title: Angiogenic factor with G patch and FHA domains 1 (Aggf1) regulates liver fibrosis by modulating TGF-β signaling.
abstract: Fibrosis is a common pathophysiological process following liver injury and can lead to, if left unattended to, irreversible end-stage liver disease such as cirrhosis. Hepatic stellate cells (HSCs) are a major contributor to liver fibrosis. Here we investigated the involvement of angiogenic factor with G patch and FHA domains 1 (Aggf1) in HSC activation and the underlying mechanisms. Aggf1 expression was down-regulated in the livers in three different mouse models of liver fibrosis following injury. Aggf1 expression was also suppressed in activated HSCs when compared to quiescent HSCs. Over-expression of Aggf1 alleviated liver fibrosis in mice and in cultured HSCs. RNA-sequencing (RNA-seq) analysis performed in HSCs revealed that Aggf1-dependent transcription regulates several key fibrogenic pathways. Mechanistically, Aggf1 regulated liver fibrogenesis by forming a complex with the inhibitor SMAD protein (SMAD7) thereby leading to diminished SMAD3 binding to the pro-fibrogenic gene promoters. On the contrary, SMAD7 knockdown abrogated the effect of Aggf1 and rescued HSC activation. Aggf1 expression was silenced during HSC activation/liver fibrogenesis as a result of DNA methylation. Treatment with a DNA methyltransferase inhibitor (5-Azacytidine) restored Aggf1 expression and repressed liver fibrosis in an Aggf1-dependent manner. In conclusion, our data illustrate a previously unknown role for Aggf1 and shed light on the development of novel therapeutic solutions against liver fibrosis.
authors: Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.
authors: Bisheng
authors: B
authors: Zhou
authors: Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.
authors: Sheng
authors: S
authors: Zeng
authors: Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.
authors: Luyuang
authors: L
authors: Li
authors: Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.
authors: Zhiwen
authors: Z
authors: Fan
authors: Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.
authors: Wenfang
authors: W
authors: Tian
authors: Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.
authors: Min
authors: M
authors: Li
authors: Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.
authors: Huihui
authors: H
authors: Xu
authors: Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.
authors: Xiaoyan
authors: X
authors: Wu
authors: Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China; Department of Medicine and Nursing, Jiangsu Jiankang Vocational University, Nanjing, China.
authors: Mingming
authors: M
authors: Fang
authors: Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China. Electronic address: yjxu@njmu.edu.cn.
authors: Yong
authors: Y
authors: Xu
mesh_terms: D042501:Angiogenic Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D015536:Down-Regulation; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D051381:Rats; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: C000620722:AGGF1 protein, rat; C000619510:Aggf1 protein, mouse; D042501:Angiogenic Proteins; D016212:Transforming Growth Factor beta
keywords: DNA methylation; Hepatic stellate cell; Liver fibrosis; SMAD; TGF-β signaling; Transcriptional regulation