MicroRNA Let-7 targets AMPK and impairs hepatic lipid metabolism in offspring of maternal obese pregnancies.
MicroRNA Let-7 targets AMPK and impairs hepatic lipid metabolism in offspring of maternal obese pregnancies.
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DOI：
10.1038/s41598-021-88518-8
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发表时间：
2021-04-26
影响因子：
4.6
通讯作者：
Torsoni AS
中科院分区：
文献类型：
--
作者：
Simino LAP;Panzarin C;Fontana MF;de Fante T;Geraldo MV;Ignácio-Souza LM;Milanski M;Torsoni MA;Ross MG;Desai M;Torsoni AS
妊娠期间的营养状况可能会导致一种称为代谢编程的现象，这种现象可以由表观遗传机制触发。Let-7家族是最早被发现的microRNA之一，与代谢过程密切相关。生物信息学分析显示，编码AMPK α2的基因Prkaa 2是Let-7的预测靶标。在此，我们旨在研究Let-7是否在母体肥胖导致的后代NAFLD发展中对AMPKα2水平起作用。Let-7水平在肥胖母鼠的新生小鼠肝脏中上调，而Prkaa 2水平下调。Let-7水平与血清葡萄糖、胰岛素和NEFA密切相关，并且用葡萄糖和NEFA体外处理AML 12导致更高的Let-7表达。转染Let-7a模拟物导致AMPKα2水平下调，而转染Let-7a抑制剂则削弱NEFA介导的Prkaa 2水平降低和NEFA驱动的脂肪蓄积。Let-7a抑制剂在肥胖母鼠后代的离体肝切片中的转染恢复了磷酸化AMPK α2水平。总之，Let-7a似乎调节肝脏AMPKα2蛋白水平，并导致肥胖母鼠后代的早期肝脏代谢紊乱。
Nutritional status during gestation may lead to a phenomenon known as metabolic programming, which can be triggered by epigenetic mechanisms. The Let-7 family of microRNAs were one of the first to be discovered, and are closely related to metabolic processes. Bioinformatic analysis revealed that Prkaa2, the gene that encodes AMPK α2, is a predicted target of Let-7. Here we aimed to investigate whether Let-7 has a role in AMPKα2 levels in the NAFLD development in the offspring programmed by maternal obesity. Let-7 levels were upregulated in the liver of newborn mice from obese dams, while the levels of Prkaa2 were downregulated. Let-7 levels strongly correlated with serum glucose, insulin and NEFA, and in vitro treatment of AML12 with glucose and NEFA lead to higher Let-7 expression. Transfection of Let-7a mimic lead to downregulation of AMPKα2 levels, while the transfection with Let-7a inhibitor impaired both NEFA-mediated reduction of Prkaa2 levels and the fat accumulation driven by NEFA. The transfection of Let-7a inhibitor in ex-vivo liver slices from the offspring of obese dams restored phospho-AMPKα2 levels. In summary, Let-7a appears to regulate hepatic AMPKα2 protein levels and lead to the early hepatic metabolic disturbances in the offspring of obese dams.
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