کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
3299223 1209924 2006 13 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Fatty Acid Ethyl Esters Cause Pancreatic Calcium Toxicity via Inositol Trisphosphate Receptors and Loss of ATP Synthesis
موضوعات مرتبط
علوم پزشکی و سلامت پزشکی و دندانپزشکی بیماری‌های گوارشی
پیش نمایش صفحه اول مقاله
Fatty Acid Ethyl Esters Cause Pancreatic Calcium Toxicity via Inositol Trisphosphate Receptors and Loss of ATP Synthesis
چکیده انگلیسی

Background & AimsFatty acid ethyl esters are ethanol metabolites inducing sustained, toxic elevations of the acinar cytosolic free calcium ion concentration ([Ca2+]C) implicated in pancreatitis. We sought to define the mechanisms of this elevation.MethodsIsolated mouse pancreatic acinar cells were loaded with fluorescent dyes for confocal microscopy to measure [Ca2+]C (Fluo 4, Fura Red), endoplasmic reticulum calcium ion concentration ([Ca2+]ER, Mg Fluo 4), mitochondrial membrane potential (TMRM), ADP:ATP ratio (Mg Green), and NADH autofluorescence in response to palmitoleic acid ethyl ester and palmitoleic acid (10–100 μmol/L). Whole-cell patch clamp was used to measure the calcium-activated chloride current and apply ethanol metabolites and/or ATP intracellularly.ResultsIntracellular delivery of ester induced oscillatory increases of [Ca2+]C and calcium-activated currents, inhibited acutely by caffeine (20 mmol/L), but not atropine, indicating involvement of inositol trisphosphate receptor channels. The stronger effect of extracellular ester or acid caused depletion of [Ca2+]ER, not prevented by caffeine, but associated with depleted ATP, depleted NADH autofluorescence, and depolarized mitochondria, suggesting calcium-ATPase pump failure because of lack of ATP. Intracellular ATP abolished the sustained rise in [Ca2+]C, although oscillatory signals persisted that were prevented by caffeine. Inhibition of ester hydrolysis markedly reduced its calcium-releasing effect and consequent toxicity.ConclusionsFatty acid ethyl ester increases [Ca2+]C through inositol trisphosphate receptors and, following hydrolysis, through calcium-ATPase pump failure from impaired mitochondrial ATP production. Lowering cellular fatty acid substrate concentrations may reduce cell injury in pancreatitis.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Gastroenterology - Volume 130, Issue 3, March 2006, Pages 781–793
نویسندگان
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