Download PDF
Semin Liver Dis 2002; 22(3): 227-240
DOI: 10.1055/s-2002-34501
Copyright © 2002 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Functional Heterogeneity of Cholangiocytes

Marco Marzioni1 , Shannon S. Glaser2 , Heather Francis2 , Jo Lynne Phinizy2 , Gene LeSage3 , Gianfranco Alpini1,3,4
  • 1Medical Physiology, The Texas A&M University System HSC, COM, Temple, Texas
  • 2Division of Research and Education, Scott & White Hospital, Temple Texas
  • 3Department of Internal Medicine, Scott & White Hospital, Temple, Texas
  • 4Internal Medicine and Medical Physiology, The Texas A & M University System HSC, COM and Central Texas Veterans Health Care System, Temple, Texas
Further Information

Publication History

Publication Date:
02 October 2002 (online)

    Permissions and Reprints

ABSTRACT

The objective of this article is to summarize the findings related to the notion that cholangiocytes, within small and large intrahepatic ducts, are heterogeneous regarding (1) morphology; (2) secretion in response to hormones and peptides and to bile acids; and (3) proliferation in response to injury or toxins, including bile duct ligation (BDL), acute carbon tetrachloride (CCl4) administration, chronic feeding of bile salts (i.e., taurocholate [TC] or taurolithocholate [TLC]) or α-naphthylisothiocyanate (ANIT). After an overview of the morphology of the biliary epithelium, we provide a summary of cholangiocyte function, the in vivo models, and the in vitro experimental tools (i.e., small and large cholangiocytes or small and large intrahepatic bile duct units [IBDU]), which allowed us to demonstrate cholangiocyte heterogeneity. After a discussion on the receptors, transporters, and channels that are heterogeneously expressed by cholangiocytes, we discuss the different-sized ducts that differentially respond to injury and toxins. Finally, we review the human diseases that selectively target specific-sized ducts.

KEYWORDS

Ductal secretion - intrahepatic biliary epithelium - liver injury - proliferation - secretin

