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Articles in PresS, published online ahead of print October 2, 2002
Am J Physiol Gastrointest Liver Physiol, 10.1152/ajpgi.00245.2002
Submitted on June 24, 2002
Accepted on September 23, 2002
1 Department of Gastroenterology, University of Ancona, Ancona, Italy
2 Department of Internal Medicine, Scott and White Hospital, Temple, TX, USA; Department of Medical Physiology, The Texas A&M University System Health Science Center, Temple, TX, USA; Department of Research, Central Texas Veterans Health Care System, Temple, TX, USA
3 Department of Research and Education, Scott and White Hospital, Temple, TX, USA
4 Department of Gastroenterology, University of Rome, Rome, Italy
5 Department of Medical Physiology, The Texas A&M University System Health Science Center, Temple, TX, USA
6 Department of Research, Central Texas Veterans Health Care System, Temple, TX, USA
7 Department of Internal Medicine, Scott and White Hospital, Temple, TX, USA
* To whom correspondence should be addressed. E-mail: gene.lesage{at}uth.tmc.edu.
Bile acids are cytoprotective in hepatocytes by activating phosphatidylinositol 3-kinase (PI3-K) and its downstream signal AKT. Aims: To determine if feeding taurocholate to CCl4-treated rats reduces cholangiocyte apoptosis and if this cytoprotective effect is dependent on PI3-K. Results: Cholangiocyte proliferation, secretion and apoptosis were determined in cholangiocytes from BDL, CCl4-treated BDL rats and CCl4-treated taurocholate fed rats. In vitro, we tested if CCl4 induces apoptosis and if 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 pre-incubation 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. Conclusions: 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.
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