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ORIGINAL RESEARCH ARTICLE

Taurocholic Acid Feeding Prevents Tumor Necrosis Factor-–Induced Damage of Cholangiocytes by a PI3K–Mediated Pathway

Yoshiyuki Ueno^*, Heather Francis, Shannon Glaser^,, Sharon DeMorrow, Julie Venter, Antonio Benedetti, Giammarco Fava, Marco Marzioni and Gianfranco Alpini^,||,¶,1

^* Department of Medicine, Tohoku University School of Medicine, Aobaku, Sendai 980-8574, Japan; Division of Research and Education and Department of Medicine, Scott & White Hospital and The Texas A&M University System Health Science Center College of Medicine, Temple, Texas 76504; Department of Gastroenterology Universita’ Politecnica delle Marche, 60121 Ancona, Italy; and ^|| Central Texas Veterans Health Care System and ^¶ Systems Biology and Translational Medicine, Scott & White Hospital and The Texas A&M University System Health Science Center College of Medicine, Temple, Texas 76504

To whom requests for reprints should be addressed at ¹ Central Texas Veterans Health Care System, The Texas A&M University System Health Science Center College of Medicine, Medical Research Building, 702 S.W. H. K. Dodgen Loop, Temple, TX 76504. E-mail: galpini{at}tamu.edu or galpini{at}medicine.tamhsc.edu

Cholangiopathies, such as primary biliary cirrhosis and primary sclerosis cholangitis, are characterized at the end stage by ductopenia due to increased cholangiocyte apoptosis and decreased cholangiocyte proliferation. Although cholangiocyte proliferation is associated with an increased number of intra-hepatic bile ducts and secretin-stimulated ductal secretion, ductopenia is coupled with decreased ductal mass and secretin-induced ductal secretory activity. We have shown that a single injection of actinomycin D + tumor necrosis factor- (TNF- ) to bile duct–ligated (BDL) rats induces cholangiocyte injury, which is characterized by loss of cholangiocyte proliferation, and secretory activity and by an increase in cholangiocyte apoptosis. We also have shown that taurocholic acid both in vivo and in vitro stimulates cholangiocyte proliferation. We hypothesize that taurocholic acid feeding protects cholangiocytes against TNF- –induced apoptosis through a phosphatidylinositol-3-kinase (PI3K)–dependent pathway. Immediately after BDL, rats were fed taurocholic acid or control diet in the absence/presence of daily injections of wortmannin for 1 week. Seven days later, control-fed or taurocholic acid–fed rats were treated with a single intraperitoneal injection of actinomycin D + TNF- . Twenty-four hours later we evaluated: (i) cholangiocyte apoptosis and proliferation in liver sections and (ii) basal and secretin-stimulated bile and bicarbonate secretion in bile fistula rats. Taurocholic acid feeding prevented TNF- –induced increases in cholangiocyte apoptosis and decreases in growth and secretin-stimulated bile and bicarbonate secretion, changes that were blocked by PI3K inhibition. The PI3K survival pathway is important in bile acid protection against immune-mediated cholangiocyte injury in cholestatic liver diseases.

Key Words: apoptosis • bile flow • intrahepatic biliary epithelium • proliferation • secretin