REFERENCES

  • 1 Alpini G, Prall R T, LaRusso N F. The pathobiology of biliary epithelia. In: Arias IM, Boyer JL, Chisari FV, et al., eds. The Liver; Biology & Pathobiology, 4th ed Philadelphia, PA: Lippincott Williams & Wilkins 2001 0: 421-435
    Google Scholar
  • 2 Kanno N, LeSage G, Glaser S, Alvaro D, Alpini G. Functional heterogeneity of the intrahepatic biliary epithelium.  Hepatology . 2000;  31 555-561
    CrossrefPubMedGoogle Scholar
  • 3 Ludwig J. New concepts in biliary cirrhosis.  Semin Liver Dis . 1987;  7 293-301
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Sasaki H, Schaffner F, Popper H. Bile ductules in cholestasis: morphologic evidence for secretion and absorption in man.  Lab Invest . 1967;  16 84-95
    PubMedGoogle Scholar
  • 5 Schaffner F, Popper H. Electron microscopic studies of normal and proliferated bile ductules.  Am J Pathol . 1961;  38 393-410
    PubMedGoogle Scholar
  • 6 Alpini G, Glaser S, Robertson W. Large but not small intrahepatic bile ducts are involved in secretin-regulated ductal bile secretion.  Am J Physiol . 1997;  272 G1064-G1074
    PubMedGoogle Scholar
  • 7 Alpini G, Glaser S S, Ueno Y. Heterogeneity of the proliferative capacity of rat cholangiocytes after bile duct ligation.  Am J Physiol . 1998;  274 G767-G775
    PubMedGoogle Scholar
  • 8 Alpini G, Roberts S, Kuntz S M. Morphological, molecular, and functional heterogeneity of cholangiocytes from normal rat liver.  Gastroenterology . 1996;  110 1636-1643
    CrossrefPubMedGoogle Scholar
  • 9 Alpini G, Ulrich C, Roberts S. Molecular and functional heterogeneity of cholangiocytes from rat liver after bile duct ligation.  Am J Physiol . 1997;  272 G289-G297
    PubMedGoogle Scholar
  • 10 Nathanson M H, Boyer J L. Mechanisms and regulation of bile secretion.  Hepatology . 1991;  14 551-566
    CrossrefPubMedGoogle Scholar
  • 11 Alpini G, Lenzi R, Sarkozi L, Tavoloni N. Biliary physiology in rats with bile ductular cell hyperplasia. Evidence for a secretory function of proliferated bile ductules.  J Clin Invest . 1988;  81 569-578
    PubMedGoogle Scholar
  • 12 Ohtani O, Kikuta A, Ohtsuka A, Taguchi T, Murakami T. Microvasculature as studied by the microvascular corrosion casting/scanning electron microscope method. I. Endocrine and digestive system.  Arch Histol Jpn . 1983;  46 1-42
    CrossrefPubMedGoogle Scholar
  • 13 Terada T, Ishida F, Nakanuma Y. Vascular plexus around intrahepatic large bile ducts in normal livers and portal hypertension.  J Gastroenterol Hepatol . 1989;  1 276-278
    PubMedGoogle Scholar
  • 14 Yamamoto K, Phillips M J. A hitherto unrecognized bile ductular plexus in normal rat liver.  Hepatology . 1984;  4 381-385
    PubMedGoogle Scholar
  • 15 Gaudio E, Onori P, Pannarale L, Alvaro D. Hepatic microcirculation and peribiliary plexus in experimental biliary cirrhosis: A morphological study.  Gastroenterology . 1996;  111 1118-1124
    CrossrefPubMedGoogle Scholar
  • 16 LeSage G D, Glaser S S, Marucci L. Acute carbon tetrachloride feeding induces damage of large but not small cholangiocytes from BDL rat liver.  Am J Physiol . 1999;  276 G1289-G1301
    PubMedGoogle Scholar
  • 17 Alpini G, Ueno Y, Glaser S, Phinizy J L, Francis H, LeSage G. Bile acid feeding stimulates proliferative activity of both small and large cholangiocytes through activation and membrane translocation of protein kinase C alpha.  Hepatology . 2001;  34 868-876
    CrossrefPubMedGoogle Scholar
  • 18 LeSage E G, Alvaro D, Benedetti A. Cholinergic system modulates growth, apoptosis, and secretion of cholangiocytes from bile duct-ligated rats.  Gastroenterology . 1999;  117 191-199
