Impaired activities of cyclic adenosine monophosphate-responsive element binding protein, protein kinase A and calcium-independent phospholipase A2 are involved in deteriorated regeneration of cirrhotic liver after partial hepatectomy in rats.

Aims:  This study is to elucidate whether cyclic adenosine monophosphate (cAMP)-mediated signal is involved in lower regenerative potential of cirrhotic liver. Methods:  Hepatic cAMP concentration, activities of protein kinase A (PKA), c-AMP responsive element binding protein (CREB) and Ca2+-independent phospholipase A2 (iPLA2) and regeneration rate were compared between rats with thioacetamide-induced cirrhotic and normal livers after two-third hepatectomy. Results:  The liver regeneration estimated by the rates of [3H]-thymidine incorporation and staining of proliferating cell nuclear antigen was significantly lower in the cirrhotic group. CREB, PKA and iPLA2 activities, assessed by western blots and electromobility shift assay, were significantly impaired after hepatectomy in the cirrhosis group. PKA and iPLA2 silencing by siRNA transfection significantly inhibited CREB activity and cell growth in transformed hepatocytes in vitro. Conclusions:  CREB dysfunction, mediated by PKA and iPLA2 suppression, may be involved in the deteriorated liver regeneration in the cirrhotic rats.