Fatty Acid Binding Protein 4 Regulates Intracellular Lipid Accumulation in Human Trophoblasts

Abstract

Context: Maternal obesity, gestational diabetes (GDM), or type 2 diabetes (T2DM) is associated with altered lipid metabolism and fetal overgrowth. Objective: The objective of the study was to test the hypothesis that hyperlipidemia and hyperinsulinemia regulate lipid content and expression of lipid-trafficking proteins in human placental trophoblasts. Study Design: Pregnant women were prospectively enrolled for clinical specimens collection, and cultured human trophoblasts were used for experiments. Setting: This was a translational study conducted at an academic biomedical research center. Patients or Other Participants: Normal weight, obese, or obese with gestational diabetes or type 2 diabetes pregnant women (n = 10 in each group) undergoing scheduled cesarean delivery at term were enrolled. Interventions: Cultured primary human trophoblasts, exposed to insulin (10 nm) and/or fatty acids mix (1200 μm) in the absence or presence of an fatty acid binding protein 4 (FABP4) inhibitor or after small interfering RNA-mediated knockdown of FABP4. Main Outcome Measures: Serum lipid levels were analyzed in the maternal venous and fetal cord blood. Placental biopsies and cultured trophoblasts were analyzed for FABP expression and lipid accumulation. Results: Obese diabetic women and their fetuses had elevated serum triglyceride levels. Nonesterified fatty acids were elevated and triglycerides were reduced in placental villi from obese diabetic women, and this was accompanied by a 2.6-fold increase in FABP4 expression (P < 0.05). In primary human trophoblasts, fatty acids markedly increased the expression of FABP4 (20- to 40-fold, P < 0.05) and cellular triglyceride content (4-fold, P < 0.05), and this effect was attenuated by small interfering RNA-mediated knockdown of FABP4 or the selective FABP4 inhibitor BMS309403. Conclusions: Hyperlipidemia alters lipid content and increases the expression of FABP4 in trophoblasts. The reduced triglyceride content after FABP4 inhibition suggests that FABP4 is essential for trophoblast lipid accumulation.