Adrenergic receptor agonists prevent bile duct injury induced by adrenergic denervation by increased cAMP levels and activation of Akt.

Loss of parasympathetic innervation after vagotomy impairs cholangiocyte proliferation, which is associated with depressed cAMP levels, impaired ductal secretion, and enhanced apoptosis. Agonists that elevate cAMP levels prevent cholangiocyte apoptosis and restore cholangiocyte proliferation and ductal secretion. No information exists regarding the role of adrenergic innervation in the regulation of cholangiocyte function.

Autocrine/paracrine regulation of the growth of the biliary tree by the neuroendocrine hormone serotonin.

Background & Aims: The biliary tree is the target of cholangiopathies that are chronic cholestatic liver diseases characterized by loss of proliferative response and enhanced apoptosis of cholangiocytes, the epithelial cells lining the biliary tree. The endogenous factors that regulate cholangiocyte proliferation are poorly understood. Therefore, we studied the role of the neuroendocrine hormone serotonin as a modulator of cholangiocyte proliferation.

Alpha-1 adrenergic receptor agonists modulate ductal secretion of BDL rats via Ca(2+)- and PKC-dependent stimulation of cAMP.

Acetylcholine potentiates secretin-stimulated ductal secretion by Ca(2+)-calcineurin-mediated modulation of adenylyl cyclase. D2 dopaminergic receptor agonists inhibit secretin-stimulated ductal secretion via activation of protein kinase C (PKC)-gamma. No information exists regarding the effect of adrenergic receptor agonists on ductal secretion in a model of cholestasis induced by bile duct ligation (BDL).

cAMP stimulates the secretory and proliferative capacity of the rat intrahepatic biliary epithelium through changes in the PKA/Src/MEK/ERK1/2 pathway.

Background/aims: To evaluate if increased cholangiocyte cAMP levels alone are sufficient to enhance cholangiocyte proliferation and secretion.

Methods: Normal rats were treated in vivo with forskolin for two weeks. Cholangiocyte apoptosis, proliferation and secretion were evaluated.

Tauroursodeoxycholate inhibits human cholangiocarcinoma growth via Ca2+-, PKC-, and MAPK-dependent pathways.

Tauroursodeoxychate (TUDCA) is used for the treatment of cholangiopathies including primary sclerosing cholangitis, which is considered the primary risk factor for cholangiocarcinoma. The effect of TUDCA on cholangiocarcinoma growth is unknown. We evaluated the role of TUDCA in the regulation of growth of the cholangiocarcinoma cell line Mz-ChA-1.

Gastrin reverses established cholangiocyte proliferation and enhanced secretin-stimulated ductal secretion of BDL rats by activation of apoptosis through increased expression of Ca2+- dependent PKC isoforms.

Unlabelled: We posed these questions: (i) Does administration of gastrin to 1-week bile duct ligation (BDL) rats inhibits established cholangiocyte proliferation and ductal secretion? (ii) Is gastrin inhibition of cholangiocyte proliferation and secretion of BDL rats associated with enhanced apoptosis? (iii) Are gastrin's effects on cholangiocyte function associated with increased expression of protein kinase C (PKC) isoforms; and (iv) Is gastrin stimulation of cholangiocyte apoptosis regulated by the Ca2+-dependent PKC pathway?

Methods: Seven days after BDL, rats were treated with gastrin by minipumps for 14 days. Cholangiocyte proliferation was assessed by measurement of the number of PCNA and CK-19 positive cholangiocytes in sections, and PCNA expression in cholangiocytes. Ductal secretion was determined by measurement of secretin-induced cAMP levels and choleresis.

Taurocholate prevents the loss of intrahepatic bile ducts due to vagotomy in bile duct-ligated rats.

The aim of this study was to determine whether taurocholate prevents vagotomy-induced cholangiocyte apoptosis. After bile duct ligation (BDL) + vagotomy, rats were fed taurocholate for 1 wk in the absence or presence of wortmannin. Caspase involvement was evaluated by measurement of caspase 8, 9, and 3 activities.

