孕前超重/肥胖对人体胎盘和小鼠相关组织维生素D代谢酶的影响

PRE-PREGNANCY OBESITY ALTERS VITAMIN D METABOLISM RELATED ENZYMES EXPRESSION IN HUMAN PLACENTA AND MOUSE TISSUES

目的本研究旨在探讨孕前超重/肥胖是否会影响人胎盘和小鼠相关组织中维生素D代谢酶的表达。方法(1)99名正常体重女性(18.5 kg/m^(2)≤BMI<23.9 kg/m^(2))和48名孕前超重/肥胖妇女(BMI≥24.0 kg/m^(2))参与本横断面研究,产妇和新生儿信息通过问卷获得。孕妇自然分娩,分娩后采集胎盘样本。(2)将4w龄雌性C57BL/6J小鼠采用对照饮食(Ctrl)或高脂饮食(HFD)喂养10w。根据其体重比Ctrl组平均值大的百分比,将HFD喂养的小鼠分为肥胖抵抗(DIR,<10%)、超重(DIW,10%~20%)和肥胖(DIO,>20%)组,于PND21处死。检测人鼠血浆总25羟基维生素D[25(OH)D],人胎盘和小鼠胎盘和肝脏维生素D代谢酶基因和蛋白质表达水平。结果与正常体重相比,孕前超重/肥胖的孕妇血浆中总25(OH)D和1,25(OH)_(2)D_(3)的浓度显著降低。此外,孕前超重/肥胖与脐带血浆中1,25(OH)_(2)D_(3)浓度有相关性。孕前超重/肥胖胎盘中1a羟化酶(CYP27B1)、转运受体(LRP2-CUBN)和维生素D受体(VDR)的表达降低,而24羟化酶蛋白(CYP24A1)的表达呈相反趋势。在小鼠中,DIR、DIW、DIO的母体血浆中总25(OH)D和1,25(OH)_(2)D_(3)的浓度明显低于Ctrl;DIO组胎鼠血浆总25(OH)D浓度明显低于Ctrl组;HFD母体肝脏25羟化酶(CYP2R1)、VDR以及肾脏和胎盘中的CYP27B1、LRP2、CUBN、VDR的表达显著降低,CYP24A1的表达显著增加。胎鼠的结果与母鼠的结果相似。结论孕前超重/肥胖对人体胎盘和小鼠相关组织的维生素D代谢酶(CYP2R1、CYP27B1、CYP24A1、LRP2-CUBN、VDR)表达有影响,这可能是超重/肥胖孕妇和胎儿维生素D水平较低的原因。

Objective To investigate whether pre-pregnancy obesity alters the expression of vitamin D metabolism enzymes in human placenta and mouse tissues.Methods (1)Ninety-nine normal-weight women (18.5kg/m^(2)≤BMI<23.9kg/m^(2))and 48 women with pre-pregnancy overweight/obesity (BMI≥24.0kg/m^(2)) participated in this cross-sectional study.Maternal and neonatal information was obtained through questionnaires.Placenta samples were collected after parturition.(2)Four-week-old female C57BL/6J mice were fed a control diet (Ctrl) or a high fat diet (HFD) for ten weeks.Based on their body weights as percent greater than the mean of the Ctrl,HFD-fed mice were divided into diet-induced obesity-resistant(DIR;<10%),diet-induced overweight (DIW;10%-20%),and diet-induced obese (DIO;>20%) groups.All the females were mated and maintained their diet.Plasma total 25-hydroxyvitamin D (25(OH)D),1,25-dihydroxycholecalciferol(1,25(OH)_(2)D_(3)),vitamin D metabolism-related genes and proteins expression in human placentas and murine tissues were quantified.Results Human maternal plasma total 25(OH)D and 1,25(OH)_(2)D_(3) were significantly lower in pre-pregnancy overweight/obesity than in normal-weight.Moreover,pre-pregnancy overweight/obesity was associated with lower concentrations in cord plasma.Pre-pregnancy overweight/obesity decreased the expression of 1a-hydroxylase (CYP27B1),LDL-related protein 2-cublin (LRP2-CUBN) and vitamin D receptor (VDR) in placentas,while 24-hydroxylase (CYP24A1)protein expression showed a contrary trend.In mice,maternal plasma total 25(OH)D and 1,25(OH)_(2)D_(3)DIR,DIW,DIO groups were significantly lower than in the Ctrl group.Fetal plasma total 25(OH)D concentrations were significantly lower in the DIO group than in the Ctrl group.The expressions of maternal 25-hydroxylase (CYP2R1),VDR in the liver and CYP27B1,LRP2,CUBN,VDR in the kidney and placenta were significantly decreased in mice fed HFD,while CYP24A1 was significantly increased.The changes in fetal mice were similar to those in maternal mice.Conclusion The expressions of vitamin D metabolism enzymes (CYP2R1,CYP27B1,CYP24A1,LRP2-CUBN,VDR) in human placenta and murine tissues were influenced by pre-pregnancy obesity,which may explain lower vitamin D levels in maternal and fetal bodies.