Fatty Acid Ethyl Esters Cause Pancreatic Calcium Toxicity via Inositol Trisphosphate Receptors and Loss of ATP Synthesis

Criddle, David N.; Murphy, John A.; Fistetto, Gregorio; Barrow, Stephanie L.; Tepikin, Alexei V.; Neoptolemos, John P.; Sutton, Robert; Petersen, O. H.

doi:10.1053/j.gastro.2005.12.031

Cited by 249 publications

(370 citation statements)

References 49 publications

Supporting

Mentioning

346

Contrasting

Order By: Relevance

“…22 These recent findings published by Criddle et al 22 partly differ from our current work and their earlier studies. 17,21 In our current work, similar to their 2006 study, we note FAEEs to be less toxic than the parent FAs. In addition, the following points help resolve differences.…”

Section: Discussionsupporting

confidence: 83%

“…11 However, we also noted that the amount of cell death within the first hour was small compared with the >80% necrosis that occurred over the subsequent 4 hours and was insensitive to calcium chelation. 11 In 2006 Criddle et al 21 showed that FAEEs induced necrosis via conversion to FAs by an esterase sensitive to bis-(4-nitrophenyl) phosphate. However, the esterase so far has not been characterized, and the influence of bis-(4-nitrophenyl) phosphate on its activity was not measured in the study.…”

Section: Discussionmentioning

confidence: 99%

“…Their study also showed that in most cases POA was toxic at one-half the dose of POAEE. 21 The putative enzyme responsible for FAEE generation has remained elusive. The enzyme was mostly referred to as carboxylesterase 25 or cholesterol esterase in the 1990s.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Fatty Acid Ethyl Esters Are Less Toxic Than Their Parent Fatty Acids Generated during Acute Pancreatitis

Patel

Durgampudi

Noel

et al. 2016

The American Journal of Pathology

View full text Add to dashboard Cite

Although ethanol causes acute pancreatitis (AP) and lipolytic fatty acid (FA) generation worsens AP, the contribution of ethanol metabolites of FAs, ie, FA ethyl esters (FAEEs), to AP outcomes is unclear. Previously, pancreata of dying alcoholics and pancreatic necrosis in severe AP, respectively, showed high FAEEs and FAs, with oleic acid (OA) and its ethyl esters being the most abundant. We thus compared the toxicities of FAEEs and their parent FAs in severe AP. Pancreatic acini and peripheral blood mononuclear cells were exposed to FAs or FAEEs in vitro. The triglyceride of OA (i.e., glyceryl tri-oleate) or OAEE was injected into the pancreatic ducts of rats, and local and systemic severities were studied. Unsaturated FAs at equimolar concentrations to FAEEs induced a larger increase in cytosolic calcium, mitochondrial depolarization, and necro-apoptotic cell death. Glyceryl tri-oleate but not OAEE resulted in 70% mortality with increased serum OA, a severe inflammatory response, worse pancreatic necrosis, and multisystem organ failure. Our data show that FAs are more likely to worsen AP than FAEEs. Our observations correlate well with the high pancreatic FAEE concentrations in alcoholics without pancreatitis and high FA concentrations in pancreatic necrosis. Thus, conversion of FAs to FAEE may ameliorate AP in alcoholics. (Am J Pathol 2016, 186: 874e884; http://dx.doi.org/10.1016/j.ajpath.2015 Although fat necrosis has been associated with severe cases of pancreatitis for more than a century, 1,2 and alcohol consumption is a well-known risk factor for acute pancreatitis (AP), 3 only recently have we started understanding the mechanistic basis of these observations. 4e7 High amounts of unsaturated fatty acids (UFAs) have been noted in the pancreatic necrosis and sera of severe AP (SAP) patients by multiple groups. 8e12 These high UFAs seem pathogenically relevant because several studies show UFAs can cause pancreatic acinar injury or can worsen AP. 11e14 Ethanol may play a role in AP by distinct mechanisms, 3 including a worse inflammatory response to cholecystokinin, 4 increased zymogen activation, 15 basolateral enzyme release, 16 sensitization to stress, 7 FA ethyl esters (FAEEs), 17 cytosolic calcium, 18 and cell death. 19 Because the nonoxidative ethanol metabolite of fatty acids (FAs), FAEEs, were first noted to be elevated in the pancreata of dying alcoholics, they have been thought to play a role in AP. 17,19À22 Conclusive proof of the role of FAEEs in AP in comparison with their parent UFAs is lacking. Uncontrolled release of lipases into fat, whether in the pancreas or in the peritoneal cavity, may result in fat necrosis, UFA generation, which has been associated with SAP. 11,12 Pancreatic homogenates were also noted to have an ability to synthesize FAEEs from FAs and ethanol,20,23 and the putative enzyme for this was thought to be a lipase. 24,25 It has been shown that the FAEE synthase activity of the putative enzyme exceeds its lipolytic capacity by several fold. 25 Triglyceride (TG) forms >80% ...

show abstract

Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Fatty Acid Ethyl Esters Are Less Toxic Than Their Parent Fatty Acids Generated during Acute Pancreatitis

