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, Dong Min Shin, Shmuel Muallem, Min Goo Lee

Research output: Contribution to journalArticle

125 Citations (Scopus)

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

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

Fingerprint Dive into the research topics of 'Transporter-mediated bile acid uptake causes Ca<sup>2+</sup>-dependent cell death in rat pancreatic acinar cells'. Together they form a unique fingerprint.

  • Cite this

    Kim, J. Y., Kim, K. H., Lee, J. A., Namkung, W., Sun, A. Q., Ananthanarayanan, M., Suchy, F. J., Shin, D. M., Muallem, S., & 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