Ursodeoxycholate and tauroursodeoxycholate inhibit cholangiocyte growth and secretion of BDL rats through activation of PKC alpha

Abstract

Accumulating bile acids (BA) trigger cholangiocyte proliferation in chronic cholestasis. The aim of this study was to determine if ursodeoxycholate (UDCA) or tauroursodeoxycholate (TUDCA) chronic feeding prevents the increased cholangiocyte growth and secretion in bile duct-ligated (BDL) rats, if UDCA and TUDCA effects are associated with increased cholangiocyte apoptosis, and to determine if this inhibition is dependent on increased intracellular Ca(2+) ([Ca(2+)](i)) and activation of protein kinase C (PKC) alpha. Immediately after BDL, rats were fed UDCA or TUDCA (both 275 micromol/d) for 1 week. We determined the number of bile ducts in liver sections, cholangiocyte proliferation (by measurement of H(3) histone and proliferating cellular nuclear antigen in isolated cholangiocytes), and ductal secretion. In purified cholangiocytes from 1-week BDL rats, we evaluated if UDCA and TUDCA directly inhibit cholangiocyte proliferation and secretin-stimulated adenosine 3', 5'-monophosphate levels. We determined if UDCA and TUDCA activate PKC, increase [Ca(2+)](i), and alter the apical BA transporter (ABAT) expression in cholangiocytes. UDCA and TUDCA inhibited in vivo the cholangiocyte proliferation, secretion, and ABAT expression. In vitro UDCA and TUDCA inhibition of cholangiocyte growth and secretion required increased [Ca(2+)](i) and PKC alpha. In conclusion, activation of Ca(2+)-dependent PKC alpha is required for UDCA and TUDCA inhibition of cholangiocyte growth and secretion. Reduced cholangiocyte ABAT may decrease endogenous BA stimulation of cholangiocyte growth and secretion.