Bile acid feeding induces cholangiocyte proliferation and secretion: evidence for bile acid-regulated ductal secretion.
OBJECTIVE
We have shown that taurocholate (TC) and taurolithocholate (TLC) interact in vitro with normal cholangiocytes, increasing DNA synthesis, secretin receptor (SR) gene expression, and adenosine 3',5'-cyclic monophosphate (cAMP) synthesis. To further extend these in vitro studies, we tested the hypothesis that bile acids (BAs) directly stimulate cholangiocyte proliferation and secretion in vivo.


METHODS
After feeding with TC or TLC (1% for 1-4 weeks), we assessed the following in vivo: (1) ductal proliferation by both morphometry and immunohistochemistry for proliferating cell nuclear antigen (PCNA) and measurement of [3H]thymidine incorporation; and (2) the effect of secretin on bile secretion and bicarbonate secretion in vivo. Genetic expression of H3-histone and SR and intracellular cAMP levels were measured in isolated cholangiocytes.


RESULTS
After BA feeding, there was an increased number of PCNA-positive cholangiocytes and an increased number of ducts compared with control rats. [3H]Thymidine incorporation, absent in control cholangiocytes, was increased in cholangiocytes from BA-fed rats. In BA-fed rats, there was increased SR gene expression (approximately 2.5-fold) and secretin-induced cAMP levels (approximately 3.0-fold) in cholangiocytes, which was associated with de novo secretin-stimulated bile flow and bicarbonate secretion.


CONCLUSIONS
These data indicate that elevated BA levels stimulate ductal secretion and cholangiocyte proliferation.
Alpini
G
G
Department of Internal Medicine, Scott & White Hospital and Texas A&M University Health Science Center College of Medicine, USA.
Glaser
S S
SS
Ueno
Y
Y
Rodgers
R
R
Phinizy
J L
JL
Francis
H
H
Baiocchi
L
L
Holcomb
L A
LA
Caligiuri
A
A
LeSage
G D
GD
D000818:Animals; D001646:Bile / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism / Q000494:pharmacology; D001653:Bile Ducts, Intrahepatic / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D002756:Cholagogues and Choleretics / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D008099:Liver / Q000473:pathology; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D043562:Receptors, G-Protein-Coupled; D011964:Receptors, Gastrointestinal Hormone / Q000096:biosynthesis / Q000235:genetics; D012633:Secretin / Q000378:metabolism; D013656:Taurocholic Acid / Q000494:pharmacology; D013658:Taurolithocholic Acid / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism
D001647:Bile Acids and Salts; D002756:Cholagogues and Choleretics; D043562:Receptors, G-Protein-Coupled; D011964:Receptors, Gastrointestinal Hormone; C029937:secretin receptor; D012633:Secretin; D013658:Taurolithocholic Acid; D013656:Taurocholic Acid; D000242:Cyclic AMP; D013936:Thymidine