Inhibited activities in CCAAT/enhancer-binding protein, activating protein-1 and cyclins after hepatectomy in rats with thioacetamide-induced liver cirrhosis

Transcriptional activation of nuclear factor (NF)-κB, signal transducers and activators of transcription (STAT) 3, activating protein (AP)-1 and CCAAT/enhancer-binding protein (C/EBP) plays an important role in liver regeneration by modulating cell cycle regulators. The regeneration of cirrhotic liver after hepatectomy is inhibited despite intact expression of growth factors. To elucidate the mechanism involved, regeneration responses in growth factor receptors, transcription factors, and cell cycle regulators after two-thirds hepatectomy were compared between rats with thioacetamide-induced cirrhotic and normal liver. The expression of c-met and epidermal growth factor receptor analyzed by RT-PCR and immunohistochemistry did not differ between the two groups. The activities of C/EBP and AP-1 evaluated by electrophoretic mobility shift assay were significantly inhibited in the cirrhotic group compared with those in the control group, but not those of NF-κB and STAT3. The expression of cyclin-D1, -E, and -A assessed by Western blot analysis was significantly decreased in the cirrhotic group compared with the control group. The level in p21^Cip1 or p27^Kip1 did not differ between the two groups. The liver regeneration estimated by the rates of [³H]thymidine incorporation into DNA and staining of proliferating cell nuclear antigen was significantly lower in the cirrhotic rats than in the controls. In conclusion, downregulation of cyclin -D1, -E, and -A expression, which may be induced by impaired activities of C/EBP and AP-1, is responsible for the decreased regenerative capacity of cirrhotic liver after partial hepatectomy.