The objective of this review article is to discuss the role of secretin and its receptor in the regulation of the secretory activity of intrahepatic bile duct epithelial cells (i.e., cholangiocytes). After a brief overview of cholangiocyte functions, we provide an historical background for the role of secretin and its receptor in the regulation of ductal secretion. We review the newly developed experimental in vivo and in vitro tools, which lead to understanding of the mechanisms of secretin regulation of cholangiocyte functions. After a description of the intracellular mechanisms by which secretin stimulates ductal secretion, we discuss the heterogeneous responses of different-sized intrahepatic bile ducts to gastrointestinal hormones. Furthermore, we outline the role of a number of cooperative factors (e.g., nerves, alkaline phosphatase, gastrointestinal hormones, neuropeptides, and bile acids) in the regulation of secretin-stimulated ductal secretion. Finally, we discuss other factors that may also play an important role in the regulation of secretin-stimulated ductal secretion.
Cholangiocyte proliferation and loss through apoptosis occur in cholestatic liver diseases. Our aim was to determine the mechanisms of apoptosis in an animal model of ductal hyperplasia. Rats were fed alpha-naphthylisothiocyanate (ANIT) for 2 wk and subsequently fed normal chow for 1, 2, and 4 wk. Proliferation was assessed in sections by morphometry and in small and large cholangiocytes by proliferating cellular nuclear antigen immunoblots and measurement of cAMP levels. Apoptosis and reactive oxygen species (ROS) levels were also assessed. ANIT feeding increased small and large cholangiocyte proliferation and apoptosis. Cessation of ANIT feeding was associated with decreased proliferation and a further increase in apoptosis in small and large cholangiocytes. Cholangiocytes from ANIT-fed rats or exposed to ANIT in vitro showed increased apoptosis and ROS generation. ANIT-induced duct injury results in enhanced proliferation and apoptosis in small and large cholangiocytes. The mechanism of ANIT-induced apoptosis may be due to ROS generation induced directly by ANIT. Our model has implications for understanding the pathophysiology of cholangiopathies (characterized by the coexistence of cholangiocyte apoptosis and proliferation).
The objective of this review article is to discuss the latest findings related to the morphological, functional, and proliferative heterogeneity of intrahepatic bile duct epithelial cells (i.e., cholangiocytes) lining the biliary tree. In the first part of the review, after a brief overview of the major functions of cholangiocytes, we will briefly outline the in vivo animal models and the cell systems (i.e., pure subpopulations of small and large cholangiocytes and small and large intrahepatic bile duct units [IBDU]) (Fig. 1), which have been critically important to the elucidation of the functional heterogeneity of cholangiocytes in different portions of the intrahepatic biliary tree. In the second part of the review article, we will discuss the recent findings showing that the intrahepatic biliary tree is heterogeneous with regard to (1) morphology, (2) secretory processes, (3) expression of antigens/proteins, and (4) proliferative responses to liver injury/ toxins. BRIEF BACKGROUND ON CHOLANGIOCYTE FUNCTIONSCholangiocytes line the intrahepatic and extrahepatic bile ducts. 1,2 Cholangiocytes play an important role in the modification of bile of canalicular origin by a series of re-absorptive and secretory processes as bile passes through the intrahepatic biliary tree. 2-9 Ductal bile secretion is rich in bicarbonate 3,7,9,10 and contributes up to approximately 10% of total bile flow in rats. 10 Modification of canalicular bile by cholangiocytes is regulated in a coordinated fashion by a number of gastrointestinal hormones (e.g., secretin, 2,3,5,7-9 somatostatin, 9 gastrin, 7 bombesin 11 ), peptides (endothelin 1 [ET-1] 12 ), and cholinergic innervation. 13 For the intracellular mechanisms regulating cholangiocyte secretory activity, we refer to selected articles. [2][3][4][5][6][7][8][9][11][12][13][14][15][16][17][18][19][20] HETEROGENEITY OF OTHER EPITHELIAThe morphological and functional heterogeneity of other epithelia is well defined in several organs including the small intestine, kidney, and liver. [21][22][23][24][25][26][27][28] In these organs, different subpopulations of epithelial cells share the work because each subpopulation possesses unique functions. For example, rat renal cells are composed of morphologically different cells performing different functions. [21][22][23] Only cells of the proximal tubule and descending limb of Henle' s loop have transepithelial water transport activity modulated by aquaporin channels (CHIP28). 23 Epithelial cells of the small and large intestine display marked heterogeneity in the distribution of membrane transporters underlying absorptive and secretory processes. 27,28 In the liver, a number of studies support the functional heterogeneity of hepatocytes. [24][25][26] For example, periportal and perivenous hepatocytes are heterogeneous with regard to the metabolism of oxidative energy, carbohydrate and amino acids. 25 Furthermore, transport processes involved in the process of bile formation are heterogeneously distributed among hepatocytes of different lobula...
Microarray successfully displayed characteristic differential cDNA expression between small and large cholangiocytes. This technique provides molecular information, which further supports our hypothesis that small and large bile ducts have different functions.
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