Department of Clinical Laboratory, Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), 500 Yonghe Road, Nantong 226011, Jiangsu, China.
Department of Biochemistry & Molecular Biology, Medical School, Nantong University, Qi xiou Road 19, Nantong 226001, Jiangsu, China.
Toxicol Lett. 2023 Aug 15;385:42-50. doi: 10.1016/j.toxlet.2023.08.009. Epub 2023 Aug 25.
Epigenetic reader Bromodomain protein 4 (BrD4) functions as a global genomic regulator to direct hepatic stellate cell (HSC) activation (a key step in liver fibrogenesis) and liver fibrosis. The pivotal pro-fibrotic cytokine transforming growth factor-β1 (TGFβ1) signals through both Smad and Stat3 to elicit a wide array of biological effects. Stat3 is widely acknowledged as a regulator of gene transcription and is involved in fibrosis of multiple tissues. The present study focused on BrD4 function implication in the roles of TGFβ1-induced Stat3 signaling in HSC activation and liver fibrosis by using heterozygous TGFβ1 knockout mice and HSC culture. Results showed that Stat3 was required for TGFβ1-induced BrD4 expression in HSCs. BrD4 expression paralleled Stat3 activation in activated HSCs in human cirrhotic livers. BrD4 was involved in the roles of TGFβ1-induced Stat3 in HSC activation and liver fibrogenesis. Smad3 bound to phosphorylated-Stat3 and contributed to TGFβ1-induced Stat3 signaling. BrD4 expression induced by Stat3 signaling required the early-immediate gene Egr1. Egr1 had a positive feedback on Stat3 activation. In conclusion, a network consisting of Stat3 signaling, Smad3 signaling, Egr1, and BrD4 was involved in the effects of TGFβ1 on liver fibrosis, providing new toxicological mechanisms for TGFβ1 in liver fibrogenesis.
表观遗传读蛋白溴结构域蛋白 4（BrD4）作为一个全局基因组调控因子，可直接调控肝星状细胞（HSC）的激活（肝纤维化发生的关键步骤）和肝纤维化。关键的促纤维化细胞因子转化生长因子-β1（TGFβ1）通过 Smad 和 Stat3 信号传导，引发广泛的生物学效应。Stat3 被广泛认为是基因转录的调节剂，并且参与多种组织的纤维化。本研究通过使用杂合型 TGFβ1 敲除小鼠和 HSC 培养物，重点研究了 BrD4 在 TGFβ1 诱导的 Stat3 信号在 HSC 激活和肝纤维化中的作用。结果表明，Stat3 是 TGFβ1 诱导 HSCs 中 BrD4 表达所必需的。在人类肝硬化肝脏中激活的 HSCs 中，BrD4 的表达与 Stat3 激活平行。BrD4 参与了 TGFβ1 诱导的 Stat3 在 HSC 激活和肝纤维化中的作用。Smad3 与磷酸化 Stat3 结合，并有助于 TGFβ1 诱导的 Stat3 信号传导。Stat3 信号诱导的 BrD4 表达需要早期即刻基因 Egr1。Egr1 对 Stat3 激活具有正反馈作用。总之，由 Stat3 信号、Smad3 信号、Egr1 和 BrD4 组成的网络参与了 TGFβ1 对肝纤维化的影响，为 TGFβ1 在肝纤维化发生中的毒性作用提供了新的机制。