    PubMedGoogle Scholar
  • 19 LeSage G, Glaser S, Ueno Y. Regression of cholangiocyte proliferation after cessation of ANIT feeding is coupled with increased apoptosis.  Am J Physiol . 2001;  281 G182-G190
    PubMedGoogle Scholar
  • 20 LeSage G, Glaser S S, Gubba S. Regrowth of the rat biliary tree after 70% partial hepatectomy is coupled to increased secretin-induced ductal secretion.  Gastroenterology . 1996;  111 1633-1644
    PubMedGoogle Scholar
  • 21 LeSage G D, Benedetti A, Glaser S. Acute carbon tetrachloride feeding selectively damages large, but not small, cholangiocytes from normal rat liver.  Hepatology . 1999;  29 307-319
    CrossrefPubMedGoogle Scholar
  • 22 Steiner J W, Carruthers J S. Studies on the fine structure of the terminal branches of the biliary tree. I. The morphology of normal bile canaliculi, bile preductules (ducts of Hering) and bile ductules.  Am J Pathol . 1961;  38 639-661
    PubMedGoogle Scholar
  • 23 Benedetti A, Bassotti C, Rapino K, Marucci L, Jezequel A M. A morphometric study of the epithelium lining the rat intrahepatic biliary tree.  J Hepatol . 1996;  24 335-342
    CrossrefPubMedGoogle Scholar
  • 24 Kanno N, LeSage G, Glaser S, Alpini G. Regulation of cholangiocyte bicarbonate secretion.  Am J Physiol . 2001;  281 G612-G625
    PubMedGoogle Scholar
  • 25 Baiocchi L, LeSage G, Glaser S, Alpini G. Regulation of cholangiocyte bile secretion.  J Hepatol . 1999;  31 179-191
    CrossrefPubMedGoogle Scholar
  • 26 LeSage G, Glaser S, Alpini G. Regulatory mechanisms of ductal bile secretion.  Dig Liver Dis . 2000;  32 563-566
    CrossrefPubMedGoogle Scholar
  • 27 Alvaro D, Alpini G, Jezequel A M. Role and mechanisms of action of acetylcholine in the regulation of rat cholangiocyte secretory functions.  J Clin Invest . 1997;  100 1349-1362
    CrossrefPubMedGoogle Scholar
  • 28 Glaser S, Benedetti A, Marucci L. Gastrin inhibits cholangiocyte growth in bile duct ligated rats by interaction with CCK-B/gastrin receptors via IP3-, Ca2+-, and PKCα-dependent mechanisms.  Hepatology . 2000;  32 17-25
    CrossrefPubMedGoogle Scholar
  • 29 Glaser S S, Rodgers R, Phinizy J L. Gastrin inhibits secretin-induced ductal secretion by interaction with specific receptors on rat cholangiocytes.  Am J Physiol . 1997;  273 G1061-1070
    PubMedGoogle Scholar
  • 30 Tietz P S, Alpini G, Pham L D, Larusso N F. Somatostatin inhibits secretin-induced ductal hypercholeresis and exocytosis by cholangiocytes.  Am J Physiol . 1995;  269 G110-G118
    PubMedGoogle Scholar
  • 31 Cho W K, Mennone A, Rydberg S A, Boyer J L. Bombesin stimulates bicarbonate secretion from rat cholangiocytes: implications for neural regulation of bile secretion.  Gastroenterology . 1997;  113 311-321
    PubMedGoogle Scholar
  • 32 Cho W K, Boyer J L. Vasoactive intestinal polypeptide is a potent regulator of bile secretion from rat cholangiocytes.  Gastroenterology . 1999;  117 420-428
    PubMedGoogle Scholar
  • 33 Caligiuri A, Glaser S, Rodgers R E. Endothelin-1 inhibits secretin-stimulated ductal secretion by interacting with ETA receptors on large cholangiocytes.  Am J Physiol . 1998;  275 G835-G846
    PubMedGoogle Scholar
  • 34 Alpini G, Glaser S, Robertson W. Bile acids stimulate proliferative and secretory events in large but not small cholangiocytes.  Am J Physiol . 1997;  273 G518-G529
    PubMedGoogle Scholar
  • 35 Alpini G, Glaser S S, Rodgers R. Functional expression of the apical Na+-dependent bile acid transporter in large but not small rat cholangiocytes.  Gastroenterology . 1997;  113 1734-1740
