Myofibroblast-specific YY1 promotes liver fibrosis
Myofibroblast-specific YY1 promotes liver fibrosis
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肌成纤维细胞特异性YY1促进肝纤维化
DOI：
10.1016/j.bbrc.2019.05.004
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发表时间：
2019-06-30
影响因子：
3.1
通讯作者：
Jin, Zheng Gen
中科院分区：
文献类型：
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作者：
Liu, Huan;Zhang, Shuya;Jin, Zheng Gen
肝纤维化是各种慢性肝炎和肝损伤的常见后果。肌成纤维细胞通过细胞外基质（ECM）蛋白的积累，与肝纤维化的进展密切相关。然而，肌成纤维细胞中成纤维基因和ECM蛋白转录调控的分子机制在很大程度上仍然未知。使用他莫昔芬诱导的具有选择性缺失转录因子阴阳1 （YY1）的肌成纤维细胞特异性表达cre的小鼠系，我们发现在肌成纤维细胞中YY1的缺失减轻了四氯化碳诱导的肝纤维化。YY1消融对肝纤维化的保护作用伴随着YY1突变小鼠肝组织中纤维化前基因和ECM蛋白的表达减少，包括tnf - α、tgf - β、PDGF、IL-6、α - sma和Col1 α 1。此外，利用人肝星状细胞（HSC） LX-2系，我们发现siRNA处理可降低肌成纤维细胞中YY1的表达，减少肌成纤维细胞的增殖、α - sma表达和胶原沉积。总之，我们的研究结果揭示了YY1在肝肌成纤维细胞中的特殊作用，并为肝纤维化相关肝病的治疗提供了新的策略。(C) 2019 Elsevier Inc.版权所有。
Liver fibrosis is a common consequence of various chronic hepatitis and liver injuries. The myofibroblasts, through the accumulation of extracellular matrix (ECM) proteins, are closely associated with the progression of liver fibrosis. However, the molecular mechanisms underlying transcriptional regulation of fibrogenic genes and ECM proteins in myofibroblasts remain largely unknown. Using tamoxifen inducible myofibroblast-specific Cre-expressing mouse lines with selective deletion of the transcription factor Yin Yang 1 (YY1), here we show that YY1 deletion in myofibroblasts mitigates carbon tetrachloride-induced liver fibrosis. This protective effect of YY1 ablation on liver fibrosis was accompanied with reduced expression of profibrogenic genes and ECM proteins, including TNF-alpha, TGF-beta, PDGF, IL-6, alpha-SMA and Col1 alpha 1 in liver tissues from YY1 mutant mice. Moreover, using the human hepatic stellate cell (HSC) line LX-2, we found that knockdown of YY1 in myofibroblasts by siRNA treatment diminished myofibroblast proliferation, alpha-SMA expression, and collagen deposition. Collectively, our findings reveal a specific role of YY1 in hepatic myofibroblasts and suggest a new therapeutic strategy for hepatic fibrosis-associated liver diseases. (C) 2019 Elsevier Inc. All rights reserved.