Transporter-mediated bile acid uptake causes Ca2+-dependent cell death in rat pancreatic acinar cells.
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.
Kim
Joo Young
JY
Department of Pharmacology and Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea.
Kim
Kyung Hwan
KH
Lee
Jin Ah
JA
Namkung
Wan
W
Sun
An-Qiang
AQ
Ananthanarayanan
Meena
M
Suchy
Frederick J
FJ
Shin
Dong Min
DM
Muallem
Shmuel
S
Lee
Min Goo
MG
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)
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)