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Insulin Protects Pancreatic Acinar Cells from Palmitoleic Acid-induced Cellular Injury

Acute pancreatitis is a serious and sometimes fatal inflammatory disease where the pancreas digests itself. The non-oxidative ethanol metabolites palmitoleic acid (POA) and POA-ethylester (POAEE) are reported to induce pancreatitis caused by impaired mitochondrial metabolism, cytosolic Ca(2+) ([Ca(2...

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Detalles Bibliográficos
Autores principales: Samad, Aysha, James, Andrew, Wong, James, Mankad, Parini, Whitehouse, John, Patel, Waseema, Alves-Simoes, Marta, Siriwardena, Ajith K., Bruce, Jason I. E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4156068/
https://www.ncbi.nlm.nih.gov/pubmed/24993827
http://dx.doi.org/10.1074/jbc.M114.589440
Descripción
Sumario:Acute pancreatitis is a serious and sometimes fatal inflammatory disease where the pancreas digests itself. The non-oxidative ethanol metabolites palmitoleic acid (POA) and POA-ethylester (POAEE) are reported to induce pancreatitis caused by impaired mitochondrial metabolism, cytosolic Ca(2+) ([Ca(2+)](i)) overload and necrosis of pancreatic acinar cells. Metabolism and [Ca(2+)](i) are linked critically by the ATP-driven plasma membrane Ca(2+)-ATPase (PMCA) important for maintaining low resting [Ca(2+)](i). The aim of the current study was to test the protective effects of insulin on cellular injury induced by the pancreatitis-inducing agents, ethanol, POA, and POAEE. Rat pancreatic acinar cells were isolated by collagenase digestion and [Ca(2+)](i) was measured by fura-2 imaging. An in situ [Ca(2+)](i) clearance assay was used to assess PMCA activity. Magnesium green (MgGreen) and a luciferase-based ATP kit were used to assess cellular ATP depletion. Ethanol (100 mm) and POAEE (100 μm) induced a small but irreversible Ca(2+) overload response but had no significant effect on PMCA activity. POA (50–100 μm) induced a robust Ca(2+) overload, ATP depletion, inhibited PMCA activity, and consequently induced necrosis. Insulin pretreatment (100 nm for 30 min) prevented the POA-induced Ca(2+) overload, ATP depletion, inhibition of the PMCA, and necrosis. Moreover, the insulin-mediated protection of the POA-induced Ca(2+) overload was partially prevented by the phosphoinositide-3-kinase (PI3K) inhibitor, LY294002. These data provide the first evidence that insulin directly protects pancreatic acinar cell injury induced by bona fide pancreatitis-inducing agents, such as POA. This may have important therapeutic implications for the treatment of pancreatitis.