The concentration of tumor necrosis factor-α determines its protective or damaging effect on liver injury by regulating Yap activity

Previous studies have shown that tumor necrosis factor (TNF)-alpha is a mediator of hepatotoxicity in liver injury. Moreover, TNF-alpha has also been reported to have a protective effect in liver regeneration, yet the function of TNF-alpha during liver injury remains controversial. Here, we report that the concentration of TNF-alpha determines its functions. High concentrations of TNF-alpha could aggravate LPS-induced liver injury. However, the TNF-alpha level was unchanged during APAP-induced liver injury, which exerted a protective effect. We expected that the concentration of TNF-alpha may affect its function. To test this hypothesis, TNF-alpha (-/-) rats or hepatocyte cells were treated with different concentrations of TNF-alpha. We found low TNF-alpha could reduce the levels of ALT and AST in the plasma of TNF-alpha (-/-) rats and promote the proliferation of hepatocyte cells. However, the levels of ALT and AST increased gradually with increasing TNF-alpha concentration after reaching the lowest value. Moreover, we showed that TNF-alpha affects the cell proliferation and cell death of hepatocytes by regulating Yap activity. Low TNF-alpha promoted Yap1 nuclear translocation, triggering the proliferation of hepatocytes. However, high TNF-alpha triggered the phosphorylation and inactivation of Yap1, preventing its nuclear import and consequently promoting cell death. Collectively, our findings provide novel evidence that the concentration of TNF-alpha is an important factor affecting its function in liver injury, which may provide a reference for the clinical treatment of liver injury.