BILE-ACIDS STIMULATE PROLIFERATIVE AND SECRETORY EVENTS IN LARGE BUT NOT SMALL CHOLANGIOCYTES

Accumulation of bile acids (BA) and cholangiocyte proliferation occur in cholestasis, but BA effects on the proliferative and secretory capa city of cholangiocytes are undefined. Cholangiocyte proliferation coup led with increased expression of I-Is histone and secretin receptor (S R) genes and secretin-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) levels is limited to large cholangiocytes. We isolated pooled s mall and large cholangiocytes and studied the effect of taurocholic (T C) and taurolithocholic (TLC) acids on proliferation, by measurement o f HQ histone gene expression, and secretion, by measurement of SR gene expression, cAMP levels, and Cl-/HCO3- exchanger activity. In pooled cholangiocytes, TC and TLC increased H-3 histone (12-fold) and SR (3-f old) gene expression and both spontaneous (1.4-fold) and secretin-indu ced (4-fold) cAMP response. TC and TLC increased I-Is histone (10-fold ) and SR (2-fold) gene expression and secretin-induced cAMP response a nd Cl-/HCO3- exchanger activity (3-fold) only in large cholangiocytes. In large cholangiocytes, BA may have a signaling function in the modu lation of ductal secretion.