GATA4 induces liver fibrosis regression by deactivating hepatic stellate cells.

Noelia Arroyo,Franz Martín,David A Cano,Miguel G Toscano,Laura Villamayor,Mireia Ramos-Rodríguez,Lorenzo Pasquali,Ramón Muñoz-Chápuli,Rita Carmona,Irene Díaz,Anabel Rojas

doi:10.1172/jci.insight.150059

Abstract

In response to liver injury, hepatic stellate cells activate and acquire proliferative and contractile features. The regression of liver fibrosis appears to involve the clearance of activated hepatic stellate cells, either by apoptosis or by reversion toward a quiescent-like state, a process called deactivation. Thus, deactivation of active hepatic stellate cells has emerged as a novel and promising therapeutic approach for liver fibrosis. However, our knowledge of the master regulators involved in the deactivation and/or activation of fibrotic hepatic stellate cells is still limited. The transcription factor GATA4 has been previously shown to play an important role in embryonic hepatic stellate cell quiescence. In this work, we show that lack of GATA4 in adult mice caused hepatic stellate cell activation and, consequently, liver fibrosis. During regression of liver fibrosis, Gata4 was reexpressed in deactivated hepatic stellate cells. Overexpression of Gata4 in hepatic stellate cells promoted liver fibrosis regression in CCl4-treated mice. GATA4 induced changes in the expression of fibrogenic and antifibrogenic genes, promoting hepatic stellate cell deactivation. Finally, we show that GATA4 directly repressed EPAS1 transcription in hepatic stellate cells and that stabilization of the HIF2α protein in hepatic stellate cells leads to liver fibrosis.

Highlights

Liver fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM) components that might eventually lead to cirrhosis and impaired hepatic function
Our previous work demonstrated that Gata4 inactivation in embryonic hepatic stellate cells (HSCs), using the G2-Cre line, leads to liver fibrosis and this transcription factor is required to maintain the quiescence of embryonic HSCs [10]
The accumulation of ECM in Gata4 floxed mice injected with Adenoviruses expressing the Cre recombinase (Ad-Cre) was concomitant with HSCs activation, as demonstrated by the prominent expression of smooth muscle actin, α-Sma (Figure 1H, J), compared with mice treated with Ad-GFP (Figure1H, I)

Summary

Introduction

Liver fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM) components that might eventually lead to cirrhosis and impaired hepatic function. Among the signaling molecules shown to induce activation of HSCs are plateletderived growth factor (PDFG-ß), transforming growth factor ß (TGFß), and inflammatory cytokines [5] It has become increasingly clear in recent years that liver fibrosis can be reversed upon cessation of injury. Lineage tracing studies in mouse models have demonstrated that during the regression of liver fibrosis, approximately half of the aHSCs escape from apoptosis or cell senescence and revert their phenotype to an inactive or quiescent-like state, a process denominated deactivation [8]. This deactivation phenomenon has been recently described in human HSCs [9]. In this context, targeting the deactivation of aHSCs has emerged as a novel and promising therapeutic approach for liver fibrosis

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