Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Universidad Pablo de Olavide, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas (CSIC), Seville, Spain.
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain.
JCI Insight. 2021 Dec 8;6(23):e150059. doi: 10.1172/jci.insight.150059.
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.
针对肝损伤，肝星状细胞被激活并获得增殖和收缩的特征。肝纤维化的消退似乎涉及到激活的肝星状细胞的清除，要么通过细胞凋亡，要么通过向静止样状态的逆转，这个过程称为失活。因此，肝星状细胞的失活已成为肝纤维化的一种新的有前途的治疗方法。然而，我们对参与肝星状细胞失活和/或激活的主要调节因子的了解仍然有限。转录因子 GATA4 先前被证明在胚胎肝星状细胞静止中发挥重要作用。在这项工作中，我们表明，成年小鼠中 GATA4 的缺失导致肝星状细胞激活，进而导致肝纤维化。在肝纤维化的消退过程中，Gata4 在失活的肝星状细胞中重新表达。在 CCl4 处理的小鼠中过表达 Gata4 可促进肝纤维化的消退。GATA4 诱导纤维生成和抗纤维生成基因的表达变化，促进肝星状细胞失活。最后，我们表明 GATA4 可直接抑制肝星状细胞中 EPAS1 的转录，而肝星状细胞中 HIF2α 蛋白的稳定导致肝纤维化。
