Intrauterine programming mechanism for hypercholesterolemia in prenatal caffeine‐exposed female adult rat offspring
Intrauterine programming mechanism for hypercholesterolemia in prenatal caffeine‐exposed female adult rat offspring
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DOI：
10.1096/fj.201701557r
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发表时间：
2018-05
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通讯作者：
Dan Xu;Hanwen Luo;Wen Hu;Shuwei Hu;Chaoqun Yuan;Guihua Wang;Li Zhang;Hong Yu;J. Magdalou-J.-Magdalo
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作者：
Dan Xu;Hanwen Luo;Wen Hu;Shuwei Hu;Chaoqun Yuan;Guihua Wang;Li Zhang;Hong Yu;J. Magdalou-J.-Magdalo
临床和动物研究表明，高胆固醇血症及其相关疾病与宫内发育有关。我们以前的研究表明，产前咖啡因暴露(PCE)会导致胎儿过度接触母体糖皮质激素(GCs)，并导致成年大鼠子代血清总胆固醇水平升高。这项研究进一步证实了PCE诱导的雌性成年大鼠子代高胆固醇血症的宫内编程。Wistar孕鼠分别于孕9~20天灌胃咖啡因(30、60、120 mg/kg/d)，雌鼠分别于20天和12天处死，部分成年大鼠在生前进行冰水游泳刺激，诱导慢性应激。用L02细胞株验证了GCs对胆固醇代谢和表观遗传调节的影响。结果表明，PCE可引起成年子代高胆固醇血症，表现为血清总胆固醇和低密度脂蛋白(LDL-C)水平显著升高，低密度脂蛋白/高密度脂蛋白(LDL-C)/高密度脂蛋白(HDL-C)比值升高。我们进一步发现，胎儿肝脏中的胆固醇水平增加，但胎儿血液中的胆固醇水平下降，同时伴随着母亲血液中胆固醇水平的上升和胎盘胆固醇转运的减少。此外，对子宫内和出生后基础/慢性应激状态下的PCE后代的分析和体外实验结果表明，肝脏胆固醇代谢发生了GC依赖的变化，并通过3-羟基-3-甲基戊二酰辅酶A还原酶(HMGCR)组蛋白乙酰化异常与胆固醇合成酶相关。我们的结论是，为了补偿宫内胎盘来源的胎儿血胆固醇水平的下降，宫内高水平的GC激活了胎儿肝脏CCAAT增强子结合蛋白α信号，下调了Sirtuin1的表达，从而介导组蛋白乙酰化(通过H3K9ac和H3K14ac)和HMGCRs的高水平表达。这种依赖GC的胆固醇代谢编程效应持续到成年期，导致高胆固醇血症的发生。-Xu，D.，罗，H.W.，Hu，W.，Hu，S.W.，袁，C.，Wang，G.H.，Zhang，L.，Yu，H.，Magdalou，J.，Chen，L.B.，Wang，H.出生前接触咖啡因的雌性成年大鼠后代高胆固醇血症的宫内编程机制。FASE B J.32,5563-5576(2018)。Www.fasebj.org
Clinical and animal studies have indicated that hypercholesterolemia and its associated diseases have intrauterine developmental origins. Our previous studies showed that prenatal caffeine exposure (PCE) led to fetal overexposure to maternal glucocorticoids (GCs) and increased serum total cholesterol levels in adult rat offspring. This study further confirms the intrauterine programming of PCE‐induced hypercholesterolemia in female adult rat offspring. Pregnant Wistar rats were intragastrically administered caffeine (30, 60, and 120 mg/kg/d) from gestational day (GD)9 to 20. Female rat offspring were euthanized at GD20 and postnatal wk 12; several adult rat offspring were additionally subjected to ice‐water swimming stimulation to induce chronic stress prior to death. The effects of GCs on cholesterol metabolism and epigenetic regulation were verified using the L02 cell line. The results showed that PCE induced hypercholesterolemia in adult offspring, which manifested as significantly higher levels of serum total cholesterol and LDL cholesterol (LDL‐C) as well as higher ratios of LDL‐C/HDL cholesterol. We further found that the cholesterol levels were increased in fetal livers but were decreased in fetal blood, accompanied by increased maternal blood cholesterol levels and reduced placental cholesterol transport. Furthermore, analysis of PCE offspring in the uterus and in a postnatal basal/chronic stress state and the results of in vitro experiments showed that hepatic cholesterol metabolism underwent GC‐dependent changes and was associated with cholesterol synthase via abnormalities in 3‐hydroxy‐3‐methylglutaryl‐CoA reductase (HMGCR) histone acetylation. We concluded that, to compensate for intrauterine placentally derived decreases in fetal blood cholesterol levels, high intrauterine GC levels activated fetal hepatic CCAAT enhancer binding protein α signaling and down‐regulated Sirtuin1 expression, which mediated the high levels of histone acetylation (via H3K9ac and H3K14ac) and expression of HMGCR. This GC‐ dependent cholesterol metabolism programming effect was sustained through adulthood, leading to the occurrence of hypercholesterolemia.—Xu, D., Luo, H. W., Hu, W., Hu, S. W., Yuan, C., Wang, G. H., Zhang, L., Yu, H., Magdalou, J., Chen, L. B., Wang, H. Intrauterine programming mechanism for hypercholesterolemia in prenatal caffeine‐exposed female adult rat offspring. FASEB J. 32, 5563–5576 (2018). www.fasebj.org