Hypoxia-Inducible Factor-2α Promotes Liver Fibrosis by Inducing Hepatocellular Death
Raja Gopal Reddy Mooli, Dhanunjay Mukhi, Mikayla Watt, Veerababu Nagati, Sara M. Reed, N. Gandhi, Michael Oertel, Sadeesh K. Ramakrishnan
Abstract
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 (CCl4)-induced liver fibrosis. Conditional hepatocyte Hif-2α 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 CCL4-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.