Differential modulation of cellular death and survival pathways by conjugated bile acids.
BACKGROUND
The liver-derived McNtcp.24 cells transport bile acids and show distinctive responses to the two classes of conjugated bile acids. Whereas taurine-conjugated bile acids are non-toxic, glycine-conjugated bile acids efficiently induce apoptosis. The aim of this study was to determine if the differential sensitivity is limited to cells that normally transport bile acids and if bile acid binding proteins could reduce bile acid-mediated apoptosis. The apical sodium/bile acid co-transporter (asbt) was expressed in Chinese hamster ovary (CHO) cells to establish active bile acid transport in a non-liver-derived cell model (CHO.asbt). A high-affinity bile acid binder was expressed in McNtcp.24 cells.


RESULTS
The tolerance of McNtcp.24 cells to taurine-conjugated bile acids was associated with the stimulation of phosphatidylinositol 3-kinase (PI3K) activity. Treatment of CHO.asbt cells with taurine- and glycine-conjugated bile acids resulted in apoptosis. Unlike in McNtcp.24 cells, PI3K activity was not increased in CHO.asbt cells treated with taurine-conjugated bile acids. High level expression of a bile acid binder did not attenuate bile acid-induced cytotoxicity in McNtcp.24 cells.


CONCLUSIONS
The data suggest that McNtcp.24 cells possess a mechanism that can elaborate distinctive responses to the different classes of bile acids. Additionally, activation of a signaling pathway involving PI3K appears to be the dominant mechanism responsible for the tolerance of McNtcp.24 cells to taurine-conjugated bile acids.
Torchia
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EC
Canadian Institutes of Health Research Group in Molecular and Cell Biology of Lipids and Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada. enrique.torchia@stjude.org
Stolz
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A
Agellon
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LB
D000818:Animals; D017209:Apoptosis; D001647:Bile Acids and Salts / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D001692:Biological Transport; D016466:CHO Cells; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D005998:Glycine; D006913:Hydroxysteroid Dehydrogenases; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008562:Membrane Glycoproteins; D029363:Organic Anion Transporters, Sodium-Dependent; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction; D027981:Symporters; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
D001647:Bile Acids and Salts; D002352:Carrier Proteins; D020169:Caspases; D005998:Glycine; D006913:Hydroxysteroid Dehydrogenases; D008562:Membrane Glycoproteins; D029363:Organic Anion Transporters, Sodium-Dependent; D019869:Phosphatidylinositol 3-Kinases; D027981:Symporters; C037643:bile acid binding proteins; C071908:sodium-bile acid cotransporter; C435496:AKR1C2 protein, human; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)