Modulation of Cholesterol Transport by Insulin-Treated Gestational Diabetes Mellitus in Human Full-Term Placenta1

Abstract

Gestational diabetes mellitus (GDM) is a common complication of pregnancy that is characterized by glucose intolerance, leads to dyslipidemia, and is aggravated by obesity. Cholesterol is taken up by the placenta as part of lipoproteins through the scavenger receptor class B type I receptor (SRBI), low-density lipoprotein receptor (LDLR), and very low density lipoprotein receptor (VLDLR), and its efflux is then mediated by ABCA1 and ABCG1. PCSK9 is involved in the degradation of LDLR and VLDLR. The goal of this study was to evaluate the impact of GDM and prepregnancy body mass index (BMI) on cholesterol transport through the modulation of the expression of several key players. Human full-term placenta, maternal, and venous cord blood samples were obtained at delivery from normal-weight women without GDM (n = 10), normal-weight women with GDM (n = 6), and overweight/obese women with GDM (n = 6). Lipids (total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, free fatty acids, apolipoprotein A1, apolipoprotein B100) levels were evaluated in blood samples. Messenger RNA and protein expression levels (LDLR, VLDLR, SRBI, ABCA1, ABCG1, proprotein convertase subtilisin/kexin type 9, liver x receptors, peroxisome proliferator-activated receptors) were assessed in human full-term placenta, respectively, by real-time RT-PCR and Western blots. Lipoprotein lipase activity was evaluated using a commercial kit on tissue homogenates. Overall, our study demonstrates that GDM affects the maternal and neonatal lipid profiles as well as different key players of placental cholesterol transfer from the maternal to the fetal circulation, depending on the maternal BMI. These changes could affect the fetal metabolism and predispose the fetus to future metabolic diseases.

Gestational diabetes mellitus modulates neonatal high-density lipoprotein composition and its functional heterogeneity

“…Moreover, cholesterol transfer from the maternal to the neonatal circulation via the placenta might be also affected by GDM through the modulation of the expression of key receptors. Dubé et al suggested that reduced expression of ABCG1 in GDM pregnancies could be part of a compensatory mechanism to limit excessive transfer of cholesterol to the neonatal circulation; in addition, the decreased expression of ABCA1 could reflect an accumulation of cholesterol into the placenta even if the placental weight does not change in GDM pregnancies [31]. This could explain why the levels of total cholesterol, HDL, and LDL were not affected in cord blood of GDM pregnancies.…”

Adaptations of placental and cord bloodABCA1 DNA methylation profile to maternal metabolic status

“…Moreover, the reduction of placental ABCA1 mRNA has already been reported in obese and normal weight subjects with IGT and suggested to impair placental cholesterol-uptake and transport. 38 Although ABCA1 Figure 2. Placental ABCA1-cpG5 and -cpG6 DNa methylation levels according to maternal and newborn metabolic profile.…”

Review: Placental transport and metabolism of energy substrates in maternal obesity and diabetes

“…Lipid modifications were not as common in placentae from women with type 1 253 diabetes and there was preferential activation of glycosylation and acylation pathways. In 254 term placentae from normal weight or overweight/obese women with GDM, there were 255 variable effects on lipid pathways depending on BMI category, including alterations in the 256 expression of SRBI, LDLR, VLDLR, ABCA1, ABCG1, and proprotein convertase subtilisin/kexin 257 type 9 [77]. 258…”