The ANGPTL3-4-8 Axis in Normal Gestation and in Gestational Diabetes, and Its Potential Involvement in Fetal Growth

Figures

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  Figure 1. ANGPTL response to a meal test. The figure shows time curves of serum ANGPTL3, 4, and 8 in healthy control pregnant women (A) and in GDM women (C) during a meal test (fold increase over basal values). (B,D) show the Area Under the Curve values (AUC) of ANGPTL3, 4, and 8 in healthy control pregnant women and GDM women, respectively. Data are mean ± S.E.M. AUC differences were assessed by Kruskal–Wallis test, followed by Dunnett’s correction, and the time curves were compared using repeated measures ANOVA with Bonferroni post hoc test (p-values refer to differences among ANGPTLs curves). ** p < 0.01. HC: healthy control; GDM: gestational diabetes; ANGPTL3: Angiopoietin-Like Protein 3; ANGPTL4: Human Angiopoietin-Like Protein 4; ANGPTL8: Human Angiopoietin-Like Protein 8.

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  Figure 2. Comparison of gene expression in distinct parts of the placenta. (A) Heatmap comparing ANGPTLs, lipoprotein lipase and lipid transport gene expressions as a ratio between the fetal and maternal side of the placenta (left panel) in healthy control women (n = 19 in each of them) and (right panel) in the gestational diabetes group (n = 20). (B) Heatmap comparing ANGTPL3, 4, and 8 expressions on both sides of the placenta according to glucose tolerance status (HC vs. GDM). Data are represented as log2 (F/M ratio) (A) and log2 (fold change) (B). Differences assessed by two-way ANOVA multiple comparison test, followed by Bonferroni correction. Data are normalized to intraindividual gene expression on the maternal side of the placenta (A) and to the mean of the control group for each gene and side (B) and are shown as means. M and F indicate gene expressions on the maternal and fetal sides of the placenta, respectively. * p < 0.05; *** p < 0.001. HC: healthy control; GDM: gestational diabetes. ANGPTL3: Angiopoietin-Like Protein 3; ANGPTL4: Human Angiopoietin-Like Protein 4; ANGPTL8: Human Angiopoietin-Like Protein 8; LPL: Lipoprotein Lipase, CD36: Cluster of Differentiation 36; SLC27A1,…

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  Figure 3. ANGPTL expression is associated with offspring parameters in the GDM group. Heatmap of the correlation coefficients observed between ANGPTL3, 4, and 8 placental expressions and neonatal clinical variables in control (A) and GDM (B) mothers. Gene expression data are expressed as fold change. Correlations were calculated using Spearman’s correlation coefficient. * p < 0.05. HC: healthy control; GDM: gestational diabetes mellitus; M before the name of any gene expression indicates expression on the maternal side of the placenta; F before the name of any gene expression indicates expression on the fetal side of the placenta. ANGPTL3: Angiopoietin-Like Protein 3; ANGPTL4: Human Angiopoietin-Like Protein 4; ANGPTL8: Human Angiopoietin-Like Protein 8.

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  Figure 4. The relationship between the expressions of ANGPTL3, 4 and 8 and the expressions of genes involved in placental lipid transport is modified in gestational diabetes. Heatmap of the correlation coefficients observed between ANGPTL3, 4, and 8 placental expressions and the expressions of genes involved in lipid transport in control (A) and GDM (B) mothers. Gene expression data are expressed as fold change. Correlations were calculated using Spearman’s correlation coefficient. * p < 0.05. HC: healthy control; GDM: gestational diabetes mellitus; M before the name of any gene expression indicates expression on the maternal side of the placenta; F before the name of any gene expression indicates expression on the fetal side of the placenta. ANGPTL3: Angiopoietin Like Protein 3; ANGPTL4: Human Angiopoietin-Like Protein 4; ANGPTL8: Human Angiopoietin-Like Protein 8; LPL: Lipoprotein Lipase, CD36: Cluster of Differentiation 36; SLC27A1, SLC27A2, SLC27A4, and SLC27A6: Solute Carrier Family 27 Members 1, 2, 4, and 6, respectively; FABP1 and FABP3: Fatty Acid Binding Proteins 1 and 3, respectively; CPT1A and CPT1B: Carnitine Palmitoyltransferase 1A and 1B, respectively.