Patel

Durgampudi

Noel

et al. 2016

The American Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…Because ATP has a 10-fold greater affinity for Mg 2+ than ADP, and most intracellular Mg 2+ is present as Mg-ATP [22,27], the ADP:ATP ratio can be monitored. The elevation of fluorescence intensity caused by the increase in free intracellular Mg 2+ concentration suggests a reduction of (ATP) i [7]. The (ATP) i measurements were performed in standard HEPES-buffered solution.…”

Section: Materials and Solutions For The Experimentsmentioning

confidence: 99%

“…Excitation 488nm, emission was detected at >550nm with Olympus Fluoview FV10i confocal system [7]. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65…”

Section: Measurement Of Mitochondrial Transmembrane Potential ( (δψ) M )mentioning

confidence: 99%

Bile acids inhibit Na+/H+ exchanger and Cl−/HCO3 − exchanger activities via cellular energy breakdown and Ca2+ overload in human colonic crypts

Pallagi-Kunstár

Farkas

Maléth

et al. 2014

Pflugers Arch - Eur J Physiol

View full text Add to dashboard Cite

Abstract:Bile acids play important physiological role in the solubilisation and absorption of dietary lipids. However, under pathophysiological conditions, such as short bowel syndrome, they can reach the colon in high concentrations inducing diarrhea. In this study our aim was to characterise the cellular pathomechanism of bile-induced diarrhea using human samples. Colonic crypts were isolated from biopsies of patients (controls with negative colonoscopic findings) and of cholecystectomised/ileumresected patients with or without diarrhoea. In vitro measurement of the transporter activities revealed impaired Na+/H+ exchanger (NHE) and Cl-/HCO3-exchanger (CBE) activities in cholecystectomised/ileum-resected patients suffering from diarrhea, compared to control patients. Acute treatment of colonic crypts with 0.3mM chenodeoxycholate caused dose-dependent intracellular acidosis; moreover, the activities of acid/base transporters (NHE and CBE) were strongly impaired. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 3 AbstractBile acids play important physiological role in the solubilisation and absorption of dietary lipids. However, under pathophysiological conditions, such as short bowel syndrome, they can reach the colon in high concentrations inducing diarrhea. In this study our aim was to characterise the cellular pathomechanism of bile-induced diarrhea using human samples. Colonic crypts were isolated from biopsies of patients (controls with negative colonoscopic findings) and of cholecystectomised/ileum-resected patients with or without diarrhoea. In vitro measurement of the transporter activities revealed impaired Na + /H + exchanger (NHE) and Cl -/HCO 3 -exchanger (CBE) activities in cholecystectomised/ileum-resected patients suffering from diarrhea, compared to control patients. Acute treatment of colonic crypts with 0.3mM chenodeoxycholate caused dose-dependent intracellular acidosis; moreover, the activities of acid/base transporters (NHE and CBE) were strongly impaired. This concentration of chenodeoxycholate did not cause morphological changes in colonic epithelial cells, although significantly reduced the intracellular ATP level, decreased mitochondrial transmembrane potential and caused sustained intracellular Ca 2+ elevation. We also showed that chenodeoxycholate induced Ca 2+ release from the endoplasmic reticulum and extracellular Ca 2+ influx contributing to the Ca 2+ elevation. Importantly, our results suggest that the chenodeoxycholate induced inhibition of NHE activities was ATP-dependent, whereas the inhibition of CBE activity was mediated by the sustained Ca 2+ elevation.We suggest that bile acids inhibit the function of ion transporters via cellular energy breakdown and Ca 2+ overload in human colonic epithelial cells, which can reduce fluid and electrolyte absorption in the colon and promote ...

show abstract

Molecular Genetics of Chronic Pancreatitis

Szmola

Whitcomb

2009

Encyclopedia of Life Sciences

View full text Add to dashboard Cite

Chronic pancreatitis is a progressive inflammatory condition of the pancreas that results in impairment of both exocrine and endocrine functions of the gland. The finding that a mutation in the cationic trypsinogen gene ( PRSS1 ) causes hereditary pancreatitis was a major breakthrough that stimulated intensive research into the genetics of chronic pancreatitis. Further disease‐causing mutations were identified in the PRSS1 gene, and mutations in novel genes ( SPINK1 , CFTR , CTRC , CASR ) have been described in patients with idiopathic chronic pancreatitis. Genetic and biochemical studies highlighted the importance of the tightly regulated balance between trypsin activation and inactivation in the pathogenesis of pancreatitis.

show abstract

Fatty Acid Ethyl Esters Cause Pancreatic Calcium Toxicity via Inositol Trisphosphate Receptors and Loss of ATP Synthesis

Cited by 249 publications

References 49 publications

Fatty Acid Ethyl Esters Are Less Toxic Than Their Parent Fatty Acids Generated during Acute Pancreatitis

Fatty Acid Ethyl Esters Are Less Toxic Than Their Parent Fatty Acids Generated during Acute Pancreatitis

Bile acids inhibit Na+/H+ exchanger and Cl−/HCO3 − exchanger activities via cellular energy breakdown and Ca2+ overload in human colonic crypts

Molecular Genetics of Chronic Pancreatitis

Contact Info

Product

Resources

About