Taurocholate feeding prevents CCl4-induced damage of large cholangiocytes through PI3-kinase-dependent mechanism.
Bile acids are cytoprotective in hepatocytes by activating phosphatidylinositol-3-kinase (PI3-K) and its downstream signal AKT. Our aim was to determine whether feeding taurocholate to CCl(4)-treated rats reduces cholangiocyte apoptosis and whether this cytoprotective effect is dependent on PI3-K. Cholangiocyte proliferation, secretion, and apoptosis were determined in cholangiocytes from bile duct ligation (BDL), CCl(4)-treated BDL rats, and CCl(4)-treated taurocholate-fed rats. In vitro, we tested whether CCl(4) induces apoptosis and whether loss of cholangiocyte proliferation and secretion is dependent on PI3-K. The CCl(4)-induced cholangiocyte apoptosis and loss of cholangiocyte proliferation and secretion were reduced in CCl(4)-treated rats fed taurocholate. CCl(4)-induced cholangiocyte apoptosis, loss of cholangiocytes secretion, and proliferation were prevented by preincubation with taurocholate. Taurocholate cytoprotective effects were ablated by wortmannin. Taurocholate prevented, in vitro, CCl(4)-induced decrease of phosphorylated AKT protein expression in cholangiocytes. The cytoprotective effects of taurocholate on CCl(4) effects on cholangiocyte proliferation and secretion were abolished by wortmannin. Taurocholate protects cholangiocytes from CCl(4)-induced apoptosis by a PI3-K-dependent mechanism. Bile acids are important in the prevention of drug-induced ductopenia in cholangiopathies.
Marucci
Luca
L
Department of Gastroenterology, University of Ancona, Italy.
Alpini
Gianfranco
G
Glaser
Shannon S
SS
Alvaro
Domenico
D
Benedetti
Antonio
A
Francis
Heather
H
Phinizy
Jo Lynne
JL
Marzioni
Marco
M
Mauldin
Jeremy
J
Venter
Julie
J
Baumann
Brandy
B
Ugili
Laura
L
LeSage
Gene
G
D000818:Animals; D017304:Annexin A5 / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001652:Bile Ducts / Q000473:pathology; D002252:Carbon Tetrachloride Poisoning / Q000473:pathology* / Q000517:prevention & control*; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002469:Cell Separation; D002756:Cholagogues and Choleretics / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D007677:Kidney Function Tests; D008099:Liver / Q000473:pathology*; D008297:Male; D009929:Organ Size; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D011916:Rats, Inbred F344; D013656:Taurocholic Acid / Q000494:pharmacology*
D017304:Annexin A5; D020169:Caspases; D002756:Cholagogues and Choleretics; D000242:Cyclic AMP; D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D013656:Taurocholic Acid; C494920:Akt1 protein, rat