H19 lncRNA alters methylation and expression of Hnf4α in the liver of metformin-exposed fetuses.
H19 lncRNA alters methylation and expression of Hnf4α in the liver of metformin-exposed fetuses.
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DOI：
10.1038/cddis.2017.392
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发表时间：
2017-12-07
影响因子：
9
通讯作者：
Huang Y
中科院分区：
文献类型：
--
作者：
Deng J;Mueller M;Geng T;Shen Y;Liu Y;Hou P;Mamillapalli R;Taylor HS;Paidas M;Huang Y
二甲双胍是全球使用最广泛的抗糖尿病药物。然而，人类和动物研究表明，产前二甲双胍暴露可能会增加成年后代代谢紊乱的风险，但其基础机制仍不清楚。在这里，我们报告了二甲双胍暴露的小鼠胎儿表现出H19长非编码RNA的表达升高，这诱导低甲基化和肝细胞核因子4α（HNF 4 α）的表达增加。HNF 4 α作为肝细胞形态和功能分化所必需的转录因子，在促肝细胞分化基因的表达调控中也发挥着不可或缺的作用。一致地，人类肝细胞系中H19的过表达导致甲基化降低和Hnf 4 α表达增加，同时糖异生程序被激活。从机制上讲，我们发现Hnf 4 α的甲基化变化是由H19介导的S-腺苷高半胱氨酸水解酶调节诱导的。我们还提供了证据表明H19表达的改变是二甲双胍对胎肝的直接影响。我们的研究结果表明，来自母亲的二甲双胍可以直接作用于胎儿肝脏，改变Hnf 4 α表达，这是肝脏发育和功能的关键因素，并且这种H19/Hnf 4 α介导的途径的干扰可能有助于成人代谢异常的胎儿起源。
Metformin is the most widely used anti-diabetic medication worldwide. However, human and animal studies suggest that prenatal metformin exposure may increase the risk of metabolic disorders in adult offspring, yet the underpinning mechanism remains unclear. Here we report that metformin-exposed mouse fetuses exhibit elevated expression of the H19 long noncoding RNA, which induces hypomethylation and increased expression of hepatocyte nuclear factor 4α (HNF4α). As a transcription factor essential for morphological and functional differentiation of hepatocytes, HNF4α also has an indispensable role in the regulation of expression of gluconeogenic genes. Consistently, H19 overexpression in a human liver cell line leads to decreased methylation and increased expression of Hnf4α, with concomitant activation of the gluconeogenic program. Mechanistically, we show that the methylation change of Hnf4α is induced by H19-mediated regulation of S-adenosylhomocysteine hydrolase. We also provide evidence that altered H19 expression is a direct effect of metformin in the fetal liver. Our results suggest that metformin from the mother can directly act upon the fetal liver to modify Hnf4α expression, a key factor for both liver development and function, and that perturbation of this H19/Hnf4α-mediated pathway may contribute to the fetal origin of adult metabolic abnormalities.
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影响因子：
4.8
作者：
Naiki, T;Nagaki, M;Moriwaki, H
通讯作者：
Moriwaki, H
影响因子：
3.7
作者：
Salomaki, Henriikka;Heinaniemi, Merja;Koulu, Markku
通讯作者：
Koulu, Markku
DOI：
10.1038/nrd.2016.151
发表时间：
2016-11
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Rines AK;Sharabi K;Tavares CD;Puigserver P
通讯作者：
Puigserver P
影响因子：
--
作者：
MCCANCE, DR;PETTITT, DJ;BENNETT, PH
通讯作者：
BENNETT, PH
DOI：
10.1152/ajpregu.2001.281.3.r960
发表时间：
2001-09-01
影响因子：
2.8
作者：
Moss, TJM;Sloboda, DM;Newnham, JP
通讯作者：
Newnham, JP