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Am J Physiol Gastrointest Liver Physiol 284: G290-G301, 2003. First published October 2, 2002; doi:10.1152/ajpgi.00245.2002
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Vol. 284, Issue 2, G290-G301, February 2003

Taurocholate feeding prevents CCl4-induced damage of large cholangiocytes through PI3-kinase-dependent mechanism

Luca Marucci6,*, Gianfranco Alpini1,2,4,*, Shannon S. Glaser3, Domenico Alvaro5, Antonio Benedetti6, Heather Francis1, Jo Lynne Phinizy1, Marco Marzioni2, Jeremy Mauldin2, Julie Venter2, Brandy Baumann2, Laura Ugili6, and Gene LeSage1

1 Department of Internal Medicine and 2 Medical Physiology, 3 Division of Research and Education, Scott & White Hospital and The Texas A&M University System Health Science Center, College of Medicine and 4 Central Texas Veterans Health Care System, Temple, Texas 76504; 5 Division of Gastroenterology, University of Rome, La Sapienza, Rome, Italy 00100; and 6 Department of Gastroenterology, University of Ancona, Ancona, Italy 60131

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 CCl4-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), CCl4-treated BDL rats, and CCl4-treated taurocholate-fed rats. In vitro, we tested whether CCl4 induces apoptosis and whether loss of cholangiocyte proliferation and secretion is dependent on PI3-K. The CCl4-induced cholangiocyte apoptosis and loss of cholangiocyte proliferation and secretion were reduced in CCl4-treated rats fed taurocholate. CCl4-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, CCl4-induced decrease of phosphorylated AKT protein expression in cholangiocytes. The cytoprotective effects of taurocholate on CCl4 effects on cholangiocyte proliferation and secretion were abolished by wortmannin. Taurocholate protects cholangiocytes from CCl4-induced apoptosis by a PI3-K-dependent mechanism. Bile acids are important in the prevention of drug-induced ductopenia in cholangiopathies.

cytoprotection; biliary epithelium; bile acids

* L. Marucci and G. Alpini share the first authorship.




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