Regulation Of GSK-3β On Rat Liver Regeneration And Its Mechanism

GSK-3 was discovered over 20 years ago as one of several protein kinases that phosphorylated and inactivated glycogen synthase and, hence, regulate glucose metabolism. However, increasing knowledge has changed the image of GSK-3 to that of a broadly influential enzyme that is crucial regulator of many cellular functions. The cellular processes, that GSK-3 participates, range from cell membrane-to-nucleus signaling, gene transcription to cell cycle progression and survival. A recent study has demonstrated that GSK-3β-/- mice died of massive hepatocyte apoptosis during development, which suggests GSK-3βhas a profound influence on regulating liver development. And MEFs from these mice have a deficiency in inflammatory response to many cytokines such as TNF-α, LPS, which is caused by affecting the activity of transcription factors NF-κB.It has been demonstrated that the activation of NF-κB pathway during liver regeneration after partial hepatectomy appears to be a required event to prevent apoptosis and to allow for normal cell cycle progression. Hepatocyte resistance to TNF -α-induced apoptosis is dependent on activation of the transcription factor NF-κB.Considering the multiple function of GSK-3β, and still its role in regulating liver regeneration has not been reported, we aimed to answer the following questions. 1. How GSK-3βreacts during liver regeneration. 2. Whether inhibition of GSK-3βinfluences the process of liver regeneration. 3. Whether the mechanisms of GSK-3βin regulating liver regeneration involves TNF-α-NF-κB pathway.Here we investigated the effects of GSK-3βinhibition on liver regeneration after partial hepatectomy in the rat. The potent and selective GSK-3βinhibitor SB216763 (0.6 mg/kg intravenously) or vehicle (10% dimethyl sulfoxide) was administered 30 min before 70% partial hepatectomy. Liver regeneration was estimated by the cell proliferation, apoptosis, and the related cell signaling and cycling proteins. In 30 min after hepatectomy in the rat, GSK-3βwas found to be translocated to the nucleus, but GSK-3βinhibitor SB216763 that could phosphorylate residue Ser9 on GSK-3βdid not attenuated the accumulation. Consequently, the inhibition of GSK-3βdecreased the nuclear factor-κB activity, the NF-κB-dependent gene expression and COX2 expression, but enhanced p21WAF1/Cip1 transcription. Moreover, the injection of SB216763 impaired the proliferation cell nuclear antigen (PCNA) index and increased the apoptosis of liver compared to the vehicle. GSK-3βplays an important role in rat liver regeneration. We conclude it may partially result from the inhibition of the NF-κB pathway and enhancement of p21 WAF1/Cip1 expression.