Hepatic miR-378 modulates serum cholesterol levels by regulating hepatic bile acid synthesis.
Hepatic miR-378 modulates serum cholesterol levels by regulating hepatic bile acid synthesis.
复制标题
肝脏 miR-378 通过调节肝胆汁酸合成来调节血清胆固醇水平
作者：
Sun C;Liu W;Lu Z;Li Y;Liu S;Tang Z;Yan Y;Li Z;Feng H;Zhang D;Liu Y;Fang ZZ;Jiang C;Ding Q;Jiang J;Ying H
基本原理：对甲状腺激素（TH）对胆固醇代谢作用的进一步了解将有助于确定高胆固醇血症的新治疗靶点。TH调节的microRNA（miRNAs）参与TH控制的生物学过程;然而，TH调节的miRNAs是否以及如何介导TH的降胆固醇作用仍不清楚。我们的目的是鉴定TH调节的具有降胆固醇作用的microRNA并探索其潜在机制。方法：通过微阵列和RNA-seq技术分别鉴定小鼠肝脏TH调控的microRNA和mmu-miR-378- 3 p（miR-378）调控的基因。采用编码miR-378、Mafg和针对Mafg的shRNA、miR-378、肝脏特异性miR-378转基因小鼠和miR-378敲除小鼠的重组腺病毒来研究肝脏miR-378和MAFG在胆固醇和胆汁酸稳态中的作用。通过使用UFLC-Triple-time of Flight/MS测定胆盐种类的水平。结果：在这里，我们表明肝脏miR-378受到TH的正调控。小鼠肝脏中miR-378的瞬时过表达降低了血清胆固醇水平，伴随着初级胆汁酸合成途径中关键酶表达的增加以及胆汁和粪便胆汁酸水平的相应增加。一致地，具有肝脏miR-378中度过表达的肝脏特异性miR-378转基因小鼠显示出降低的血清胆固醇水平和对饮食诱导的高胆固醇血症的抗性，而缺乏miR-378的小鼠显示出胆汁酸和胆固醇稳态的缺陷。从机制上讲，肝脏miR-378通过转录抑制因子MAFG调节经典和替代胆汁酸合成途径中关键酶的表达，从而调节胆汁酸和胆固醇代谢。结论：TH响应性肝脏miR-378能够通过调节经典和替代BA合成途径来调节血清胆固醇水平。我们的研究不仅确定了肝脏miR-378以前未描述的作用，还提供了新的降胆固醇方法。
Rationale: An improved understanding of thyroid hormone (TH) action on cholesterol metabolism will facilitate the identification of novel therapeutic targets for hypercholesterolemia. TH-regulated microRNAs (miRNAs) have been implicated in TH-controlled biological processes; however, whether and how TH-regulated miRNAs mediate the cholesterol-lowering effect of TH remains unclear. Our aim was to identify TH-regulated microRNAs that have cholesterol-lowering effects and explore the underlying mechanism. Method: Microarray and RNA-seq were performed to identify TH-regulated microRNAs and the genes regulated by mmu-miR-378-3p (miR-378) in the liver of mice, respectively. Recombinant adenoviruses encoding miR-378, Mafg, and shRNA for Mafg, antagomiR-378, liver-specific miR-378 transgenic mice, and miR-378 knockout mice were employed to investigate the roles of hepatic miR-378 and MAFG in cholesterol and bile acid homeostasis. The levels of bile salt species were determined by using UFLC-Triple-time of flight/MS. Results: Here, we show that hepatic miR-378 is positively regulated by TH. Transient overexpression of miR-378 in the liver of mice reduces serum cholesterol levels, accompanied with an increase in the expression of key enzymes in primary bile acid synthetic pathways and corresponding increases in biliary and fecal bile acid levels. Consistently, liver-specific miR-378 transgenic mice with moderate overexpression of hepatic miR-378 display decreased serum cholesterol levels and resistance to diet-induced hypercholesterolemia, while mice lacking miR-378 exhibit defects in bile acid and cholesterol homeostasis. Mechanistically, hepatic miR-378 regulates the expression of key enzymes in both classic and alternative bile acid synthetic pathways through MAFG, a transcriptional repressor, thereby modulating bile acid and cholesterol metabolism. Conclusions: TH-responsive hepatic miR-378 is capable of modulating serum cholesterol levels by regulating both the classic and alternative BA synthetic pathways. Our study not only identifies a previously undescribed role of hepatic miR-378 but also provides new cholesterol-lowering approaches.
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