Obesity-Induced Down-Regulation of the Mitochondrial Translocator Protein (TSPO) Impairs Placental Steroid Production
Obesity-Induced Down-Regulation of the Mitochondrial Translocator Protein (TSPO) Impairs Placental Steroid Production
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DOI：
10.1210/jc.2014-2792
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发表时间：
2015-01-01
影响因子：
5.8
通讯作者：
Hauguel-de Mouzon, Sylvie
中科院分区：
文献类型：
--
作者：
Lassance, Luciana;Haghiac, Maricela;Hauguel-de Mouzon, Sylvie
背景：低浓度的雌二醇和孕酮是不良妊娠结局的标志，母体肥胖也是如此。在怀孕期间，胎盘胆固醇是性类固醇的唯一来源。胆固醇转运是性激素生物合成的限制步骤，主要由线粒体外膜中的转位蛋白介导。目的：研究母亲肥胖在胎盘性类固醇生物合成和转位蛋白调节中的作用。设计/对象：144名肥胖(体重指数30-35 kg/m(2))和90名瘦(体重指数19-25 kg/m(2))孕妇(分别为OP和LP)在预定足月剖宫产时招募。地点：本研究在俄亥俄州克利夫兰的MetroHealth医学中心进行。主要观察指标：测量孕妇的代谢成分(空腹血糖、胰岛素、瘦素、雌二醇、孕酮和总胆固醇)和胎盘重量。对胎盘(线粒体和膜分离)和脐血胆固醇值进行验证。结果：OP患者血浆雌二醇、孕酮水平明显低于LP患者(P<0.05)。母血和脐血胆固醇在组间无差异。OP胎盘组织中柠檬酸合成酶活性和线粒体密度的标志物线粒体DNA无明显变化，但线粒体胆固醇浓度降低了40%。OP胎盘组织中TSPO基因和蛋白表达降低2倍。体外培养的滋养层细胞通过脂多糖和长链饱和脂肪酸激活天然免疫通路，使TSPO的表达减少2-3倍(P<；0.05)。结论：妊娠期肥胖通过对线粒体TSPO的负性调节，损害了线粒体的类固醇合成功能。
Context: Low concentrations of estradiol and progesterone are hallmarks of adverse pregnancy outcomes as is maternal obesity. During pregnancy, placental cholesterol is the sole source of sex steroids. Cholesterol trafficking is the limiting step in sex steroid biosynthesis and is mainly mediated by the translocator protein (TSPO), present in the mitochondrial outer membrane.Objective: The objective of the study was to investigate the effects of maternal obesity in placental sex steroid biosynthesis and TSPO regulation.Design/Participants: One hundred forty-four obese (body mass index 30-35 kg/m(2)) and 90 lean (body mass index 19-25 kg/m(2)) pregnant women (OP and LP, respectively) recruited at scheduled term cesarean delivery. Placenta and maternal blood were collected.Setting: This study was conducted at MetroHealth Medical Center (Cleveland, Ohio).Main Outcome Measures: Maternal metabolic components (fasting glucose, insulin, leptin, estradiol, progesterone, and total cholesterol) and placental weight were measured. Placenta (mitochondria and membranes separated) and cord blood cholesterol values were verified. The expression and regulation of TSPO and mitochondrial function were analyzed.Results: Plasma estradiol and progesterone concentrations were significantly lower (P < .04) in OP as compared with LP women. Maternal and cord plasma cholesterol were not different between groups. Placental citrate synthase activity and mitochondrial DNA, markers of mitochondrial density, were unchanged, but the mitochondrial cholesterol concentrations were 40% lower in the placenta of OP. TSPO gene and protein expressions were decreased 2-fold in the placenta of OP. In vitro trophoblast activation of the innate immune pathways with lipopolysaccharide and long-chain saturated fatty acids reduced TSPO expression by 2- to 3-fold (P < .05).Conclusion: These data indicate that obesity in pregnancy impairs mitochondrial steroidogenic function through the negative regulation of mitochondrial TSPO.