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Gastrin Inhibits Cholangiocyte Growth in Bile Duct–Ligated Rats by Interaction With Cholecystokinin-B/Gastrin Receptors viad-myo-Inositol 1,4,5-Triphosphate–, Ca2+-, and Protein Kinase C α–Dependent Mechanisms

Authors
Journal
Hepatology
0270-9139
Publisher
Wiley Blackwell (John Wiley & Sons)
Publication Date
Volume
32
Issue
1
Identifiers
DOI: 10.1053/jhep.2000.8265
Disciplines
  • Biology

Abstract

Abstract We studied the role of gastrin in regulating cholangiocyte proliferation induced by bile duct ligation (BDL). In purified cholangiocytes, we evaluated (1) for the presence of cholecystokinin-B (CCK-B)/gastrin receptors, (2) the effect of gastrin on d -myo-Inositol 1,4,5-triphosphate (IP 3 ) levels, and (3) the effect of gastrin on DNA synthesis and adenosine 3′, 5′-monophosphate (cAMP) levels in the absence or presence of CCK-A (L-364,718) and CCK-B/gastrin (L-365,260) receptor inhibitors, 1,2-bis(2-aminophenoxy)-ethane-N,N,N′,N′-tetraacetic acid tetrakis(acetxymethyl ester) (BAPTA/AM; an intracellular Ca 2+ chelator), and 2 protein kinase C (PKC) inhibitors, 1-(5-Isoquinolinylsulfonyl)-2-methylpiperazine (H7) and staurosporin. To evaluate if gastrin effects on cholangiocyte proliferation are mediated by the isoform PKCα, we evaluated (1) for the presence of PKCα in cholangiocytes and (2) the effect of gastrin on the PKCα protein expression in a triton-soluble (containing cytoplasm + membrane) and a triton-insoluble (containing cytoskeleton) fraction. To evaluate the effects of gastrin in vivo, immediately following BDL, gastrin or bovine serum albumin (BSA) was infused by minipumps for 7 days to rats and we measured cholangiocyte growth and cAMP levels. We found CCK-B/gastrin receptors on cholangiocytes. Gastrin increased IP 3 levels. Gastrin inhibited DNA synthesis and cAMP synthesis in cholangiocytes. Gastrin effects on cholangiocyte functions were blocked by L-365,260, BAPTA/AM, H7, and staurosporin but not by L-364,718. Gastrin induced translocation of PKCα from cholangiocyte cytoskeleton to membrane. In vivo, gastrin decreased cholangiocyte growth and cAMP synthesis compared with controls. We concluded that gastrin inhibits cholangiocyte growth in BDL rats by interacting with CCK-B/gastrin receptors through a signal transduction pathway involving IP 3 , Ca 2+, and PKCα. (Hepatology 2000;32:17-25.)

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