High Maternal Serum Estradiol Levels Induce Dyslipidemia in Human Newborns via a Hepatic HMGCR Estrogen Response Element.
High Maternal Serum Estradiol Levels Induce Dyslipidemia in Human Newborns via a Hepatic HMGCR Estrogen Response Element.
复制标题
高母生血清雌二醇水平通过肝HMGCR雌激素反应元件诱导人类新生儿的血脂异常。
DOI：
10.1038/srep10086
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发表时间：
2015-05-11
影响因子：
4.6
通讯作者：
Huang HF
中科院分区：
文献类型：
--
作者：
Meng Y;Lv PP;Ding GL;Yu TT;Liu Y;Shen Y;Hu XL;Lin XH;Tian S;Lv M;Song Y;Guo MX;Ke ZH;Xu H;Sheng JZ;Shi FT;Huang HF
虽然宫内环境对后代的健康至关重要，但高母体血清雌二醇（E2）对后代脂质代谢的影响及其机制尚不清楚。我们发现，卵巢刺激（OS）可导致整个妊娠期妇女的E2水平升高。引人注目的是，他们的新生儿显示出总胆固醇（TC）和低密度脂蛋白胆固醇（LDL-C）水平升高，与新生儿中的E2呈正相关。在体外，E2剂量依赖性地刺激TC和LDL-C分泌，并增加胆固醇合成限速酶3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR）在HepG 2细胞和小鼠胎肝细胞中的表达。在体内，在OS小鼠模型中检测到高母体E2，并且胎肝也显示出显著更高的HMGCR表达。值得注意的是，在HMGCR启动子中发现了雌激素反应元件（ERE），这表明高母体血清E2可以通过ERE上调胎儿肝细胞中HMGCR的表达，从而诱导后代TC和LDL-C水平升高。结论：OS可诱导高母体E2环境，其通过启动子中的ERE上调胎肝细胞中的HMGCR表达，并诱导新生儿TC和LDL-C水平升高，这可能与成年期代谢疾病风险增加有关。
While the intrauterine environment is essential for the health of offspring, the impact of high maternal serum estradiol (E2) on lipid metabolism in offspring and the mechanisms are unknown. We found that ovarian stimulation (OS) could result in high E2 levels in women throughout pregnancy. Strikingly, their newborns showed elevated total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels that were positively related with E2 in newborns. In vitro, E2 dose-dependently stimulated TC and LDL-C secretion, and increased expression of the cholesterol synthesis rate-limiting enzyme 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) in HepG2 cells and mouse fetal hepatocytes. In vivo, high maternal E2 was detected and fetal livers also showed significantly higher HMGCR expression in an OS mouse model. Notably, an estrogen response element (ERE) was identified in the HMGCR promoter, indicating that high maternal serum E2 could up-regulate HMGCR expression in fetal hepatocytes via an ERE that in turn induces elevated levels of TC and LDL-C in offspring. Conclusion: OS can induce a high maternal E2 environment, which up-regulates HMGCR expression in fetal hepatocytes via an ERE in the promoter, and induces elevated levels of TC and LDL-C in newborns that may be related to increased risk of metabolic disease in adulthood.
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