GATA4 induces liver fibrosis regression by deactivating hepatic stellate cells

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 towards a quiescentlike state, a process denominated 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 de/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 cells quiescence. In this work, we show that lack of GATA4 in adult mice causes hepatic stellate cell activation and consequently, liver fibrosis. During regression of liver fibrosis, Gata4 is reexpressed in deactivated hepatic stellate cells. Overexpression of Gata4 in hepatic stellate cells promotes liver fibrosis regression in CCl4-treated mice. GATA4 induces changes in the expression of fibrogenic and antifibrogenic genes promoting hepatic stellate cell deactivation. Finally, we show that GATA4 directly represses EPAS1 transcription in hepatic stellate cells and that stabilization of the HIF2α protein in hepatic stellate cells leads to liver fibrosis.

Increased Tropism of Extracellular Vesicles Derived from Palmitic Acid-Treated Hepatocytes to Activated Hepatic Stellate Cells

“…Liver fibrosis is a major consequence of chronic liver disease, in which excessive deposition of extracellular matrix is driven by activation of hepatic stellate cells (HSCs) [ 1 ]. HSCs are non-parenchymal cells that exist in the space of Disse between hepatocytes and sinusoidal endothelial cells, and account for approximately 10% of the total number of liver-resident cells [ 2 , 3 , 4 ]. In liver fibrosis, activated HSCs (aHSCs) are the main source of extracellular matrix, especially collagen, which is produced by transforming growth factor-β (TGF-β) stimulation [ 2 ].…”

“…Several reports have shown the involvement of signaling pathways in the regulation of HSC activation, especially the reversion of aHSCs to quiescent state-HSCs (qHSCs) via in vivo analyses [ 4 , 5 ]. However, in vivo analyses are susceptible to off-target effects on hepatocytes that account for approximately 70% of the total number of liver-resident cells.…”

Hepatic Stellate Cells: Dictating Outcome in Nonalcoholic Fatty Liver Disease

“… 154 , 155 , 156 Several transcription factors, such as PPARγ, GATA-binding factor 6 (GATA6), GATA-binding factor 4 (GATA4), and transcription factor 21 (TCF21), have been implicated in regulating the deactivation of hepatic stellate cells. 157 , 158 , 159 In a model of CCl 4 -induced liver injury, mice with hepatic stellate cell–specific deletion of GATA6 or PPARγ are more susceptible to fibrosis development. 159 Moreover, regression of liver fibrosis is significantly reduced in hepatic stellate cell–specific GATA6-deficient mice and in hepatic stellate cell–specific PPARγ-deficient mice as compared with wild-type mice, therefore suggesting that both GATA6 and PPARγ are critical for maintaining the inactivated phenotype of hepatic stellate cells.…”

Single-cell Gene Regulation Network Inference by Large-scale Data Integration

“…5c, f). Finally, we built a co-regulatory GRN of GATA4 and its downstream targets EPAS1 (44) in liver hepatoblasts (HB) (Fig. 5g).…”