Mooli Raja Gopal Reddy, Mukhi Dhanunjay, Watt Mikayla, Nagati Veerababu, Reed Sara M, Gandhi Nikita K, Oertel Michael, Ramakrishnan Sadeesh K
Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Int J Mol Sci. 2024 Dec 6;25(23):13114. doi: 10.3390/ijms252313114.
The activation of hypoxia-inducible factors (HIF)-1α and 2α in the liver is closely linked to the progression of fatty liver diseases. Prior studies indicated that disrupting hepatocyte HIF-2α attenuates diet-induced hepatic steatosis, subsequently decreasing fibrosis. However, the direct role of hepatocyte HIF-2α in liver fibrosis has not been addressed. Hepatic HIF-2α expression was examined in mouse model of carbon tetrachloride (CCl)-induced liver fibrosis. Conditional hepatocyte knockout mice were employed to investigate the role of hepatocyte HIF-2α in fibrosis. Markers of apoptosis, proliferation, inflammation, and fibrosis were assessed through biochemical, molecular, and histological analyses. We found an induction of HIF-2α in CCL-injected liver injury and fibrosis mouse models. Hepatocyte-specific deletion of HIF-2α attenuated stellate cell activation and fibrosis, with no significant difference in inflammation. Disrupting hepatocyte HIF-2α led to reduced injury-mediated hepatocellular apoptosis. Surviving hepatocytes exhibited hypertrophy, which was strongly associated with the activation of c-JUN signaling. Our study demonstrates a direct role of hepatocyte HIF-2α in liver fibrosis by promoting hepatocyte apoptosis. The reduction in apoptosis and induction of hepatocyte hypertrophy following HIF-2α disruption is closely linked to enhanced c-JUN signaling, a survival mechanism in response to liver injury. These findings highlight HIF-2α as a potential therapeutic target for liver fibrosis.
肝脏中缺氧诱导因子（HIF）-1α和2α的激活与脂肪性肝病的进展密切相关。先前的研究表明，破坏肝细胞HIF-2α可减轻饮食诱导的肝脂肪变性，进而减少纤维化。然而，肝细胞HIF-2α在肝纤维化中的直接作用尚未得到探讨。在四氯化碳（CCl）诱导的肝纤维化小鼠模型中检测了肝脏HIF-2α的表达。采用条件性肝细胞敲除小鼠来研究肝细胞HIF-2α在纤维化中的作用。通过生化、分子和组织学分析评估细胞凋亡、增殖、炎症和纤维化的标志物。我们发现在注射CCl的肝损伤和纤维化小鼠模型中HIF-2α被诱导。肝细胞特异性缺失HIF-2α可减轻星状细胞激活和纤维化，炎症方面无显著差异。破坏肝细胞HIF-2α导致损伤介导的肝细胞凋亡减少。存活的肝细胞表现出肥大，这与c-JUN信号的激活密切相关。我们的研究表明肝细胞HIF-2α通过促进肝细胞凋亡在肝纤维化中起直接作用。HIF-2α破坏后凋亡减少和肝细胞肥大的诱导与增强的c-JUN信号密切相关，c-JUN信号是一种对肝损伤的存活机制。这些发现突出了HIF-2α作为肝纤维化潜在治疗靶点的作用。
