Abstract
Trans-differentiation of quiescent hepatic stellate cells (HSC) to myofibroblasts is a hallmark event in liver fibrosis. Previous studies have led to the discovery that myocardin-related transcription factor A (MRTF-A) is a key regulator of HSC trans-differentiation or, activation. In the present study we investigated the interplay between MRTF-A and c-Abl (encoded by Abl1), a tyrosine kinase, in this process. We report that hepatic expression levels of c-Abl were down-regulated in MRTF-A knockout (KO) mice compared to wild type (WT) littermates in several different models of liver fibrosis. MRTF-A deficiency also resulted in c-Abl down-regulation in freshly isolated HSCs from the fibrotic livers of mice. MRTF-A knockdown or inhibition repressed c-Abl in cultured HSCs in vitro. Further analyses revealed that MRTF-A directly bound to the Abl1 promoter to activate transcription by interacting with Sp1. Reciprocally, pharmaceutical inhibition of c-Abl suppressed MRTF-A activity. Mechanistically, c-Abl activated extracellular signal-regulated kinase (ERK), which in turn phosphorylated MRTF-A and promoted MRTF-A nuclear trans-localization. In conclusion, our data suggest that a c-Abl-MRTF-A positive feedback loop contributes to HSC activation and liver fibrosis.
Highlights
Liver fibrosis is generally perceived as a host defense mechanism in response to a myriad of danger signals that include pathogens, toxins, and nutrients/metabolites (Duffield et al, 2013)
Liver fibrosis was induced in wild type (WT) and myocardinrelated transcription factor A (MRTF-A) knockout (KO) mice by several different methods
Chromatin Immunoprecipitation (ChIP) assays performed in both LX-2 cells (Figure 3G) and primary mouse hepatic stellate cells (HSC) (Figure 3H) confirmed that association of MRTF-A with the proximal c-Abl promoter, but not the distal c-Abl promoter, was significantly augmented during HSC activation
Summary
Liver fibrosis is generally perceived as a host defense mechanism in response to a myriad of danger signals that include pathogens, toxins, and nutrients/metabolites (Duffield et al, 2013). Liver fibrosis parallels proliferation and migration of myofibroblasts, which produce and secret extracellular matrix (ECM) proteins such as collagen type I, collagen type III, and fibronectin (Kisseleva, 2017). Myofibroblasts are typically characterized by the expression of signature genes including alpha smooth muscle actin (α-SMA). Origins of hepatic myofibroblasts have been a topic of heated debate recent fate-mapping experiments suggest that hepatic stellate cells (HSCs) are the predominant source for activated myofibroblasts in the fibrotic liver independent of the etiology (Mederacke et al, 2013). HSCs adopt a quiescent state in the normal
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