Dysregulated phosphorylation and nuclear translocation of cyclic AMP response element binding protein (CREB) in rat...

Binge ethanol during chronic ethanol abuse augments liver injury but the underlying mechanism remains unknown. CREB (cyclic AMP response element binding protein) is implicated as a key transcription factor in liver regeneration and hepatic glucose and lipid metabolism. We examined the effects of ethanol on the phosphorylation of CREB in hepatocytes, and in vivo in rat liver after chronic ethanol binge. For in vivo studies, rats were fed ethanol in liquid diet for 4 weeks followed by single binge administration of ethanol (intragastric, 5 g/kg body weight). Four hours after binge administration, liver samples were collected and analyzed. Treatment of hepatocytes with ethanol caused increased phosphorylation of p38 MAPK (mitogen activated protein kinase), MSK-1 (mitogen and stress activated kinase) and CREB in the nuclear compartment without activation of ERK1/2 (extracellular regulated kinase); whereas angiotensin II induced activation of CREB was accompanied by activation of ERK1/2. In chronic ethanol-binge studies, analysis of the whole cell extracts showed increased phosphorylation of CREB, with no effect on CREB protein levels; increased phospho-ERK1/2, and decreased phospho-p38 MAPK. In contrast, the nuclear levels of phospho-CREB and CREB protein were reduced. Reduction in phospho-CREB and CREB proteins in the nuclear extracts was accompanied by suppression of mRNA levels for CPT-1 (carnitine palmitoyl transferase-1) and increase in hepatic steatosis after binge. It is concluded that binge ethanol causes defect in the nuclear accumulation of CREB protein, phospho-CREB, and an exaggerated hepatic steatosis. These in vivo effects are distinct from the effects of ethanol on hepatocytes in vitro.