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

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 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.

journal_name

Gastroenterology

journal_title

Gastroenterology

authors

Kim JY,Kim KH,Lee JA,Namkung W,Sun AQ,Ananthanarayanan M,Suchy FJ,Shin DM,Muallem S,Lee MG

doi

10.1053/gast.2002.33617

keywords:

subject

Has Abstract

pub_date

2002-06-01 00:00:00

pages

1941-53

issue

eissn

0016-5085

issn

1528-0012

pii

S0016508502000288

journal_volume

122

pub_type

杂志文章

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