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

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. Graphical abstract

Proteomics and phosphoproteomics analysis of vitreous in idiopathic epiretinal membrane patients

“…Inhibition of follistatin‐like 1 significantly inhibits TGF‐β1‐stimulated cell migration and ECM accumulation; follistatin‐like 1 is thus a therapeutic target for the treatment of liver fibrosis [29].…”

Anti-CD20 Therapy Alters the Protein Signature in Experimental Murine AIH, but Not Exclusively towards Regeneration

“…In addition, others have already shown that rituximab may induce Ccl20 expression in human blood [39]. Furthermore, the expression of Fst is associated with liver fibrosis [40,41], while the downregulation of Clstn2 was observed in progressive RA [42]. At this point, it is reasonable to speculate about a connection between the cytokine release syndrome and rituximab, which is certainly known in certain circumstances [43].…”

Mechanism and Therapeutic Targets of c-Jun-N-Terminal Kinases Activation in Nonalcoholic Fatty Liver Disease

“…Fstl1 binds to TGF-β1 and negatively regulates TGF-β1 signaling in lung development. Interestingly, Fstl1 neutralizing antibody attenuates CCL4 induced liver fibrosis [ 136 ]. Further studies are required to reconcile results from developmental and disease models.…”