ATF3-mediated transactivation of CXCL14 in HSCs during liver fibrosis

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2024-10-02 DOI:10.1002/ctm2.70040

Xinmiao Li, Lifan Lin, Yifei Li, Weizhi Zhang, Zhichao Lang, Jianjian Zheng

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引用次数: 0

Abstract

Background and aims

Myofibroblasts, the primary producers of extracellular matrix, primarily originate from hepatic stellate cells (HSCs), and their activation plays a pivotal role in liver fibrosis. This study aimed to investigate the function of CXC motif ligand 14 (CXCL14) in the progression of liver fibrosis.

Approach and results

CXCL14 knockdown significantly reduced the extent of liver fibrosis. Using Ingenuity pathway analysis and qRT-PCR, activating transcription factor 3 (ATF3) was identified as a key upstream regulator of CXCL14 expression. Mechanistically, ATF3 was shown to bind to the CXCL14 promoter, promoting its transactivation by TGF-β in HSCs. Notably, both global CXCL14 deletion (CXCL14^−/−) and HSC/myofibroblast-specific CXCL14 knockdown significantly attenuated liver fibrosis in mice. RNA-seq comparisons between CXCL14^−/− and WT mice highlighted Jak2 as the most significantly downregulated gene, implicating its role in the antifibrotic effects of CXCL14 suppression on HSC inactivation. Moreover, Jak2 overexpression reversed the inhibition of liver fibrosis caused by CXCL14 knockdown in vivo.

Conclusions

These findings unveil a novel ATF3/CXCL14/Jak2 signalling axis in liver fibrosis, presenting potential therapeutic targets for the disease.

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肝纤维化过程中 ATF3 介导的造血干细胞中 CXCL14 的转录激活。

背景和目的：肌成纤维细胞是细胞外基质的主要制造者，主要来源于肝星状细胞（HSCs），其活化在肝纤维化中起着关键作用。本研究旨在探讨CXC马达配体14（CXCL14）在肝纤维化进程中的功能：方法与结果：CXCL14基因敲除能明显减轻肝纤维化的程度。通过Ingenuity通路分析和qRT-PCR，活化转录因子3（ATF3）被确定为CXCL14表达的关键上游调节因子。从机制上看，ATF3 与 CXCL14 启动子结合，促进造血干细胞中 TGF-β 的转录激活。值得注意的是，全基因 CXCL14 缺失（CXCL14-/-）和造血干细胞/肌成纤维细胞特异性 CXCL14 基因敲除都能显著减轻小鼠肝纤维化。CXCL14-/-和WT小鼠的RNA-seq比较显示，Jak2是下调最明显的基因，这表明它在CXCL14抑制造血干细胞失活的抗纤维化作用中发挥了作用。此外，Jak2的过表达逆转了CXCL14敲除对体内肝纤维化的抑制作用：这些发现揭示了肝纤维化中一个新的 ATF3/CXCL14/Jak2 信号轴，为该疾病提供了潜在的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.