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Biology Articles » Anatomy & Physiology » Bile acid interactions with cholangiocytes » Overview of the regulation of ASBT expression in cholangiocytes

Overview of the regulation of ASBT expression in cholangiocytes
- Bile acid interactions with cholangiocytes

 
Alteration of bile acid transporter activity may occur physiologically in response to local bile acid concentrations to fine tune bile acid transport capacity. For instance, ASBT has been shown by some studies to be upregulated in the ileum with increased intestinal bile concentration[39], so as to provide increased intestinal bile acid transport activity in response to increased intestinal bile acid load. Alternatively, bile acid transporter expression may be chronically modified in pathologic conditions to prevent intracellular accumulation of toxic bile acids due to altered bile acid metabolism or retention[40]. For instance, in chronic cholestasis due to bile duct obstruction, there is downregulation of hepatocyte sinusoid transporters and upregulation of hepatocyte canalicular transporters that provides the combined effect to reduce hepatocyte intracellular retention of bile acids that occurs with cholestasis[41]. Regulation of bile acid transporters may also occur regionally within anatomical confines of an organ. For instance, ASBT expression is present exclusively in the distal ileum (and not proximal small bowel)[42], restricted to the mature enterocytes lining the villus, with little or no detectable expression in the small intestinal crypt. Sinusoidal transporters are present to a greater degree in the periportal region compared to the pericentral region of the hepatic lobule[41]. Temporally, regulation of bile acid transporters has been shown to occur gradually through changes in gene expression[39,40,43,44], or acutely by changes in cell membrane transporter content by transporter translocation[45,46] or by changes in the rate of protein degradation.
 
Acute regulation of ASBT in cholangiocytes
Previous studies have shown that ASBT transport activity acutely increases in cholangiocytes and ileal epithelial cells by a cAMP-dependent mechanism[38,47]. In cholangiocytes, increased cAMP induced by secretin doubles Na+-dependent bile acid uptake in isolated cholangiocytes[38] and in perfused bile duct fragments[48]. This effect is likely due to protein translocation, since pretreatment of cholangiocytes with the microtubule inhibitor colchicine prevents the cAMP-induced increase of Na+-dependent bile acid transport[38]. The effects of secretin on protein translocation of ASBT to the apical membrane of cholangiocytes were studied employing isolated apical membranes from cholangiocytes[38]. These studies showed that cAMP increases apical membrane ASBT only in the absence of colchicine. A model for cAMP-dependent recycling of ASBT in the cholangiocyte apical membrane is shown in Figure 2. The model shows that cAMP increases apical ASBT membrane content, but also suggests that ASBT recycles back to latent intracellular stores once the secretin/cAMP stimulus has abated. This mechanism for acute induction of ABAT activity in cholangiocytes has been proposed to provide an accentuation of cholehepatic bile acid shunting in the postprandial period, thus accentuating bile flow and biliary lipid secretion (see cholehepatic shunting section above)[38].
 
Chronic regulation of ASBT expression in cholangiocytes
ASBT expression in cholangiocytes changes chronically in response to biliary bile acid concentrations, the presence of cholestasis[7-9,15] or inflammation. With increase in biliary bile acid concentration, due to feeding taurocholate to rats, there is an increase in total liver ASBT[7]. In this model, the increased ASBT is due to both increased number of cholangiocytes in the liver and the maintenance of ASBT expression per cell. In bile duct ligated rats depleted of biliary bile acids for 12 h by external biliary drainage, there is a marked decrease in cholangiocyte ASBT gene and protein expression and transport activity[49]. ASBT gene and protein expression and transport activity can be restored in bile-depleted rats by infusion of taurocholate to maintain biliary bile acid concentration[49]. These studies employing bile acid feeding and bile acid depletion show that ASBT expression in cholangiocytes is chronically regulated in a direct proportion to biliary bile acid concentration. In contrast to taurocholate feeding which increases cholangiocyte ASBT expression, feeding ursodeoxycholic acid to bile duct ligated rats markedly reduces cholangiocyte ASBT gene and protein expression and taurocholate transport activity[8]. Although the mechanism for differential effects of different bile acids on ABAT expression in cholangiocytes has not been defined; they are consistent with our studies showing differential effects of different bile acids on cholangiocyte secretion and proliferation (see below).
   
