Chronic hepatic diseases often involve fibrosis as a pivotal factor in their progression. This study investigates the regulatory mechanisms of Yin Yang 1 (YY1) in hepatic fibrosis. Our data reveal that YY1 binds to the prolyl hydroxylase domain 1 (PHD1) promoter. Rats treated with carbon tetrachloride (CCl₄) display heightened fibrosis in liver tissues, accompanied by increased levels of YY1, PHD1, and the fibrosis marker alpha-smooth muscle actin (α-SMA). Elevated levels of YY1, PHD1, and α-SMA are observed in the liver tissues of CCl₄-treated rats, primary hepatic stellate cells (HSCs) isolated from fibrotic liver tissues, and transforming growth factor beta-1 (TGF-β1)-induced HSCs. The human HSC cell line LX-2, upon YY1 overexpression, exhibits enhanced TGF-β1-induced activation, leading to increased expression of extracellular matrix (ECM)-related proteins and inflammatory cytokines. YY1 silencing produces the opposite effect. YY1 exerts a positive regulatory effect on the activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway and PHD1 expression. PHD1 silencing rescues the promotion of YY1 in cell activation, ECM-related protein expression, and inflammatory cytokine production in TGF-β1-treated LX-2 cells. Overall, our findings propose a model wherein YY1 facilitates TGF-β1-induced HSC activation, ECM-related protein expression, and inflammatory cytokine production by promoting PHD1 expression and activating the PI3K/AKT signaling pathway. This study positions YY1 as a promising therapeutic target for hepatic fibrosis.

中文翻译：

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阴阳1促进肝纤维化过程中肝星状细胞的活化、炎症和细胞外基质沉积

慢性肝病通常涉及纤维化，这是其进展的关键因素。本研究探讨阴阳1（YY1）在肝纤维化中的调节机制。我们的数据表明 YY1 与脯氨酰羟化酶结构域 1 ( PHD1 ) 启动子结合。用四氯化碳 (CCl ₄ ) 治疗的大鼠显示肝组织纤维化加剧，伴随着 YY1、PHD1 和纤维化标记物 α-平滑肌肌动蛋白 (α-SMA) 水平的增加。在 CCl ₄处理的大鼠的肝组织、从纤维化肝组织中分离的原代肝星状细胞 (HSC) 以及转化生长因子 β-1 (TGF-β1)中观察到 YY1、PHD1 和 α-SMA 水平升高。诱导的 HSC。人 HSC 细胞系 LX-2 在 YY1 过表达后，表现出增强的 TGF-β1 诱导的激活，导致细胞外基质 (ECM) 相关蛋白和炎症细胞因子的表达增加。 YY1 沉默会产生相反的效果。 YY1 对磷脂酰肌醇 3 激酶 (PI3K)/蛋白激酶 B (AKT) 信号通路的激活和 PHD1 表达发挥正向调节作用。在 TGF-β1 处理的 LX-2 细胞中，PHD1 沉默可挽救 YY1 在细胞活化、ECM 相关蛋白表达和炎症细胞因子产生中的促进作用。总的来说，我们的研究结果提出了一个模型，其中 YY1 通过促进 PHD1 表达和激活 PI3K/AKT 信号通路来促进 TGF-β1 诱导的 HSC 激活、ECM 相关蛋白表达和炎症细胞因子产生。这项研究将 YY1 定位为肝纤维化有前景的治疗靶点。