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