Basic–liver, pancreas, and biliary tractFatty Acid Ethyl Esters Cause Pancreatic Calcium Toxicity via Inositol Trisphosphate Receptors and Loss of ATP Synthesis
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Cell Preparation and Solutions
Freshly isolated pancreatic acinar cells and acinar cell clusters of 2 or 3 cells were prepared from the pancreases of adult CD1 mice using collagenase (Worthington Biochemical Corporation, Lakewood, NJ) as in our previous work.8, 14 All experiments were performed at room temperature (23°C–25°C), and all cells were used within 4 hours of isolation. The extracellular solution contained (mmol/L): 140 NaCl, 4.7 KCl, 1.13 MgCl2, 1 CaCl2, 10 D-glucose, 10 HEPES (adjusted to pH 7.35 using NaOH); in
Intracellular Fatty Acid Ethyl Ester Induces Oscillatory [Ca2+]C Increases
Intracellular application of palmitoleic acid ethyl ester (100 μmol/L, with 850 mmol/L ethanol to maintain solubility) via a patch-pipette (whole-cell recording configuration) induced repetitive [Ca2+]C spikes accompanied by associated calcium-activated chloride ion currents in voltage-clamped single pancreatic acinar cells (Figure 1A; 16 of 18 cells). The [Ca2+]C oscillations were similar to those observed following external application of physiologic doses of secretagogues.21 In many cases,
Discussion
Our new experiments show for the first time that fatty acid ethyl ester causes toxic elevation of [Ca2+]C in pancreatic acinar cells through activation of inositol trisphosphate receptors and inhibition of ATP production that results in SERCA and PMCA pump failure. Patch-clamp experiments in the whole-cell configuration identified the 2 effects to be largely independent because oscillations of [Ca2+]C occurred with direct intracellular ester application, as well as with extracellular ester when
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Supported by Programme, Cooperative, and Component grants from the Medical Research Council (United Kingdom) and an Amelie Waring Clinical Research Fellowship from CORE (to J.M.).
O.H.P. is a Medical Research Council professor.