The liver is a major target for both short- and long-term actions of ethanol. The mechanisms that mediate the response of cells and tissues to chronic intake of ethanol are unknown, but it is likely that both adaptive and deleterious responses are triggered by short-term interactions of the cell with ethanol. Cellular signaling processes are candidates to mediate the connection between short- and long-term actions of ethanol. Receptor-coupled signal transduction systems in the plasma membrane of many different cell types are affected by ethanol. In the liver, the signaling processes associated with phospholipases C and D are particularly responsive to ethanol. In this review, we investigate the direct and indirect short-term effects of ethanol on the signal transduction systems in liver and discuss the possible implications for the responses of the liver to chronic ethanol exposure.
Phospholipase C (PLC)‐mediated signal transduction processes in rat hepatocytes are subject to modulation by protein phosphatases (PPases) and protein kinases, including protein kinase A (PKA) and protein kinase C. Ethanol (EtOH) stimulates PLC activity in liver cells in the absence of hormones, and EtOH pretreatment inhibits the subsequent stimulation of PLC by hormonal stimuli. There is evidence that protein kinase activities are involved in these actions of EtOH. We investigated the effects of okadaic acid (OKA), a PPase inhibitor, and 8‐(4‐chlorophenylthio)adenosine 3′:5′‐cyclic monophosphate (cpt‐cAMP), a cell permeant cAMP analog that activates PKA, on EtOH‐induced PLC activation. In addition, we studied the combined effects of cpt‐cAMP and EtOH/OKA on vasopressin‐induced PLC activation. PLC activation (cytosolic Ca2+ mobilization and inositol trisphosphate accumulation) induced by EtOH and vasopressin was inhibited by treatment with OKA, and was potentiated by cpt‐cAMP. OKA treatment prevented the effect of cpt‐cAMP. Pretreatment with EtOH caused inhibition of vasopressin‐induced PLC activation. EtOH also decreased the enhancing effect of cpt‐cAMP on the responses to vasopressin. The susceptibility to enhancement by cpt‐cAMP plotted as a function of the initial rate of vasopressin‐induced Ca2+ mobilization in EtOH‐treated cells was similar to the pattern observed in OKA‐treated cells. These data suggest that interactions of OKA and PKA on EtOH‐induced PLC activation occurred at the level of G‐protein, and indicate that EtOH may act as an inhibitory agent of PPase.
The activation of phosphoinositide-specific phospholipase C by ethanol was compared in hepatocytes isolated from ethanol-fed rats and from pair-fed control animals. Ethanol (100-300 mM) caused a dose-dependent transient increase in cytosolic free Ca2+ levels in indo-1-loaded hepatocytes from both groups of animals. The rate of Ca2+ increase was similar in hepatocytes from control and ethanol-fed rats, but the decay of the Ca2+ increase was somewhat slower in the latter preparation. The ethanol-induced Ca2+ increase caused activation of glycogen phosphorylase, with 50% response at 50 mM-ethanol and a maximal response at 150-200 mM-ethanol, not significantly different in hepatocytes from control and ethanol-fed animals. Ins(1,4,5)P3 formation in response to ethanol (300 mM) or vasopressin (2 nM or 40 nM) was also similar in the two preparations. It is concluded that long-term ethanol feeding does not lead to an adaptive response with respect to the ethanol-induced phospholipase C activation in rat hepatocytes. The ability of ethanol in vitro to decrease membrane molecular order in liver plasma membranes from ethanol-fed and control rats was measured by e.s.r. Membranes from ethanol-fed animals had a significantly lower baseline order parameter compared with control preparations (0.313 and 0.327 respectively), indicative of decreased membrane molecular order. Addition of 100 mM-ethanol significantly decreased the order parameter in control preparations by 2.1%, but had no effect on the order parameter of plasma membranes from ethanol-fed rats, indicating that the plasma membranes had developed tolerance to ethanol, similar to other membranes in the liver. Thus the membrane structural changes associated with this membrane tolerance do not modify the ethanol-induced activation of phospholipase C. The transient activation of phospholipase C by ethanol in hepatocytes may play a role in maintaining an adaptive phenotype in rat liver.
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