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- Bile acid interactions with cholangiocytes

In earlier studies of hepatobiliary physiology, it was generally concluded that biliary components do not appreciably interact with bile ducts and after canalicular secretion, bile acids and lipids pass through the biliary system as if bile ducts were inactive conduits[1]. Twenty-five years ago, the cholehepatic shunt pathway was proposed to explain the hypercholeretic nature of certain bile acids[2,3]. This hypothesis suggested that bile acids, in a protonated, uncharged form, undergo passive biliary absorption, followed by transfer of bile acids back to hepatocytes for re-secretion into bile (Figure 1)[2]. Later, other studies suggested that in the presence of complete bile duct obstruction, canalicular secretion of bile acids persists and bile acids may pass back through cholangiocytes to the circulation instead of the entering the intestine[4]. Subsequent to the discovery of the expression of a bile acid transporter on the apical membrane of cholangiocytes (apical sodium-dependent bile acid transporter or ASBT)[5-8], there has been renewed interest in the potential of cholehepatic shunting of bile acids. Cholangiocyte ASBT adapts to chronic cholestasis induced by bile duct obstruction by upregulation of cholangiocyte transport capacity potentially leading to augmentation of cholehepatic shunting of bile acids and protection from cholestatic liver injury due to hepatocellular retention of bile acids[9].
Bile acids also interact with cholangiocytes leading to alteration of cholangiocyte secretion, proliferation, apoptosis and differentiation[7,8,10-12]. In both hepatocytes and stellate cells, bile acids when present intracellularly in low concentrations (e.g. less than 10 mmol/L) function as intracellular signals triggering wide variety of protein kinases, changes in intracellular Ca2+ and phosphorylation of proteins. Since bile acids do not appreciably enter cells in the absence of a membrane transporter, the expression of bile acid transporter is required for bile acid signaling, and the degree of bile acid transporter expression may determine the sensitivity of cells to bile acid signaling. Thus the bile acid transporter functions in some respects like a membrane receptor, determining both selective and sensitivity of the cell reactions to bile acid agonists. Bile acids, alter Ca2+, cAMP, PKC and PI3K intercellular signaling systems in cholangiocytes. ASBT function was shown to be required for signaling and the level of ASBT expression correlated with cholangiocyte sensitivity to bile acids[7,8,10,13,14]. As a manifestation of the signaling properties of bile acids in cholangiocytes, studies show that bile acids may directly stimulate cholangiocyte proliferation and secretion[11,12] and thus accumulating bile acids due to chronic cholestasis may promote the ductal hyperplasia that occurs in chronic cholestatic liver disease. Changes in biliary bile acid composition or concentration may also modulate cholangiocyte survival[15,16]. Increasing biliary bile acid concentration, by bile acid feeding, reduces cholangiocyte apoptosis induced by CCl4 or vagotomy in rats[15,16]. As another potential signaling function, bile acids may alter cholangiocyte differentiation, since small bile ducts following chronic exposure to bile acids begin expressing proteins and functions normally only present in large intrahepatic bile ducts[7]. Therapeutic bile acids (ursodeoxycholate), perhaps surprisingly, have opposing effects on cholangiocyte function compared to endogenous bile acids. Ursodeoxycholate appears to reduce cholangiocyte proliferation and reduce bile mass in animal models of bile duct hyperplasia[8]. The implications of these findings are discussed later.
The purpose of this review is familiarizing the reader in the role of bile acids in cholangiocyte biology and pathophysiology. Recent studies unexpectedly show that cholangiocytes transport bile acids and adapt to changes in biliary bile acids. Considering that one of the fundamental events in cholestasis is the retention in the liver of com-ponents that are normally secreted in bile, alternative pathways for elimination of biliary components would be an important adaptation of the liver to cholestasis. The review will outline mechanisms for bile acid transport in cholangiocytes, the role of bile acid regulation of cholangiocyte proliferation, secretion and apoptosis in animal models and human diseases. First the mechanisms for bile acid uptake at the cholangiocyte apical membrane will be reviewed. Second, basolateral bile acid efflux mechanisms are outlined. Third, the current evidence for cholehepatic shunting of bile acids is summarized. Next the mechanisms responsible for acute and chronic regulation of ASBT activity in cholangiocytes are reviewed. Finally, the concept of intracellular bile acid acting as signaling molecules in cholangiocytes will be developed and the evidence for bile acid regulation of cholangiocyte secretion, proliferation and survival will be summarized.

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