Chronic alcohol feeding potentiates hormone-induced calcium signalling in hepatocytes

Paula J. Bartlett, Anil Noronha Antony, Amit Agarwal, Mauricette Hilly, Victoria L. Prince, Laurent Combettes, Jan B. Hoek, Lawrence D. Gaspers

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Key points: 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 IP3 receptor 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+]i increases 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 IP3 formation, leading to aberrant calcium increases, which may contribute to hepatocyte injury.

Original languageEnglish (US)
Pages (from-to)3143-3164
Number of pages22
JournalJournal of Physiology
Volume595
Issue number10
DOIs
StatePublished - May 15 2017

All Science Journal Classification (ASJC) codes

  • Physiology

Keywords

  • alcohol
  • calcium signalling
  • hepatocyte

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    Bartlett, P. J., Antony, A. N., Agarwal, A., Hilly, M., Prince, V. L., Combettes, L., Hoek, J. B., & Gaspers, L. D. (2017). Chronic alcohol feeding potentiates hormone-induced calcium signalling in hepatocytes. Journal of Physiology, 595(10), 3143-3164. https://doi.org/10.1113/JP273891