State Key Laboratory of Cell Differentiation and Regulation, College of Life Sciences, Henan Normal University, Xinxiang, 453007, China.
Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China.
Sci Rep. 2023 Jul 6;13(1):10946. doi: 10.1038/s41598-023-38144-3.
Liver fibrosis is caused by chronic hepatic injury and may lead to cirrhosis, and even hepatocellular carcinoma. When hepatic stellate cells (HSCs) are activated by liver injury, they transdifferentiate into myofibroblasts, which secrete extracellular matrix proteins that generate the fibrous scar. Therefore, it is extremely urgent to find safe and effective drugs for HSCs activation treatment to prevent liver against fibrosis. Here, we reported that PDZ and LIM domain protein 1 (PDLIM1), a highly conserved cytoskeleton organization regulator, was significantly up-regulated in fibrotic liver tissues and TGF-β-treated HSC-T6 cells. Through transcriptome analysis, we found that knockdown of PDLIM1 resulted in a significant downregulation of genes related to inflammation and immune-related pathways in HSC-T6 cells. Moreover, PDLIM1 knockdown significantly inhibited the activation of HSC-T6 cells and the trans-differentiation of HSC-T6 cells into myofibroblasts. Mechanistically, PDLIM1 is involved in the regulation of TGF-β-mediated signaling pathways in HSCs activation. Thus, targeting PDLIM1 may provide an alternative method to suppress HSCs activation during liver injury. CCCTC-binding factor (CTCF), a master regulator of genome architecture, is upregulated during HSCs activation. PDLIM1 knockdown also indirectly reduced CTCF protein expression, however, CTCF binding to chromatin was not significantly altered by CUT&Tag analysis. We speculate that CTCF may cooperate with PDLIM1 to activate HSCs in other ways. Our results suggest that PDLIM1 can accelerate the activation of HSCs and liver fibrosis progression and could be a potential biomarker for monitoring response to anti-fibrotic therapy.
肝纤维化是由慢性肝损伤引起的，可能导致肝硬化，甚至肝癌。当肝星状细胞（HSCs）被肝损伤激活时，它们会向肌成纤维细胞转化，分泌细胞外基质蛋白，产生纤维疤痕。因此，寻找安全有效的 HSCs 激活治疗药物来预防肝纤维化是极其迫切的。在这里，我们报道 PDZ 和 LIM 结构域蛋白 1（PDLIM1），一种高度保守的细胞骨架组织调节剂，在纤维化肝组织和 TGF-β 处理的 HSC-T6 细胞中显著上调。通过转录组分析，我们发现 PDLIM1 的敲低导致 HSC-T6 细胞中与炎症和免疫相关途径相关的基因显著下调。此外，PDLIM1 的敲低显著抑制了 HSC-T6 细胞的激活和 HSC-T6 细胞向肌成纤维细胞的转化。在机制上，PDLIM1 参与了 HSCs 激活中 TGF-β 介导的信号通路的调节。因此，靶向 PDLIM1 可能为抑制肝损伤期间 HSCs 激活提供一种替代方法。CCCTC 结合因子（CTCF）是基因组结构的主要调节因子，在 HSCs 激活时上调。PDLIM1 的敲低也间接降低了 CTCF 蛋白的表达，但 CUT&Tag 分析并未显著改变 CTCF 与染色质的结合。我们推测 CTCF 可能以其他方式与 PDLIM1 合作激活 HSCs。我们的结果表明，PDLIM1 可以加速 HSCs 的激活和肝纤维化的进展，可能是监测抗纤维化治疗反应的潜在生物标志物。
