miR-552-3p modulates transcriptional activities of FXR and LXR to ameliorate hepatic glycolipid metabolism disorder
文献类型：期刊论文
| 作者 | Fan, Lei2,3; Lai, Rongtao1; Ma, Ningning2,3,4; Dong, Yunxia2,3; Li, Yu2,3; Wu, Qian2; Qiao, Junwen2 ; Lu, Henglei2; Gong, Likun2,3; Tao, Zhouteng2
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| 刊名 | JOURNAL OF HEPATOLOGY
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| 出版日期 | 2021 |
| 卷号 | 74期号:1页码:8-19 |
| 关键词 | miR-552-3p Transcriptional gene regulation Intranuclear miRNAs Glycolipid metabolic disease NR1 subfamily |
| ISSN号 | 0168-8278 |
| DOI | 10.1016/j.jhep.2020.07.048 |
| 通讯作者 | Chen, Jing(jingchen@simm.ac.cn) ; Xie, Qing(xieqingrjh@163.com) ; Ren, Jin(jren@cdser.simm.ac.cn) |
| 英文摘要 | 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. |
| WOS关键词 | NUCLEAR RECEPTORS ; LIVER ; EXPRESSION ; AGONIST ; RXR |
| 资助项目 | `Personalized Medicines-Molecular Signature-based Drug Discovery and Development', Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12040333] ; National Natural Science Foundation of China[81870401] ; National Science and Technology Major Project `Key New Drug Creation and Manufacturing Program', China[2018ZX09101001-003-007] ; National Science and Technology Major Project `Key New Drug Creation and Manufacturing Program', China[2018ZX09201017-004] ; National Science and Technology Major Project `Key New Drug Creation and Manufacturing Program', China[2019 ZX09732002-013] ; Shanghai Committee of Science and Technology, China[18DZ2290200] |
| WOS研究方向 | Gastroenterology & Hepatology |
| 语种 | 英语 |
| WOS记录号 | WOS:000600406800003 |
| 出版者 | ELSEVIER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/296326]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Chen, Jing; Xie, Qing; Ren, Jin |
| 作者单位 | 1.Shanghai Jiao Tong Univ, Sch Med, Ruijin Hosp, Dept Infect Dis, 197 Ruijin 2nd Rd, Shanghai 200025, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Drug Safety Evaluat & Res, State Key Lab Drug Res, 501 Haike Rd, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, Beijing, Peoples R China 4.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China |
| 推荐引用方式 GB/T 7714 | Fan, Lei,Lai, Rongtao,Ma, Ningning,et al. miR-552-3p modulates transcriptional activities of FXR and LXR to ameliorate hepatic glycolipid metabolism disorder[J]. JOURNAL OF HEPATOLOGY,2021,74(1):8-19. |
| APA | Fan, Lei.,Lai, Rongtao.,Ma, Ningning.,Dong, Yunxia.,Li, Yu.,...&Ren, Jin.(2021).miR-552-3p modulates transcriptional activities of FXR and LXR to ameliorate hepatic glycolipid metabolism disorder.JOURNAL OF HEPATOLOGY,74(1),8-19. |
| MLA | Fan, Lei,et al."miR-552-3p modulates transcriptional activities of FXR and LXR to ameliorate hepatic glycolipid metabolism disorder".JOURNAL OF HEPATOLOGY 74.1(2021):8-19. |
入库方式： OAI收割
来源：上海药物研究所
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