Fatty acid ethyl esters cause pancreatic calcium toxicity via inositol trisphosphate receptors and loss of ATP synthesis

Criddle, David N., Murphy, John, Fistetto, Gregorio, Barrow, Stephanie, Tepikin, Alexei V., Neoptolemos, John P., Sutton, Robert and Petersen, Ole Holger ORCID: https://orcid.org/0000-0002-6998-0380 2006. Fatty acid ethyl esters cause pancreatic calcium toxicity via inositol trisphosphate receptors and loss of ATP synthesis. Gastroenterology 130 (3) , pp. 781-793. 10.1053/j.gastro.2005.12.031

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Abstract

Background & Aims Fatty 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. Methods Isolated 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. Results Intracellular 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. Conclusions Fatty 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences Systems Immunity Research Institute (SIURI)
Subjects:	Q Science > Q Science (General)
Publisher:	Elsevier
ISSN:	0016-5085
Last Modified:	25 Oct 2022 10:10
URI:	https://orca.cardiff.ac.uk/id/eprint/61335

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