    PubMedGoogle Scholar
  • 36 Lazaridis K N, Pham L, Tietz P. Rat cholangiocytes absorb bile acids at their apical domain via the ileal sodium-dependent bile acid transporter.  J Clin Invest . 1997;  100 2714-2721
    PubMedGoogle Scholar
  • 37 Alpini G, Ulrich II C, Phillips J, Pham L, Miller L, LaRusso N. Upregulation of secretin receptor gene expression in rat cholangiocytes after bile duct ligation.  Am J Physiol . 1994;  266 G922-G928
    PubMedGoogle Scholar
  • 38 Alvaro D, Mennone A, Boyer J L. Role of kinases and phosphatases in the regulation of fluid secretion and Cl-/HCO3 - exchange in cholangiocytes.  Am J Physiol . 1997;  273 G303-G313
    PubMedGoogle Scholar
  • 39 Fitz J G, Basavappa S, McGill J, Melhus O, Cohn J A. Regulation of membrane chloride currents in rat bile duct epithelial cells.  J Clin Invest . 1993;  91 319-328
    PubMedGoogle Scholar
  • 40 Alvaro D, Benedetti A, Marucci L. The function of alkaline phosphatase in the liver: regulation of intrahepatic biliary epithelium secretory activities in the rat.  Hepatology . 2000;  32 174-184
    CrossrefPubMedGoogle Scholar
  • 41 Alvaro D, Cho W K, Mennone A, Boyer J L. Effect of secretion on intracellular pH regulation in isolated rat bile duct epithelial cells.  J Clin Invest . 1993;  92 1314-1325
    PubMedGoogle Scholar
  • 42 Alpini G, Lenzi R, Zhai W R. Bile secretory function of intrahepatic biliary epithelium in the rat.  Am J Physiol . 1989;  257 G124-G133
    PubMedGoogle Scholar
  • 43 LeSage G, Glaser S, Robertson W. Partial hepatectomy induces proliferative and secretory events in small cholangiocytes (Abst).  Gastroenterology . 1996;  110 A1250
    PubMedGoogle Scholar
  • 44 Tsuruoka S, Takeda M, Yoshitomi K, Imai M. Cellular heterogeneity of ammonium ion transport across the basolateral membrane of the hamster medullary thick ascending limb of Henle's loop.  J Clin Invest . 1993;  92 1881-1888
    PubMedGoogle Scholar
  • 45 Guggino W B. Functional heterogeneity in the early distal tubule of the Amphiuma kidney: evidence for two modes of Cl- and K+ transport across the basolateral cell membrane.  Am J Physiol . 1986;  250 F430-F440
    PubMedGoogle Scholar
  • 46 Nielsen S, Smith B L, Christensen E I, Knepper M A, Agre P. CHIP28 water channels are localized in constitutively water-permeable segments of the nephron.  J Cell Biol . 1993;  120 371-383
    CrossrefPubMedGoogle Scholar
  • 47 Lopez C A, Hoyer J R, Wilson P D, Waterhouse P, Denhardt D T. Heterogeneity of osteopontin expression among nephrons in mouse kidneys and enhanced expression in sclerotic glomeruli.  Lab Invest . 1993;  69 355-363
    PubMedGoogle Scholar
  • 48 Bachmann S, Bostanjoglo M, Schmitt R, Ellison D H. Sodium transport-related proteins in the mammalian distal nephron-distribution, ontogeny and functional aspects.  Anat Embryol (Berl) . 1999;  200 447-468
    CrossrefPubMedGoogle Scholar
  • 49 Fromm M, Hegel U. Segmental heterogeneity of epithelial transport in rat large intestine.  Pflugers Arch . 1978;  378 71-83
    PubMedGoogle Scholar
  • 50 Knickelbein R G, Aronson P S, Dobbins J W. Membrane distribution of sodium-hydrogen and chloride-bicarbonate exchangers in crypt and villus cell membranes from rabbit ileum.  J Clin Invest . 1988;  82 2158-2163
    PubMedGoogle Scholar
  • 51 Katz N, Jungermann K. Metabolic heterogeneity of the liver. In: Tavoloni N, Berk PD, eds. Hepatic Transport and Bile Secretion: Physiology and Pathophysiology New York: Raven Press 1993: 55-70
    Google Scholar
