Affiliation:
1. Second Military Medical University
2. Chinese Academy of Medical Sciences
Abstract
Abstract
Background
Hepatocarcinogenesis is initiated by repeated hepatocyte death and liver damage, and the underlying mechanisms mediating cell death and the subsequent carcinogenesis remain to be fully investigated. Immunoresponsive gene 1 (IRG1) and its enzymatic metabolite itaconate are known to suppress inflammation in myeloid cells, and its expression in liver parenchymal hepatocytes is currently determined. However, the potential roles of IRG1 in hepatocarcinogenesis are still unknown.
Methods
Hepatocyte-specific IRG1 knockout mice were constructed to examine the role of IRG1 in hepatocarcinogenesis using diethylnitrosamine (DEN) and stelic animal model (STAM)-induced mouse models. Molecular and biological experiments were performed to explore the mechanisms of hepatic IRG1 in promoting hepatocyte apoptosis and carcinogenesis in vivo and in vitro.
Results
Here, using the diethylnitrosamine (DEN)-induced hepatocarcinogenesis mouse model, we found that IRG1 expression in hepatocytes was markedly induced upon DEN administration. The DEN-induced IRG1 was then determined to promote the intrinsic mitochondrial apoptosis of hepatocytes and liver damage, thus enhancing the subsequent hepatocarcinogenesis. However, the pro-apoptotic and carcinogenesis-promotive functions of IRG1 were independent on its catalytic product itaconate. Mechanistically, we found that the mitochondrial IRG1 could associate and trap anti-apoptotic Mcl-1 to inhibit the interaction between Mcl-1 and pro-apoptotic Bim, thus promoting Bim activation and downstream Bax mitochondrial translocation, and then releasing cytochrome c and initiating apoptosis.
Conclusions
The inducible mitochondrial IRG1 promotes hepatocyte apoptosis and the following hepatocarcinogenesis, which provides mechanistic insight and a potential target for preventing liver injury and HCC.
Publisher
Research Square Platform LLC