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MALAT1介导EZH2募集至GFER启动子区域抑制急性肝损伤中正常肝细胞增殖。

MALAT1-mediated EZH2 Recruitment to the GFER Promoter Region Curbs Normal Hepatocyte Proliferation in Acute Liver Injury.

作者信息

Chen Li, Kang Xintong, Meng Xiujuan, Huang Liang, Du Yiting, Zeng Yilan, Liao Chunfeng

机构信息

Department of Infectious Diseases, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China.

Department of Hepatology, Public Health Clinical Center of Chengdu, Chengdu, Sichuan, China.

出版信息

J Clin Transl Hepatol. 2023 Feb 28;11(1):97-109. doi: 10.14218/JCTH.2021.00391. Epub 2022 Apr 15.

DOI:10.14218/JCTH.2021.00391
PMID:36406327
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9647095/
Abstract

BACKGROUND AND AIMS

The goal of this study was to investigate the mechanism by which the long noncoding RNA MALAT1 inhibited hepatocyte proliferation in acute liver injury (ALI).

METHODS

Lipopolysaccharide (LPS) was used to induce an ALI cellular model in HL7702 cells, in which lentivirus vectors containing MALAT1/EZH2/GFER overexpression or knockdown were introduced. A series of experiments were performed to determine their roles in liver injury, oxidative stress injury, and cell biological processes. The interaction of MALAT1 with EZH2 and enrichment of EZH2 and H3K27me3 in the GFER promoter region were identified. Rats were treated with MALAT1 knockdown or GFER overexpression before LPS induction to verify the results derived from the assay.

RESULTS

MALAT1 levels were elevated and GFER levels were reduced in ALI patients and the LPS-induced cell model. MALAT1 knockdown or GFER overexpression suppressed cell apoptosis and oxidative stress injury induced cell proliferation, and reduced ALI. Functionally, MALAT1 interacted directly with EZH2 and increased the enrichment of EZH2 and H3K27me3 in the GFER promoter region to reduce GFER expression. Moreover, MALAT1/EZH2/GFER was activated the AMPK/mTOR signaling pathway.

CONCLUSION

Our study highlighted the inhibitory role of reduced MALAT1 in ALI through the modulation of EZH2-mediated GFER.

摘要

背景与目的

本研究旨在探究长链非编码RNA MALAT1抑制急性肝损伤（ALI）中肝细胞增殖的机制。

方法

使用脂多糖（LPS）在HL7702细胞中诱导ALI细胞模型，其中导入了含有MALAT1/EZH2/GFER过表达或敲低的慢病毒载体。进行了一系列实验以确定它们在肝损伤、氧化应激损伤和细胞生物学过程中的作用。鉴定了MALAT1与EZH2的相互作用以及EZH2和H3K27me3在GFER启动子区域的富集情况。在LPS诱导前对大鼠进行MALAT1敲低或GFER过表达处理，以验证实验结果。

结果

ALI患者和LPS诱导的细胞模型中MALAT1水平升高而GFER水平降低。MALAT1敲低或GFER过表达可抑制细胞凋亡和氧化应激损伤诱导的细胞增殖，并减轻ALI。在功能上，MALAT1直接与EZH2相互作用，并增加EZH2和H3K27me3在GFER启动子区域的富集，从而降低GFER表达。此外，MALAT1/EZH2/GFER激活了AMPK/mTOR信号通路。

结论

我们的研究强调了通过调节EZH2介导的GFER，降低MALAT1在ALI中的抑制作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff96/9647095/d26751182839/JCTH-11-097-g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff96/9647095/d26751182839/JCTH-11-097-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff96/9647095/5db48b49a947/JCTH-11-097-g001.jpg
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