Bromodomain protein 4 mediates the roles of TGFβ1-induced Stat3 signaling in mouse liver fibrogenesis

• Published in: Toxicology letters 2023-08, Vol.385, p.42-50
• Main Authors: Xu, Feifan, Lu, Sidan, Jia, Xin, Zhou, Yajun
• Format: Article
• Language: English
• Subjects: Bromodomain protein 4; Hepatic stellate cell; Liver fibrosis; Signal transducer and activator of transcription-3; Transforming growth factor-β1
• ISSN: 0378-4274; 1879-3169
• DOI: 10.1016/j.toxlet.2023.08.009

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. [Display omitted] •Stat3 signaling mediates TGFβ1-induced BrD4 expression in HSCs.•Stat3 signaling required BrD4 for promoting HSC activation and liver fibrosis.•TGFβ1-stimulated Stat3 signaling promotes BrD4 expression by Egr1.•TGFβ1-induced Stat3 signaling cross-talks with Smad3 signaling in HSCs.•Egr1 had a positive feedback on Stat3 activation in HSCs.