EDITORIAL FOCUS
Focus on "Cholangiocytes exhibit dynamic, actin-dependent apical membrane turnover"

Pamela S. Tietz and Nicholas F. LaRusso

Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Medical School, Clinic, and Foundation, Rochester, Minnesota 55905


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IN THE PAST DECADE, there has been an explosion of interest in and information about cholangiocytes, the epithelial cells that line the intrahepatic bile ducts. This increased attention relates to at least three developments: first, the evolution of new experimental models and techniques to directly study cholangiocyte biology; second, the recognition that cholangiocytes are of considerable intrinsic biological interest, particularly with regard to their roles in the transport of water, ions, and solutes, their heterogeneity, and their proliferative capacity; and third, the growing appreciation that cholangiocytes represent the targets of a group of genetic, developmental, immune-mediated, malignant, infectious, and iatrogenic conditions and diseases that we have termed the cholangiopathies.

Recent data from a variety of laboratories have supported the hypothesis that the secretory and absorptive activities of cholangiocytes for water, ions, and solutes likely involve membrane recycling (3). More specifically, the concept has evolved that key flux proteins (that is, proteins involved in solute, ion, and water transport, including channels, transporters, and exchangers) are both introduced into and removed from the apical membrane of cholangiocytes by insertional exocytosis and retrieval endocytosis, respectively, in response to the presence of choleretic and cholestatic agonists (2). Moreover, a key requirement for this recycling process is the cholangiocyte cytoskeleton and recently described molecular motors (i.e., dynein and kinesin).

In the current article in focus (Ref. 1, see p. C1042 in this issue), Doctor et al. provide additional novel and important evidence supporting an important role for vesicular trafficking in the modification of the apical cholangiocyte membrane. Their key observations in cultured human and rat cholangiocytes include 1) high rates of basal exocytosis and endocytosis, 2) cAMP modulation of exocytosis, 3) an important role for the actin cytoskeleton and submembranous vesicles in vesicle trafficking, and 4) the observation that filamentous actin encapsulates a subpopulation of endocytic vesicles (1). Their findings, together with previously published data, support an important role for regulated vesicle recycling in modification of the cholangiocyte apical membrane, a process that presumably has physiological relevance to cholangiocyte function.

As with any important research, the results generate as many questions as they answer. For example, the interplay of agonists and the identity of specific actin or other cytoskeleton-associated proteins and their functional role in intracellular vesicle trafficking remain to be elucidated. Moreover, the work adds additional credence to the existence of multiple steps along the trafficking pathway that are likely regulated by different as yet unidentified proteins that are recruited in a cascade fashion and that may have common expression among secretory epithelia (although the possibility that they are unique to cholangiocytes needs to be considered).

Although not directly addressed by Doctor et al. (1), the possibility that specific lipids may be involved in the regulation of intracellular trafficking in polarized epithelial cells, including cholangiocytes, will likely be an additional area of important attention in the future (5). The apical membrane of cholangiocytes is unusual in its lipid composition (i.e., uniquely high cholesterol-to-phospholipid ratio), and the possibility that the unusual features of the apical cholangiocyte membrane may be involved in a regulatory fashion in the agonist-induced recycling of flux proteins must be considered (4).

Unquestionably, then, recycling of flux proteins as a regulatory mechanism in transporting epithelia, including cholangiocytes, has become increasingly recognized as important. The work of Doctor et al. (1) provides new dimensions from a technological as well as a conceptional viewpoint to this area. Future insights into the role of vesicle trafficking in cholangiocytes and other transporting epithelia will require particular attention to the new technologies described in this article.


    FOOTNOTES

Address for reprint requests and other correspondence: N. F. LaRusso, Center for Basic Research in Digestive Diseases, Mayo Medical School, Clinic, and Foundation, 200 First St. SW, Rochester, MN 55905 (E-mail: larusso.nicholas{at}mayo.edu).

10.1152/ajpcell.00603.2001


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1.   Doctor, R, Dahl R, Fouassier L, Kilic G, and Fitz JG. Cholangiocytes exhibit dynamic, actin-dependent apical membrane turnover. Am J Physiol Cell Physiol 282: C1042-C1052, 2002[Abstract/Free Full Text].

2.   Marinelli, RA, Tietz PS, Pham LD, Rueckert L, Agre P, and LaRusso NF. Secretin induces the apical insertion of aquaporin-1 water channels in rat cholangiocytes. Am J Physiol Gastrointest Liver Physiol 276: G280-G286, 1999[Abstract/Free Full Text].

3.   Masyuk, A, Marinelli RA, and LaRusso NF. Water transport by epithelia of the digestive tract. Gastroenterology 122: 545-562, 2002[ISI][Medline].

4.   Tietz, PS, Holman RT, Miller LJ, and LaRusso NF. Isolation and characterization of rat cholangiocyte vesicles enriched in apical or basolateral plasma membrane domains. Biochemistry 34: 15436-15443, 1995[ISI][Medline].

5.   Zegers, MM, and Hoekstra D. Mechanisms and functional features of polarized membrane traffic in epithelial and hepatic cells. Biochem J 336: 257-269, 1998[ISI][Medline].


Am J Physiol Cell Physiol 282(5):C982-C983
0363-6143/02 $5.00 Copyright © 2002 the American Physiological Society




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