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Targeting Follistatin like 1 ameliorates liver fibrosis induced by carbon tetrachloride through TGF-β1-miR29a in mice

Authors :
Xin-Yi Xu
Yan Du
Xue Liu
Yilin Ren
Yingying Dong
Hong-Yu Xu
Jin-Song Shi
Dianhua Jiang
Xin Xu
Lian Li
Zheng-Hong Xu
Yan Geng
Source :
Cell Communication and Signaling, Vol 18, Iss 1, Pp 1-12 (2020)
Publication Year :
2020
Publisher :
BMC, 2020.

Abstract

Abstract Background Hepatic fibrosis is a pathological response of the liver to a variety of chronic stimuli. Hepatic stellate cells (HSCs) are the major source of myofibroblasts in the liver. Follistatin like 1 (Fstl1) is a secreted glycoprotein induced by transforming growth factor-β1 (TGF-β1). However, the precise functions and regulation mechanisms of Fstl1 in liver fibrogenesis remains unclear. Methods Hepatic stellate cell (HSC) line LX-2 stimulated by TGF-β1, primary culture of mouse HSCs and a model of liver fibrosis induced by CCl4 in mice was used to assess the effect of Fstl1 in vitro and in vivo. Results Here, we found that Fstl1 was significantly up regulated in human and mouse fibrotic livers, as well as activated HSCs. Haplodeficiency of Fstl1 or blockage of Fstl1 with a neutralizing antibody 22B6 attenuated CCl4-induced liver fibrosis in vivo. Fstl1 modulates TGF-β1 classic Samd2 and non-classic JNK signaling pathways. Knockdown of Fstl1 in HSCs significantly ameliorated cell activation, cell migration, chemokines C-C Motif Chemokine Ligand 2 (CCL2) and C-X-C Motif Chemokine Ligand 8 (CXCL8) secretion and extracellular matrix (ECM) production, and also modulated microRNA-29a (miR29a) expression. Furthermore, we identified that Fstl1 was a target gene of miR29a. And TGF-β1 induction of Fstl1 expression was partially through down regulation of miR29a in HSCs. Conclusions Our data suggests TGF-β1-miR29a-Fstl1 regulatory circuit plays a key role in regulation the HSC activation and ECM production, and targeting Fstl1 may be a strategy for the treatment of liver fibrosis. Video Abstract Graphical abstract

Details

Language :
English
ISSN :
1478811X
Volume :
18
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Cell Communication and Signaling
Publication Type :
Academic Journal
Accession number :
edsdoj.99f6a7e484144dabb58eee93378555c7
Document Type :
article
Full Text :
https://doi.org/10.1186/s12964-020-00610-0