected by an increased loss from the ALA compartment rather than by changed fluxes into the other compartments. Plasma total lipids may not be the most appropriate lipid fraction for the quantification of hepatic n-3 fatty acid conversion. The authors conclude that the limited incorporation of dietary ALA into the phospholipid pool contributes to the low hepatic conversion of dietary ALA to EPA. The conversion of EPA to DPA, which involves an elongation reaction, might be an additional bottleneck within the hepatic n-3 cascade. (Editor's comments)
