Molecular and functional heterogeneity of cholangiocytes from rat
liver after bile duct ligation.
Alpini, Gianfranco, Charles Ulrich, Stuart Roberts, John O. Phillips,
Yoshiyuki Ueno, Prasad V. Podila, Oscar Colegio, Gene D. Lesage,
Laurence J. Miller, Nicholas F. Larusso.
Center for Basic Research in Digestive Diseases, Division of
Gastroenterology and Internal Medicine, and Department of
Biochemistry and Molecular Biology, Mayo Medical School, Clinic, and
Foundation, Rochester, MN, 55905
APStracts 3:0178G, 1996.
Cholangiocytes, the epithelial cells that line intrahepatic bile
ducts, participate in bile secretion via basal and agonist-stimulated
absorption and secretion of solutes and water. Based on subtle
structural differences between cholangiocytes lining small versus
large bile ducts, as well as known phenotypic variations among
transporting epithelia in other organs (e.g., renal tubules and small
intestine), we demonstrated that cholangiocytes are functionally
heterogeneous along the intrahepatic biliary tree of normal rats. In
studies reported here, we confirm and extend the concept of
functional heterogeneity of cholangiocytes by employing the bile duct
ligated rat, an important model of cholestasis associated with
selective cholangiocyte proliferation, commonly used to evaluate bile
duct secretory processes. Using novel isolation and separatory
techniques, we prepared subpopulations of essentially pure small,
medium, and large cholangiocytes from bile duct ligated rats and
compared them with regard to gene expression and basal or agonist
-responsive transport activities. While similar levels of transcripts
for [gamma]-glutamyltranspeptidase and cytokeratin 19, two
cholangiocyte-specific proteins, and glyceraldehyde-3-phosphate
dehydrogenase, a house-keeping gene, were present in all three
subpopulations, genes for several proteins involved in solute
transport [Cl-/HCO3- exchanger, cystic fibrosis transmembrane
regulator (CFTR) and secretin receptor (SR)] were expressed only in
medium and large cholangiocytes. Consistent with these findings,
secretin increased intracellular levels of cAMP and 36Cl- efflux
rates in medium and large but not small cholangiocytes. Also,
forskolin/cpt-cAMP stimulated 36Cl- efflux rates only in medium and
large cholangiocytes, consistent with selective functional expression
of CFTR in these subpopulations. These results support the molecular
and functional heterogeneity of cholangiocytes within the
intrahepatic biliary ductal system and are consistent with the notion
that hormone-regulated transport of solutes after bile duct ligation
occurs principally in medium and large cholangiocytes in a fashion
similar to that observed in normal rat liver.
Received 1 March 1996; accepted in final form 30 August 1996.
APS Manuscript Number G81-6.
Article publication pending Am. J. Physiol. (Gastrointest. Liver
Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 19 September 1996