Taurohyodeoxycholate- and tauroursodeoxycholate-induced hypercholeresis is augmented in bile duct ligated rats.

Background/aims: Taurohyodeoxycholate (THDCA) and tauroursodeoxycholate (TUDCA) induce more bile flow per molecule excreted compared to endogenous bile acids. The aim of this study is to determine if the hypercholeretic effect of tauroursodeoxycholate or taurohyodeoxycholate in normal and bile duct ligated (BDL) rats is due to increased ductal secretion.

Methods: Normal or BDL rats were infused with tauroursodeoxycholate or taurohyodeoxycholate and bile flow, bicarbonate, bile salt, cholesterol, and phospholipid secretion were measured.

Development and characterization of secretin-stimulated secretion of cultured rat cholangiocytes.

We sought to develop a cholangiocyte cell culture system that has preservation of receptors, transporters, and channels involved in secretin-induced secretion. Isolated bile duct fragments, obtained by enzyme perfusion of normal rat liver, were seeded on collagen and maintained in culture up to 18 wk. Cholangiocyte purity was assessed by staining for gamma-glutamyl transpeptidase (gamma-GT) and cytokeratin-19 (CK-19).

Dopaminergic inhibition of secretin-stimulated choleresis by increased PKC-gamma expression and decrease of PKA activity.

To determine the role and mechanisms of action by which dopaminergic innervation modulates ductal secretion in bile duct-ligated rats, we determined the expression of D1, D2, and D3 dopaminergic receptors in cholangiocytes. We evaluated whether D1, D2 (quinelorane), or D3 dopaminergic receptor agonists influence basal and secretin-stimulated choleresis and lumen expansion in intrahepatic bile duct units (IBDU) and cAMP levels in cholangiocytes in the absence or presence of BAPTA-AM, chelerythrine, 1-(5-isoquinolinylsulfonyl)-2-methyl piperazine (H7), or rottlerin. We evaluated whether 1) quinelorane effects on ductal secretion were associated with increased expression of Ca(2+)-dependent PKC isoforms and 2) increased expression of PKC causes inhibition of PKA activity.

Taurocholate feeding prevents CCl4-induced damage of large cholangiocytes through PI3-kinase-dependent mechanism.

Bile acids are cytoprotective in hepatocytes by activating phosphatidylinositol-3-kinase (PI3-K) and its downstream signal AKT. Our aim was to determine whether feeding taurocholate to CCl(4)-treated rats reduces cholangiocyte apoptosis and whether this cytoprotective effect is dependent on PI3-K. Cholangiocyte proliferation, secretion, and apoptosis were determined in cholangiocytes from bile duct ligation (BDL), CCl(4)-treated BDL rats, and CCl(4)-treated taurocholate-fed rats.

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

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).

Functional heterogeneity of cholangiocytes.

The objective of this article is to summarize the findings related to the notion that cholangiocytes, within small and large intrahepatic ducts, are heterogeneous regarding (1) morphology; (2) secretion in response to hormones and peptides and to bile acids; and (3) proliferation in response to injury or toxins, including bile duct ligation (BDL), acute carbon tetrachloride (CCl 4 ) administration, chronic feeding of bile salts (i.e., taurocholate [TC] or taurolithocholate [TLC]) or alpha-naphthylisothiocyanate (ANIT).

Insulin inhibits secretin-induced ductal secretion by activation of PKC alpha and inhibition of PKA activity.

Insulin stimulates canalicular bile flow by interaction with hepatocytes. Insulin regulates the function of a number of epithelia through activation and membrane translocation of Ca(2+)-dependent PKC isoforms. No information exists regarding insulin regulation of ductal bile secretion.

Stimulation of alpha2-adrenergic receptor inhibits cholangiocarcinoma growth through modulation of Raf-1 and B-Raf activities.

Growth factor signaling, mediated by the mitogen-activated protein kinase (MAPK) cascade, induces cell mitosis. Adenosine 3',5'-monophosphate (cAMP) may inhibit or stimulate mitosis (depending on the cell type) through the activation of MAPK and Raf proteins. Among Raf proteins, Raf-1 and B-Raf differentially regulate mitosis.

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

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.