title: Transporter-mediated bile acid uptake causes Ca2+-dependent cell death in rat pancreatic acinar cells.
abstract: OBJECTIVE
  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 Ca(2+) 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 [Ca(2+)](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 Ca(2+) ATPase pump to chronically deplete part of the Ca(2+) stored in the endoplasmic reticulum. This in turn led to the activation of capacitative Ca(2+) entry and a chronic [Ca(2+)](i) load. The increase in [Ca(2+)](i) and Ca(2+) load activated the inflammation-associated signals of c-Jun amino-terminal kinases and NF-kappaB and led to cell death, which was inhibited by buffering [Ca(2+)](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 Ca(2+) signaling.
authors.affiliation: Department of Pharmacology and Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Joo Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Kyung Hwan
authors.initials: KH
authors.lastname: Kim
authors.forename: Jin Ah
authors.initials: JA
authors.lastname: Lee
authors.forename: Wan
authors.initials: W
authors.lastname: Namkung
authors.forename: An-Qiang
authors.initials: AQ
authors.lastname: Sun
authors.forename: Meena
authors.initials: M
authors.lastname: Ananthanarayanan
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Suchy
authors.forename: Dong Min
authors.initials: DM
authors.lastname: Shin
authors.forename: Shmuel
authors.initials: S
authors.lastname: Muallem
authors.forename: Min Goo
authors.initials: MG
authors.lastname: Lee
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000494:pharmacology; D002118:Calcium / Q000502:physiology*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D002352:Carrier Proteins / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D004338:Drug Combinations; D006913:Hydroxysteroid Dehydrogenases; D007158:Immunologic Techniques; D066298:In Vitro Techniques; D008562:Membrane Glycoproteins; D010179:Pancreas / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D015398:Signal Transduction / Q000502:physiology; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
chemical_list: D001647:Bile Acids and Salts; D002118:Calcium; D000252:Calcium-Transporting ATPases; D002352:Carrier Proteins; D004338:Drug Combinations; D006913:Hydroxysteroid Dehydrogenases; D008562:Membrane Glycoproteins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C037643:bile acid binding proteins; C435496:AKR1C2 protein, human; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)