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

Authors
 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 
Citation
 GASTROENTEROLOGY, Vol.122(7) : 1941-1953, 2002 
Journal Title
 GASTROENTEROLOGY 
ISSN
 0016-5085 
Issue Date
2002
MeSH
Animals ; Bile Acids and Salts/pharmacology ; Calcium/physiology* ; Calcium-Transporting ATPases/antagonists & inhibitors ; Carrier Proteins/metabolism* ; Cell Death/drug effects ; Cell Death/physiology ; Drug Combinations ; Hydroxysteroid Dehydrogenases* ; Immunologic Techniques ; In Vitro Techniques ; Membrane Glycoproteins* ; Pancreas/cytology ; Pancreas/drug effects ; Pancreas/physiology* ; Rats ; Reverse Transcriptase Polymerase Chain Reaction ; Sarcoplasmic Reticulum Calcium-Transporting ATPases ; Signal Transduction/physiology
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.
Full Text
http://www.sciencedirect.com/science/article/pii/S0016508502000288
DOI
10.1053/gast.2002.33617
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
2. College of Dentistry (치과대학) > Dept. of Oral Biology (구강생물학교실) > 1. Journal Papers
Yonsei Authors
Kim, Kyung Hwan(김경환)
Kim, Joo Young(김주영) ORCID logo https://orcid.org/0000-0003-2623-1491
Shin, Dong Min(신동민) ORCID logo https://orcid.org/0000-0001-6042-0435
Lee, Min Goo(이민구) ORCID logo https://orcid.org/0000-0001-7436-012X
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/144667
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