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Bile acids induce necrosis in pancreatic stellate cells dependent on calcium entry and sodium‐driven bile uptake
KEY POINTS: Acute biliary pancreatitis is a sudden and severe condition initiated by bile reflux into the pancreas. Bile acids are known to induce Ca(2+) signals and necrosis in isolated pancreatic acinar cells but the effects of bile acids on stellate cells are unexplored. Here we show that cholate...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5088250/ https://www.ncbi.nlm.nih.gov/pubmed/27406326 http://dx.doi.org/10.1113/JP272774 |
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author | Ferdek, Pawel E. Jakubowska, Monika A. Gerasimenko, Julia V. Gerasimenko, Oleg V. Petersen, Ole H. |
author_facet | Ferdek, Pawel E. Jakubowska, Monika A. Gerasimenko, Julia V. Gerasimenko, Oleg V. Petersen, Ole H. |
author_sort | Ferdek, Pawel E. |
collection | PubMed |
description | KEY POINTS: Acute biliary pancreatitis is a sudden and severe condition initiated by bile reflux into the pancreas. Bile acids are known to induce Ca(2+) signals and necrosis in isolated pancreatic acinar cells but the effects of bile acids on stellate cells are unexplored. Here we show that cholate and taurocholate elicit more dramatic Ca(2+) signals and necrosis in stellate cells compared to the adjacent acinar cells in pancreatic lobules; whereas taurolithocholic acid 3‐sulfate primarily affects acinar cells. Ca(2+) signals and necrosis are strongly dependent on extracellular Ca(2+) as well as Na(+); and Na(+)‐dependent transport plays an important role in the overall bile acid uptake in pancreatic stellate cells. Bile acid‐mediated pancreatic damage can be further escalated by bradykinin‐induced signals in stellate cells and thus killing of stellate cells by bile acids might have important implications in acute biliary pancreatitis. ABSTRACT: Acute biliary pancreatitis, caused by bile reflux into the pancreas, is a serious condition characterised by premature activation of digestive enzymes within acinar cells, followed by necrosis and inflammation. Bile acids are known to induce pathological Ca(2+) signals and necrosis in acinar cells. However, bile acid‐elicited signalling events in stellate cells remain unexplored. This is the first study to demonstrate the pathophysiological effects of bile acids on stellate cells in two experimental models: ex vivo (mouse pancreatic lobules) and in vitro (human cells). Sodium cholate and taurocholate induced cytosolic Ca(2+) elevations in stellate cells, larger than those elicited simultaneously in the neighbouring acinar cells. In contrast, taurolithocholic acid 3‐sulfate (TLC‐S), known to induce Ca(2+) oscillations in acinar cells, had only minor effects on stellate cells in lobules. The dependence of the Ca(2+) signals on extracellular Na(+) and the presence of sodium–taurocholate cotransporting polypeptide (NTCP) indicate a Na(+)‐dependent bile acid uptake mechanism in stellate cells. Bile acid treatment caused necrosis predominantly in stellate cells, which was abolished by removal of extracellular Ca(2+) and significantly reduced in the absence of Na(+), showing that bile‐dependent cell death was a downstream event of Ca(2+) signals. Finally, combined application of TLC‐S and the inflammatory mediator bradykinin caused more extensive necrosis in both stellate and acinar cells than TLC‐S alone. Our findings shed new light on the mechanism by which bile acids promote pancreatic pathology. This involves not only signalling in acinar cells but also in stellate cells. |
format | Online Article Text |
