title: Chronic alcohol feeding potentiates hormone-induced calcium signalling in hepatocytes.
abstract: 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 Ca2+-mobilizing hormones resulting in a leftward shift in the concentration-response relationship and the transition from oscillatory to more sustained and prolonged Ca2+increases. Our data demonstrate that alcohol-dependent adaptation in the Ca2+signalling pathway occurs at the level of hormone-induced inositol 1,4,5 trisphosphate (IP3) production and does not involve changes in the sensitivity of the IP3receptor or size of internal Ca2+stores. We suggest that prolonged and aberrant hormone-evoked Ca2+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 ([Ca2+]i) increases, which can adversely affect mitochondrial Ca2+levels, reactive oxygen species production and energy metabolism. Our data indicate that chronic alcohol feeding induces a leftward shift in the dose-response for Ca2+-mobilizing hormones resulting in more sustained and prolonged [Ca2+]iincreases in both cultured hepatocytes and hepatocytes within the intact perfused liver. Ca2+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 (IP3) 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 IP3formation, leading to aberrant calcium increases, which may contribute to hepatocyte injury.
authors.affiliation: Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School Rutgers, The State University of New Jersey, Newark, NJ, 07103, USA.
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Bartlett
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors.forename: Anil Noronha
authors.initials: AN
authors.lastname: Antony
authors.affiliation: Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School Rutgers, The State University of New Jersey, Newark, NJ, 07103, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Agarwal
authors.affiliation: INSERM UMR-S 757, Université de Paris-Sud, bât 443, 91405, Orsay, France.
authors.forename: Mauricette
authors.initials: M
authors.lastname: Hilly
authors.affiliation: Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School Rutgers, The State University of New Jersey, Newark, NJ, 07103, USA.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Prince
authors.affiliation: INSERM UMR-S 757, Université de Paris-Sud, bât 443, 91405, Orsay, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Combettes
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors.forename: Jan B
authors.initials: JB
authors.lastname: Hoek
authors.affiliation: Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School Rutgers, The State University of New Jersey, Newark, NJ, 07103, USA.
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: Gaspers
mesh_terms: D000428:Alcohol Drinking / Q000378:metabolism*; D000437:Alcoholism / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D017207:Rats, Sprague-Dawley; D010738:Type C Phospholipases / Q000378:metabolism*; D014667:Vasopressins / Q000494:pharmacology
chemical_list: D014667:Vasopressins; D015544:Inositol 1,4,5-Trisphosphate; D010738:Type C Phospholipases; D002118:Calcium
keywords: alcohol; calcium signalling; hepatocyte