Transporter-mediated bile acid uptake causes Ca2+-dependent cell death in rat pancreatic acinar cells

Joo Young Kim, Kyung Hwan Kim, Jin Ah Lee, Wan Namkung, An Qiang Sun, Meena Ananthanarayanan, Frederick J. Suchy, DongMin Shin, Shmuel Muallem, Min Goo Lee

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Abstract

Background & Aims: The mechanism by which cholelithiasis increases the risk of acute pancreatitis remains obscure. Because bile acids can enter the pancreas either by luminal diffusion or by interstitial leakage during gallstone impaction and pancreatitis is associated with impaired Ca2+ signaling, we examined the effect of bile acids on pancreatic acinar cell signaling and the associated intracellular events. Methods: Rat pancreatic acinar cells were isolated. by collagenase digestion and the effects of bile acids on [Ca2+]i signaling, cell survival, inflammatory signals, and the molecular and functional expressions of bile uptake transporters were analyzed. Results: Bile acids specifically inhibited the sarco/endoplasmic reticulum Ca2+ ATPase pump to chronically deplete part of the Ca2+ stored in the endoplasmic reticulum. This in turn led to the activation of capacitative Ca2+ entry and a chronic [Ca2+]i load. The increase in [Ca2+]i and Ca2+ load activated the inflammation associated signals of c-Jun amino-terminal kinases and NF-κB and led to cell death, which was inhibited by buffering [Ca2+]i with 1,2-bis(2-aminophenoxy)ethane N, N, N, N′-tetraacetic acid. A comprehensive molecular analysis of bile acid transporters revealed that pancreatic acinar cells express the bile uptake transporters Na+-taurocholate co-transporting polypeptide and organic anion transporting polypeptide in the luminal and basolateral membranes, respectively. Bile acid uptake into acinar cells was in part Na+-dependent and in part Na+-independent, suggesting that both transporters contribute to bile acid influx into acinar cells. Conclusions: These results suggest that bile acids can be transported into pancreatic acinar cells through specific membrane transporters and induce cell death by impairing cellular Ca2+ signaling.

Original languageEnglish
Article number00028
Pages (from-to)1941-1953
Number of pages13
JournalGastroenterology
Volume122
Issue number7
DOIs
Publication statusPublished - 2002 Jan 1

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Acinar Cells
Bile Acids and Salts
Cell Death
Bile
Pancreatitis
Sarcoplasmic Reticulum Calcium-Transporting ATPases
Taurocholic Acid
Peptides
Ethane
Cholelithiasis
Membrane Transport Proteins
JNK Mitogen-Activated Protein Kinases
Gallstones
Collagenases
bile acid binding proteins
Endoplasmic Reticulum
Anions
Pancreas
Digestion
Cell Survival

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

Cite this

Kim, J. Y., Kim, K. H., Lee, J. A., Namkung, W., Sun, A. Q., Ananthanarayanan, M., ... Lee, M. G. (2002). Transporter-mediated bile acid uptake causes Ca2+-dependent cell death in rat pancreatic acinar cells. Gastroenterology, 122(7), 1941-1953. [00028]. https://doi.org/10.1053/gast.2002.33617
Kim, Joo Young ; Kim, Kyung Hwan ; Lee, Jin Ah ; Namkung, Wan ; Sun, An Qiang ; Ananthanarayanan, Meena ; Suchy, Frederick J. ; Shin, DongMin ; Muallem, Shmuel ; Lee, Min Goo. / Transporter-mediated bile acid uptake causes Ca2+-dependent cell death in rat pancreatic acinar cells. In: Gastroenterology. 2002 ; Vol. 122, No. 7. pp. 1941-1953.
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abstract = "Background & Aims: The mechanism by which cholelithiasis increases the risk of acute pancreatitis remains obscure. Because bile acids can enter the pancreas either by luminal diffusion or by interstitial leakage during gallstone impaction and pancreatitis is associated with impaired Ca2+ signaling, we examined the effect of bile acids on pancreatic acinar cell signaling and the associated intracellular events. Methods: Rat pancreatic acinar cells were isolated. by collagenase digestion and the effects of bile acids on [Ca2+]i signaling, cell survival, inflammatory signals, and the molecular and functional expressions of bile uptake transporters were analyzed. Results: Bile acids specifically inhibited the sarco/endoplasmic reticulum Ca2+ ATPase pump to chronically deplete part of the Ca2+ stored in the endoplasmic reticulum. This in turn led to the activation of capacitative Ca2+ entry and a chronic [Ca2+]i load. The increase in [Ca2+]i and Ca2+ load activated the inflammation associated signals of c-Jun amino-terminal kinases and NF-κB and led to cell death, which was inhibited by buffering [Ca2+]i with 1,2-bis(2-aminophenoxy)ethane N, N, N, N′-tetraacetic acid. A comprehensive molecular analysis of bile acid transporters revealed that pancreatic acinar cells express the bile uptake transporters Na+-taurocholate co-transporting polypeptide and organic anion transporting polypeptide in the luminal and basolateral membranes, respectively. Bile acid uptake into acinar cells was in part Na+-dependent and in part Na+-independent, suggesting that both transporters contribute to bile acid influx into acinar cells. Conclusions: These results suggest that bile acids can be transported into pancreatic acinar cells through specific membrane transporters and induce cell death by impairing cellular Ca2+ signaling.",
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Kim, JY, Kim, KH, Lee, JA, Namkung, W, Sun, AQ, Ananthanarayanan, M, Suchy, FJ, Shin, D, Muallem, S & Lee, MG 2002, 'Transporter-mediated bile acid uptake causes Ca2+-dependent cell death in rat pancreatic acinar cells', Gastroenterology, vol. 122, no. 7, 00028, pp. 1941-1953. https://doi.org/10.1053/gast.2002.33617

