The influence of placental metabolism on fatty acid transfer to the fetus

Abstract

The factors determining fatty acid transfer across the placenta are not fully understood. This study used a combined experimental and computational modeling approach to explore placental transfer of nonesterified fatty acids and identify the rate-determining processes. Isolated perfused human placenta was used to study the uptake and transfer of ¹³C-fatty acids and the release of endogenous fatty acids. Only 6.2 ± 0.8% of the maternal ¹³C-fatty acids taken up by the placenta was delivered to the fetal circulation. Of the unlabeled fatty acids released from endogenous lipid pools, 78 ± 5% was recovered in the maternal circulation and 22 ± 5% in the fetal circulation. Computational modeling indicated that fatty acid metabolism was necessary to explain the discrepancy between uptake and delivery of ¹³C-fatty acids. Without metabolism, the model overpredicts the fetal delivery of ¹³C-fatty acids 15-fold. Metabolic rate was predicted to be the main determinant of uptake from the maternal circulation. The microvillous membrane had a greater fatty acid transport capacity than the basal membrane. This study suggests that incorporation of fatty acids into placental lipid pools may modulate their transfer to the fetus. Future work needs to focus on the factors regulating fatty acid incorporation into lipid pools.

Keywords: compartmental modelling; dual placental perfusion; fatty acids; lipid computational model; placenta; placental transport.

Fig. 1.

Compartmental model schematic for fatty acid transfer across the placenta. R is the maternal reservoir; M is the maternal intervillous space; S is the syncytiotrophoblast fatty acid pool (intracellular fatty acids available for transport) and P is the metabolic pool, both contained in the syncytiotrophoblast volume; and F is the fetal compartment of the placenta, representing the fetal capillary volume. The maternal circulation was perfused in closed circuit with flow Q_M = 8.4 ml/min. J_MVM and J_BM (μmol/min) are the net fluxes across the placental membranes MVM and BM, respectively. J_acc and J_rel (μmol/min) are the metabolic fluxes representing the accumulation and release due to placental metabolism. The fetal circulation was perfused in an open circuit with flow Q_F = 4 ml/min.

Fig. 2.

Experimental data versus model prediction for palmitic acid. A: Data for the ¹³C-palmitic acid (¹³C-PA) added to the maternal reservoir. B: Data for the endogenous palmitic acid (C16:0) released from placental tissue. The experimental data are represented as hollow circles and the model predictions by solid and dashed lines. The syncytiotrophoblast prediction (S) is represented by a dashed line due to the lack of measurements available to compare with the model.

Fig. 3.

Comparison of ¹³C-fatty acid uptake and transfer in the perfused placenta. A: ¹³C-fatty acid taken up by the placenta from the maternal circulation as a percentage of the amount initially present in the reservoir. B: ¹³C-fatty acid delivered to the fetal circulation as a percentage of the amount taken up by the placenta. ¹³C-LA, linoleic acid-labeled fatty acid; ¹³C-OA, oleic acid-labeled fatty acid; ¹³C-PA, palmitic acid-labeled fatty acid. No statistical differences were found. Data are expressed as mean ± SEM (n = 6).

Fig. 4.

The release of endogenous fatty acids from the perfused placenta: mass balance results (t = 0–180 min). A: Endogenous fatty acid release by the placenta. B: Percentages of the fatty acid release recovered in the maternal circulation and in the fetal circulation as part of the total released. Maternal recovery was significantly higher than fetal recovery for all fatty acids except C20:5n3 (P < 0.01). All values are expressed as mean ± SEM (n = 6).

Fig. 5.

Maximum transport rate model parameters for MVM and BM. A: ¹³C-LA, linoleic acid-labeled fatty acid; ¹³C-OA, oleic acid-labeled fatty acid; ¹³C-PA, palmitic acid-labeled fatty acid. B: Endogenous fatty acids membrane rate capacities (marked with “a”) differed from the rest of the endogenous fatty acids except those marked with “b” (P < 0.01), which were not different from the rest of the substrates (P < 0.05). Fatty acids marked with “c” differed from the rest of the endogenous fatty acids (P < 0.05). All values are expressed as mean ± SEM (n = 6).

Fig. 6.

Endogenous fatty acid model parameter estimation for the metabolic pool pathway. A: Metabolic pool release pathway rate constant (k_r0,endo, μmol/l/min). The substrates labeled “a” differed from the rest of the endogenous fatty acids (P < 0.01). B: Metabolic pool accumulation pathway constant (k_a, per minute). Substrates labeled “a” differ from the rest of the endogenous fatty acids. Substrates labeled “b” differ from the rest of the endogenous fatty acids but not within the same group (P < 0.01). Substrates labeled “c,” “d,” and “e” differed from the rest of the endogenous fatty acids but not within the same group (P < 0.01). All values are expressed as mean ± SEM (n = 6).

Fig. 7.

Sensitivity analysis for the model parameters with respect to the total uptake and delivery of ¹³C-palmitic acid (¹³C-PA). The x axis represents the fold change in parameters compared with the reference values. v_MVM, and v_BM are the maximum flux capacities of the MVM and BM, respectively. k_a,tra and k_r,tra are the accumulation and release rate constants for placental metabolism. K is the fatty acid membrane dissociation constant. Q_M and Q_F are the maternal and fetal flow rates. V_R, V_M, V_S, and V_F are the volumes of the reservoir, maternal intervillous, syncytiotrophoblast, and fetal capillary compartments, respectively. The y axis represents the change in the amount of either uptake or delivery of ¹³C-PA. A: Analysis of the estimated parameters with respect to the uptake. B: Analysis of the model parameters with respect to the uptake. C: Analysis for the estimated parameters with respect to the delivery. D: Analysis of the estimated parameters with respect to the delivery.

Fig. 8.

Experimental data can be represented over a wide range of MVM transport capacities v_MVM, as long as the metabolic accumulation rate constant k_a is adjusted. Results for ¹³C-PA are shown. The MVM rate capacity v_MVM (x axis) was varied over a range of fixed values, and the other unknown parameters were fitted again for each value of v_MVM to best represent the data. The red and yellow lines indicate the R² for the maternal-side concentrations and fetal-side concentrations after the initial phase (t ≥ 10 min). The left vertical line (dashed) is the minimum value of v_MVM below which the experimental uptake could not be represented (see text). The right vertical black line (dotted) indicates the best fit found previously. Higher values of v_MVM tend to equalize the maternal and syncytiotrophoblast fatty acid concentrations in the model (C_s normalized by the maternal vein measurement at 90 min of perfusion). This implies that for high v_MVM uptake is only determined by k_a, which approaches a constant value. Results are similar for the other fatty acids. The fluctuations in v_BM on the left are because this parameter cannot be fitted if the syncytiotrophoblast concentrations available for transport C_s are too low.