miR-552-3p modulates transcriptional activities of FXR and LXR to ameliorate hepatic glycolipid metabolism disorder
miR-552-3p modulates transcriptional activities of FXR and LXR to ameliorate hepatic glycolipid metabolism disorder
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miR-552-3p 调节 FXR 和 LXR 的转录活性以改善肝脏糖脂代谢紊乱。
DOI：
10.1016/j.jhep.2020.07.048
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发表时间：
2021-01-01
影响因子：
25.7
通讯作者：
Ren, Jin
中科院分区：
文献类型：
--
作者：
Fan, Lei;Lai, Rongtao;Ren, Jin
背景和目标：miRNAs在细胞核中的定位已经知道了十多年，但miRNAs在细胞核中的确切功能尚未完全阐明。我们先前发现，核内miR-552- 3 p对基因转录具有抑制作用，并且含有特定的AGGTCA样序列，即核受体NR 1亚家族的顺式元件。本研究旨在探讨miR-552- 3 p及其AGGTCA样序列对NR 1 s的潜在影响及其在改善肝脏糖脂代谢中的应用。建立高脂高果糖饲料喂养小鼠和AAV 2/8-miR-552- 3 p转染db/db小鼠模型，研究miR-552 - 3 p对肝脏糖脂代谢的体内影响。通过荧光共振能量转移、下拉、电泳迁移率改变和染色质免疫沉淀分析来探索miR-552- 3 p调控NR 1 s的机制。采用RT-PCR方法分析NAFLD患者和正常对照肝活检组织中miR-552- 3 p的水平。结果：MiR-552- 3 p在体外可以抑制代谢基因表达，在体内对糖脂代谢表现出有益作用。核内miR-552- 3 p主要调节LXR α和FXR通路;这是通过其与AGGTCA的互补序列结合以调节LXR α和FXR的转录活性来实现的。此外，LXR α和FXR配体可以恢复miR-552- 3 p对基因表达和糖脂代谢的影响。此外，肝脏miR-552- 3 p的水平显着降低，在肝脏样本与NAFLD患者相比，normalcontrols.Conclusions：miR-552- 3 p调节LXR α和FXR的机制，揭示了一种新的方法，miRNA介导的基因调控。此外，miR-552- 3 p的体内有益作用和临床相关性表明，它可能是治疗糖脂代谢疾病的潜在治疗靶点。在此，我们表明miR-552- 3 p具有通过调节细胞核中LXR α和FXR的转录活性来改善肝脏糖脂代谢疾病的能力。这些发现提供了证据，证明miR-552- 3 p可能作为潜在的治疗靶点。(C)2020年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: The nuclear location of miRNAs has been known for more than a decade, but the exact function of miRNAs in the nucleus has not been fully elucidated. We previously discovered that intranuclear miR-552-3p has an inhibitory role on gene transcription and contains a particular AGGTCA-like sequence, the cis-elements of the NR1 subfamily of nuclear receptors. Here, we aim to explore the potential effect of miR-5523p and its AGGTCA-like sequence on NR1s and its possible application in improving hepatic glycolipid metabolism.Methods: RNA-seq, mass spectrometry, and bioinformatics analysis were used to reveal the possible pathways influenced by miR-552-3p. High fat-high fructose diet-fed mice and db/db mice transfected with AAV2/8-miR-552-3p were established to investigate the in vivo effects of miR-552-3p on hepatic glycolipid metabolism. Fluorescence resonance energy transfer, pull-down, electrophoretic mobility shift, and chromatin immuno-precipitation assays were performed to explore the mechanism by which miR-552-3p regulates NR1s. RT-PCR was conducted to analyse miR-552-3p levels in liver biopsies from patients with NAFLD and normal controls.Results: MiR-552-3p could inhibit metabolic gene expression in vitro and displayed beneficial effects on glycolipid metabolism in vivo. Intranuclear miR-552-3p primarily regulated the LXR alpha and FXR pathways; this was achieved by its binding to the complementary sequence of AGGTCA to modulate the transcriptional activities of LXR alpha and FXR. Moreover, LXR alpha and FXR ligands could restore the effects of miR-552-3p on gene expression and glycolipid metabolism. Additionally, the hepatic miR-552-3p level was significantly decreased in liver samples from patients with NAFLD compared to normal controls.Conclusions: The mechanism by which miR-552-3p modulates LXR alpha and FXR has revealed a new method of miRNA-mediated gene regulation. In addition, the beneficial effects in vivo and clinical relevance of miR-552-3p suggest that it might be a potential therapeutic target for the treatment of glycolipid metabolic disease.Lay summary: Glycolipid metabolic diseases, which have become a major public health concern worldwide, are triggered by abnormalities in lipid and glucose metabolism. Herein, we show that miR-552-3p has the ability to ameliorate hepatic glycolipid metabolic diseases by modulating the transcriptional activities of LXR alpha and FXR in the nucleus. These findings provide evidence that miR-552-3p may serve as a potential therapeutic target. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.