Transporter-mediated bile acid uptake causes Ca2+-dependent cell death in rat pancreatic acinar cells. / Kim, Joo Young; Kim, Kyung Hwan; Lee, Jin Ah; Namkung, Wan; Sun, An Qiang; Ananthanarayanan, Meena; Suchy, Frederick J.; Shin, DongMin; Muallem, Shmuel; Lee, Min Goo.

In: Gastroenterology, Vol. 122, No. 7, 00028, 01.01.2002, p. 1941-1953.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Transporter-mediated bile acid uptake causes Ca2+-dependent cell death in rat pancreatic acinar cells

AU - Kim, Joo Young

AU - Kim, Kyung Hwan

AU - Lee, Jin Ah

AU - Namkung, Wan

AU - Sun, An Qiang

AU - Ananthanarayanan, Meena

AU - Suchy, Frederick J.

AU - Shin, DongMin

AU - Muallem, Shmuel

AU - Lee, Min Goo

PY - 2002/1/1

Y1 - 2002/1/1

N2 - Background & Aims: The mechanism by which cholelithiasis increases the risk of acute pancreatitis remains obscure. Because bile acids can enter the pancreas either by luminal diffusion or by interstitial leakage during gallstone impaction and pancreatitis is associated with impaired Ca2+ signaling, we examined the effect of bile acids on pancreatic acinar cell signaling and the associated intracellular events. Methods: Rat pancreatic acinar cells were isolated. by collagenase digestion and the effects of bile acids on [Ca2+]i signaling, cell survival, inflammatory signals, and the molecular and functional expressions of bile uptake transporters were analyzed. Results: Bile acids specifically inhibited the sarco/endoplasmic reticulum Ca2+ ATPase pump to chronically deplete part of the Ca2+ stored in the endoplasmic reticulum. This in turn led to the activation of capacitative Ca2+ entry and a chronic [Ca2+]i load. The increase in [Ca2+]i and Ca2+ load activated the inflammation associated signals of c-Jun amino-terminal kinases and NF-κB and led to cell death, which was inhibited by buffering [Ca2+]i with 1,2-bis(2-aminophenoxy)ethane N, N, N, N′-tetraacetic acid. A comprehensive molecular analysis of bile acid transporters revealed that pancreatic acinar cells express the bile uptake transporters Na+-taurocholate co-transporting polypeptide and organic anion transporting polypeptide in the luminal and basolateral membranes, respectively. Bile acid uptake into acinar cells was in part Na+-dependent and in part Na+-independent, suggesting that both transporters contribute to bile acid influx into acinar cells. Conclusions: These results suggest that bile acids can be transported into pancreatic acinar cells through specific membrane transporters and induce cell death by impairing cellular Ca2+ signaling.

AB - Background & Aims: The mechanism by which cholelithiasis increases the risk of acute pancreatitis remains obscure. Because bile acids can enter the pancreas either by luminal diffusion or by interstitial leakage during gallstone impaction and pancreatitis is associated with impaired Ca2+ signaling, we examined the effect of bile acids on pancreatic acinar cell signaling and the associated intracellular events. Methods: Rat pancreatic acinar cells were isolated. by collagenase digestion and the effects of bile acids on [Ca2+]i signaling, cell survival, inflammatory signals, and the molecular and functional expressions of bile uptake transporters were analyzed. Results: Bile acids specifically inhibited the sarco/endoplasmic reticulum Ca2+ ATPase pump to chronically deplete part of the Ca2+ stored in the endoplasmic reticulum. This in turn led to the activation of capacitative Ca2+ entry and a chronic [Ca2+]i load. The increase in [Ca2+]i and Ca2+ load activated the inflammation associated signals of c-Jun amino-terminal kinases and NF-κB and led to cell death, which was inhibited by buffering [Ca2+]i with 1,2-bis(2-aminophenoxy)ethane N, N, N, N′-tetraacetic acid. A comprehensive molecular analysis of bile acid transporters revealed that pancreatic acinar cells express the bile uptake transporters Na+-taurocholate co-transporting polypeptide and organic anion transporting polypeptide in the luminal and basolateral membranes, respectively. Bile acid uptake into acinar cells was in part Na+-dependent and in part Na+-independent, suggesting that both transporters contribute to bile acid influx into acinar cells. Conclusions: These results suggest that bile acids can be transported into pancreatic acinar cells through specific membrane transporters and induce cell death by impairing cellular Ca2+ signaling.

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DO - 10.1053/gast.2002.33617

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