AKT activator SC79 protects hepatocytes from TNF-α-mediated apoptosis and alleviates D-Gal/LPS-induced liver injury

Tumor necrosis factor-alpha (TNF-alpha) is a highly pleiotropic cytokine executing biological functions as diverse as cell proliferation, metabolic activation, inflammatory responses, and cell death. TNF-alpha can induce multiple mechanisms to initiate apoptosis in hepatocytes leading to the subsequent liver injury. Since the phosphoinositide-3-kinase/protein kinase B (PI3K/Akt) pathway is known to have a protective role in death factor-mediated apoptosis, it is our hypothesis that activation of Akt may represent a therapeutic strategy to alleviate TNF-alpha-induced hepatocyte apoptosis and liver injury. We report here that the Akt activator SC79 protects hepatocytes from TNF-alpha-induced apoptosis and protects mice from D-galactosamine (D-Gal)/lipopolysaccharide (LPS)-induced TNF-alpha-mediated liver injury and damage. SC79 not only enhances the nuclear factor-kappa B (NF-kappa B) prosurvival signaling in response to TNF-alpha stimulation, but also increases the expression of cellular FLICE (FADD-like IL-1 beta-converting enzyme)-inhibitory protein L and S (FLIPL/S), which consequently inhibits the activation of procaspase-8. Furthermore, pretreatment of the PI3K/Akt inhibitor LY294002 reverses all the SC79-induced hepatoprotective effects. These results strongly indicate that SC79 protects against TNF-alpha-induced hepatocyte apoptosis and suggests that SC79 is likely a promising therapeutic agent for ameliorating the development of liver injury. NEW & NOTEWORTHY SC79 protects hepatocytes from TNF-alpha-mediated apoptosis and mice from Gal/LPS-induced liver injury and damage. Cytoprotective effects of SC79 against TNF-alpha act through both AKT-mediated activation of NF-kappa B and upregulation of FLIPL/S.