Bile acid depletion and repletion regulate cholangiocyte growth and secretion by a phosphatidylinositol 3-kinase-dependent pathway in rats.

Abstract

BACKGROUND & AIMS:

We tested the hypothesis that during bile duct obstruction, increased biliary bile acids trigger cholangiocyte proliferation and secretion by a phosphatidylinositol 3-kinase (PI3-K)-dependent pathway.

METHODS:

In bile duct-incannulated (BDI) rats, bile duct obstruction present for 7 days was relieved for 24 hours by external bile drainage. During the 24-hour drainage period, animals received either Krebs Ringer Henseleit (the bile-depleted group), or sodium taurocholate (the bile-depleted, taurocholate-infused group). We evaluated cholangiocyte proliferation and secretin-stimulated ductal secretion. Apical bile acid transporter (ABAT) expression and bile acid transport activity was determined. In pure preparations of cholangiocytes, we examined the effect of taurocholate (in the absence or presence of wortmannin or PI 3,4-bisphosphate the lipid product of PI3-K) on cholangiocyte proliferation and secretin-stimulated cyclic adenosine 3',5'-monophosphate (cAMP) levels.

RESULTS:

Bile depletion reduced cholangiocyte proliferation and secretin-stimulated ductal secretion and ABAT expression and bile acid transport activity compared with 1-week BDI control rats. In bile-depleted, taurocholate-infused rats, cholangiocyte proliferation and secretion and ABAT expression and bile acid transport activity were maintained at levels similar to those seen in BDI control rats. In vitro, taurocholate stimulation of DNA replication and secretin-stimulated cAMP levels was blocked by wortmannin. The inhibitory effect of wortmannin on taurocholate stimulation of cholangiocyte proliferation and secretion was prevented by PI 3,4-bisphosphate.

CONCLUSIONS:

Bile acid uptake by ABAT and the PI3-K pathway are important for bile acids to signal cholangiocyte proliferation. In bile duct obstruction, increased biliary bile acid concentration and ABAT expression initiate increased cholangiocyte proliferation and secretion.

• Authors: Gianfranco Alpini, Shannon Glaser, Domenico Alvaro, Yoshiyuki Ueno, Marco Marzioni, Heather Francis, Leonardo Baiocchi, Tonino Stati, Barbara Barbaro, Jo Lynne Phinizy, Jeremy Mauldin, Gene Lesage
• Journal: Gastroenterology (Gastroenterology) Vol. 123 Issue 4 Pg. 1226-37 (Oct 2002) ISSN: 0016-5085 [Print] United States
• PMID: 12360484 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Androstadienes
• Bicarbonates
• Bile Acids and Salts
• Carrier Proteins
• Enzyme Inhibitors
• Organic Anion Transporters, Sodium-Dependent
• Phosphoinositide-3 Kinase Inhibitors
• Receptors, G-Protein-Coupled
• Receptors, Gastrointestinal Hormone
• Symporters
• secretin receptor
• sodium-bile acid cotransporter
• Cyclic AMP
• Wortmannin

Topics

• Androstadienes (pharmacology)
• Animals
• Bicarbonates (metabolism)
• Bile (metabolism)
• Bile Acids and Salts (metabolism)
• Bile Ducts (cytology, enzymology, metabolism)
• Carrier Proteins (genetics)
• Cell Division (physiology)
• Cholestasis (metabolism, pathology)
• Cyclic AMP (metabolism)
• Enzyme Inhibitors (pharmacology)
• Gene Expression (physiology)
• Male
• Organic Anion Transporters, Sodium-Dependent
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Rats
• Rats, Inbred F344
• Receptors, G-Protein-Coupled
• Receptors, Gastrointestinal Hormone (genetics)
• Symporters
• Wortmannin