Role of TLR4-Mediated PI3KAKTGSK-3β Signaling Pathway in Apoptosis of Rat Hepatocytes

Abstract EN

We investigated the mechanism of the Toll-like receptor 4- (TLR4-) mediated PI3K/AKT/GSK-3β signaling pathway in rat hepatocytes apoptosis induced by LPS.

The cultured rat hepatocytes were treated with LPS alone or first pretreated with TLR4 inhibitor, AKT inhibitor, and GSK-3β inhibitor, respectively, and then stimulated with the same dose of LPS.

Cell viability, cell apoptotic rate, and apoptosis morphology were assessed; the level of P- A K T S e r 473 , P-GSK- 3 β S e r 9 , and active Caspase-3 and the ratio of Bax/Bcl-2 were evaluated.

The results indicated that cell viability decreased, while cell apoptotic rate increased with time after LPS stimulation.

The expression of P- A K T S e r 473 and P-GSK- 3 β S e r 9 in the LPS group decreased compared with the control, while the level of active Caspase-3 and the ratio of Bax/Bcl-2 were significantly increased.

These effects were attenuated by pretreatment with CLI-095.

In addition, the apoptotic ratio decreased after pretreatment with LiCl but increased following pretreatment with LY294002.

The expression of P- A K T S e r 473 further decreased following pretreatment with LY294002 and the expression of P-GSK- 3 β S e r 9 increased following pretreatment with LiCl.

Moreover, pretreatment with CLI-095 weakened LPS-induced nuclear translocation of GSK-3β.

Our findings suggest that the TLR4-mediated PI3K/AKT/GSK-3β signaling pathway is present in rat hepatocytes and participates in apoptosis of BRL-3A cells.