CHRONIC ETHANOL-CONSUMPTION DISTURBS G-PROTEIN EXPRESSION AND INHIBITS CYCLIC-AMP DEPENDENT SIGNALING IN REGENERATING RAT-LIVER

Evidence suggests that ethanol desensitizes hepatocytes to the trophic effects of hormones. Cyclic AMP-dependent signals are important regulators of intermediary metabolism, cellular proliferation and differentiation, and modulate liver growth during hepatic regeneration. The events leading to cyclic AMP accumulation after partial hepatectomy were characterized in rats consistently fed ethanol-containing diets and compared with results in rats fed isocaloric amounts of nonethanol diet to determine whether altered cyclic AMP-dependent signal transduction contributes to ethanol-associated aberrations in hepatic growth regulation. Ethanol treatment significantly inhibited hepatic accumulation of cyclic AMP after partial hepatectomy. This was most likely the result of decreased synthesis of cyclic AMP because activation of adenylyl cyclase by agents acting through receptors (e.g., glucagon or isoproterenol), GTP-binding proteins (GTP-gamma-S) and directly on adenylyl cyclase (e.g., forskolin) was significantly inhibited in ethanol-fed rats. Both homologous and heterologous desensitization contributed to this effect. Beta1-Adrenergic receptors were relatively down-regulated 6 hr after partial hepatectomy in ethanol-fed rats, whereas glucagon receptor kinetics were similar in the two groups. Liver membrane expression of GTP-binding proteins differed markedly after partial hepatectomy in ethanol-fed and pair-fed rats. Ethanol significantly inhibited post-partial hepatectomy induction of the stimulatory G protein, G(s)alpha but led to overexpression of the inhibitory, G(i)2alpha, subunit. Steady-state messenger RNA levels of these G proteins were similar in ethanol-fed and pair-fed rats, suggesting that ethanol inhibits G protein expression posttranscriptionally. Differences in hepatic expression of the cyclic AMP-regulated gene, phosphoenolpyruvate carboxykinase, were sought to sereen for potential functional implications of altered cyclic AMP-dependent signaling. Post-partial hepatectomy induction of phosphoenolpyruvate carboxykinase expression was inhibited in ethanol-fed animals. Ethanol-induced desensitization of signaling by way of cyclic AMP-dependent paths may constitute a major obstacle to the orderly process of liver regeneration.