With chronic cholestasis due to bile duct ligation, intrahepatic bile ducts markedly increase in number (approximately 10 fold increase after 1 wk). In this model, ASBT expression per cholangiocyte is maintained[9], so that overall there is an effective increase in biliary bile acid absorptive capacity in BDL rats. We propose that the increased ASBT in BDL rats provides an alternative excretory pathway in the presence of biliary obstruction so as to prevent the bile acid stasis in the liver and the subsequent accumulation of toxic bile acids in hepatocytes[9].
   
Recently it was demonstrated that bile acids modulate ASBT expression through activation of the peroxisome proliferator-activated receptor alpha (PPARalpha)[18] and activator protein 1 (AP-1) element regulates the transcription of the rat ASBT gene[44].
   
Previous studies have shown that the stress induced alteration of ASBT genetic expression due to inflammation and bile acids is a consequence of trans-activation of the ASBT promoter by c-Jun/c-Fos and liver receptor homologue-1, respectively[10,47] and that hepatocyte nuclear factor-1a is critical for basal expression of ASBT.
   
Recently, the inflammatory cytokine IL-1b has been shown to rapidly down-regulate ASBT in the terminal ileum[50]. Dysregulation of the ASBT adaptation to cholestasis (due to increased expression of IL-1b) could blunt the compensatory up-regulation of ASBT in response to cholestasis and promote bile acid-induced liver damage. Recent data demonstrates that the ubiquitin-proteasome degradation system affects the activity of some membrane transporters[51,52]. The system is responsible for the disposal of many of the short-lived proteins in eukaryotic cells. The ubiquitin-proteasome pathway targets proteins for degradation via covalent tagging of the substrate protein with a polyubiquitin chain[53]. This degradation pathway is implicated in the regulation of many short-lived proteins involved in essential cellular functions, including cell cycle control, transcription regulation, signal transduction, and protein translocation. We speculated that the initial ASBT down-regulation due to ileal inflammation or due to IL-1b in vitro is caused by enhanced ASBT disposal by the ubiquitin-proteasome pathway. Our studies showed that ASBT is an unstable protein that is rapidly degraded with a half-life of approximately 6 h. We showed that the rapid IL-1b -dependent reduction of ASBT in cholangiocytes is due to increased ASBT disposal via the ubiquitin- proteasome pathway. IL-1b mediated down-regulation of ASBT expression requires phosphorylation of ASBT since mutation of two ASBT phosphorylation sites reduces the rate of ASBT disposal under basal conditions and markedly reduces IL-1b -dependent ubiquitination and disposal of ASBT. These results indicate that the proteasome plays an important role in the regulation of ASBT protein level in cholangiocytes.
 
Regional ASBT expression in the biliary tree
Regionalization of bile duct function occurs in rat liver[5]. Large (greater than 20 mm diameter bile ducts) that are lined by large cholangiocytes contribute to hormone-induced ductal secretion whereas small (smaller than 20 mm diameter bile ducts) do not contribute to hormone-induced ductal secretion[54,55]. Studies by Alpini et al[5] showed that ASBT is expressed in large cholangiocytes but not small cholangiocytes. The absence of ABST expression in small intrahepatic bile ducts may lead to more efficient hepatobiliary excretion of bile acids, since bile acid uptake in small ducts, closely adjacent to the canalicular bile acid secretion process, may hinder the post canalicular assembly of polymolecular bile acid-lipid micelles and vesicles. Recently, experimental models have been developed where ASBT gene, and protein expression and transport activity have been shown to extend into small bile ducts[7]. In taurocholate fed rats, a model where biliary bile acid concentrate increases approximately two fold, Alpini et al[7] found de novo ASBT expression in small ducts. The authors suggested that with expansion of the bile acid pool and increased biliary bile acid concentration, the extension of ASBT expression into small ducts leads to enhanced cholehepatic shunting of bile acids. Whether ASBT expression in small ducts alters bile acid-lipid micelles or vesicle formation has not been determined.

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