id | pubmed-5088250 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-50882502016-11-08 Bile acids induce necrosis in pancreatic stellate cells dependent on calcium entry and sodium‐driven bile uptake Ferdek, Pawel E. Jakubowska, Monika A. Gerasimenko, Julia V. Gerasimenko, Oleg V. Petersen, Ole H. J Physiol Molecular and cellular KEY POINTS: Acute biliary pancreatitis is a sudden and severe condition initiated by bile reflux into the pancreas. Bile acids are known to induce Ca(2+) signals and necrosis in isolated pancreatic acinar cells but the effects of bile acids on stellate cells are unexplored. Here we show that cholate and taurocholate elicit more dramatic Ca(2+) signals and necrosis in stellate cells compared to the adjacent acinar cells in pancreatic lobules; whereas taurolithocholic acid 3‐sulfate primarily affects acinar cells. Ca(2+) signals and necrosis are strongly dependent on extracellular Ca(2+) as well as Na(+); and Na(+)‐dependent transport plays an important role in the overall bile acid uptake in pancreatic stellate cells. Bile acid‐mediated pancreatic damage can be further escalated by bradykinin‐induced signals in stellate cells and thus killing of stellate cells by bile acids might have important implications in acute biliary pancreatitis. ABSTRACT: Acute biliary pancreatitis, caused by bile reflux into the pancreas, is a serious condition characterised by premature activation of digestive enzymes within acinar cells, followed by necrosis and inflammation. Bile acids are known to induce pathological Ca(2+) signals and necrosis in acinar cells. However, bile acid‐elicited signalling events in stellate cells remain unexplored. This is the first study to demonstrate the pathophysiological effects of bile acids on stellate cells in two experimental models: ex vivo (mouse pancreatic lobules) and in vitro (human cells). Sodium cholate and taurocholate induced cytosolic Ca(2+) elevations in stellate cells, larger than those elicited simultaneously in the neighbouring acinar cells. In contrast, taurolithocholic acid 3‐sulfate (TLC‐S), known to induce Ca(2+) oscillations in acinar cells, had only minor effects on stellate cells in lobules. The dependence of the Ca(2+) signals on extracellular Na(+) and the presence of sodium–taurocholate cotransporting polypeptide (NTCP) indicate a Na(+)‐dependent bile acid uptake mechanism in stellate cells. Bile acid treatment caused necrosis predominantly in stellate cells, which was abolished by removal of extracellular Ca(2+) and significantly reduced in the absence of Na(+), showing that bile‐dependent cell death was a downstream event of Ca(2+) signals. Finally, combined application of TLC‐S and the inflammatory mediator bradykinin caused more extensive necrosis in both stellate and acinar cells than TLC‐S alone. Our findings shed new light on the mechanism by which bile acids promote pancreatic pathology. This involves not only signalling in acinar cells but also in stellate cells. John Wiley and Sons Inc. 2016-08-08 2016-11-01 /pmc/articles/PMC5088250/ /pubmed/27406326 http://dx.doi.org/10.1113/JP272774 Text en © 2016 The Authors The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Molecular and cellular Ferdek, Pawel E. Jakubowska, Monika A. Gerasimenko, Julia V. Gerasimenko, Oleg V. Petersen, Ole H. Bile acids induce necrosis in pancreatic stellate cells dependent on calcium entry and sodium‐driven bile uptake |
title | Bile acids induce necrosis in pancreatic stellate cells dependent on calcium entry and sodium‐driven bile uptake |
title_full | Bile acids induce necrosis in pancreatic stellate cells dependent on calcium entry and sodium‐driven bile uptake |
title_fullStr | Bile acids induce necrosis in pancreatic stellate cells dependent on calcium entry and sodium‐driven bile uptake |
title_full_unstemmed | Bile acids induce necrosis in pancreatic stellate cells dependent on calcium entry and sodium‐driven bile uptake |
title_short | Bile acids induce necrosis in pancreatic stellate cells dependent on calcium entry and sodium‐driven bile uptake |
title_sort | bile acids induce necrosis in pancreatic stellate cells dependent on calcium entry and sodium‐driven bile uptake |
topic | Molecular and cellular |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5088250/ https://www.ncbi.nlm.nih.gov/pubmed/27406326 http://dx.doi.org/10.1113/JP272774 |
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