Chronic alcohol feeding potentiates hormone-induced calcium signalling in hepatocytes.

Chronic alcohol consumption causes a spectrum of liver diseases, but the pathogenic mechanisms driving the onset and progression of disease are not clearly defined. We show that chronic alcohol feeding sensitizes rat hepatocytes to Ca(2+) -mobilizing hormones resulting in a leftward shift in the concentration-response relationship and the transition from oscillatory to more sustained and prolonged Ca(2+) increases. Our data demonstrate that alcohol-dependent adaptation in the Ca(2+) signalling pathway occurs at the level of hormone-induced inositol 1,4,5 trisphosphate (IP(3) ) production and does not involve changes in the sensitivity of the IP(3) receptor or size of internal Ca(2+) stores. We suggest that prolonged and aberrant hormone-evoked Ca(2+) increases may stimulate the production of mitochondrial reactive oxygen species and contribute to alcohol-induced hepatocyte injury. ABSTRACT: 'Adaptive' responses of the liver to chronic alcohol consumption may underlie the development of cell and tissue injury. Alcohol administration can perturb multiple signalling pathways including phosphoinositide-dependent cytosolic calcium ([Ca(2+) ](i) ) increases, which can adversely affect mitochondrial Ca(2+) levels, reactive oxygen species production and energy metabolism. Our data indicate that chronic alcohol feeding induces a leftward shift in the dose-response for Ca(2+) -mobilizing hormones resulting in more sustained and prolonged [Ca(2+) ](i) increases in both cultured hepatocytes and hepatocytes within the intact perfused liver. Ca(2+) increases were initiated at lower hormone concentrations, and intercellular calcium wave propagation rates were faster in alcoholics compared to controls. Acute alcohol treatment (25 mm) completely inhibited hormone-induced calcium increases in control livers, but not after chronic alcohol-feeding, suggesting desensitization to the inhibitory actions of ethanol. Hormone-induced inositol 1,4,5 trisphosphate (IP(3) ) accumulation and phospholipase C (PLC) activity were significantly potentiated in hepatocytes from alcohol-fed rats compared to controls. Removal of extracellular calcium, or chelation of intracellular calcium did not normalize the differences in hormone-stimulated PLC activity, indicating calcium-dependent PLCs are not upregulated by alcohol. We propose that the liver 'adapts' to chronic alcohol exposure by increasing hormone-dependent IP(3) formation, leading to aberrant calcium increases, which may contribute to hepatocyte injury.