  • 52 Rabes H M. Kinetics of hepatocellular proliferation after partial resection of the liver.  Prog Liver Dis . 1976;  5 83-99
    PubMedGoogle Scholar
  • 53 Mathis G A, Walls S A, D'Amico P, Gengo T F, Sirica A E. Enzyme profile of rat bile ductular epithelial cells in reference to the resistance phenotype in hepatocarcinogenesis.  Hepatology . 1989;  9 477-485
    PubMedGoogle Scholar
  • 54 Terada T, Kono N, Nakanuma Y. Immunohistochemical and immunoelectron microscopic analyses of alpha-amylase isozymes in human intrahepatic biliary epithelium and hepatocytes.  J Histochem Cytochem . 1992;  40 1627-1635
    PubMedGoogle Scholar
  • 55 Terada T, Morita T, Hoso M, Nakanuma Y. Pancreatic enzymes in the epithelium of intrahepatic large bile ducts and in hepatic bile in patients with extrahepatic bile duct obstruction.  J Clin Pathol . 1994;  47 924-927
    PubMedGoogle Scholar
  • 56 Okada Y, Jinno K, Moriwaki S. Blood group antigens in the intrahepatic biliary tree.  J Hepatol . 1988;  6 63-70
    CrossrefPubMedGoogle Scholar
  • 57 Martinez-Anso E, Castillo J E, Diez J, Medina J F, Prieto J. Immunohistochemical detection of chloride/bicarbonate anion exchangers in human liver.  Hepatology . 1994;  19 1400-1406
    CrossrefPubMedGoogle Scholar
  • 58 Katayanagi K, Van de Water J, Kenny T. Generation of monoclonal antibodies to murine bile duct epithelial cells: identification of annexin V as a new marker of small intrahepatic bile ducts.  Hepatology . 1999;  29 1019-1025
    CrossrefPubMedGoogle Scholar
  • 59 Diakonova M, Gerke V, Ernst J. Localization of five annexins in J774 macrophages and in isolated phagosomes.  J Cell Sci . 1997;  110 1199-1213
    PubMedGoogle Scholar
  • 60 Celli A, Que F G, Gores G J, LaRusso N F. Glutathione depletion is associated with decreased Bcl-2 expression and increased apoptosis in cholangiocytes.  Am J Physiol . 1998;  275 G749-G757
    PubMedGoogle Scholar
  • 61 Charlotte F, L'Hermine A, Martin N. Immunohistochemical detection of bcl-2 protein in normal and pathological human liver.  Am J Pathol . 1994;  144 460-465
    PubMedGoogle Scholar
  • 62 Pinzani M, Milani S, De Franco R. Endothelin 1 is overexpressed in human cirrhotic liver and exerts multiple effects on activated hepatic stellate cells.  Gastroenterology . 1996;  110 534-548
    PubMedGoogle Scholar
  • 63 LeSage G, Glaser S, Alvaro D. Alpha-1 (but not beta-1) adrenergic agonists potentiate secretin-stimulated ductal secretion in bile duct ligated (BDL) rats through cross-talk between Ca2+-dependent PKC and adenylyl cyclase pathway (Abst).  Hepatology . 2001;  34 A1219
    PubMedGoogle Scholar
  • 64 Glaser S, Phinizy J L, Chowdhury U. D2 but not D1 dopaminergic agonists inhibit secretory processes of the intrahepatic biliary epithelium through a PKC-dependent mechanism (Abst).  Gastroenterology . 2000;  118 A146
    PubMedGoogle Scholar
  • 65 LeSage G, Glaser G, Marzioni M. Insulin inhibits secretin-stimulated ductal secretion in bile duct ligated (BDL) rats through activation of Ca2+-dependent protein kinase C (PKC) which leads to downregulation of protein kinase A (PKA) (Abst).  Hepatology . 2001;  34 A1228
    PubMedGoogle Scholar
  • 66 McGill J M, Basavappa S, Gettys T W, Fitz J G. Secretin activates Cl- channels in bile duct epithelial cells through a cAMP-dependent mechanism.  Am J Physiol . 1994;  266 G731-G736
    PubMedGoogle Scholar
  • 67 Strazzabosco M, Mennone A, Boyer J L. Intracellular pH regulation in isolated rat bile duct epithelial cells.  J Clin Invest . 1991;  87 1503-1512
    CrossrefPubMedGoogle Scholar
  • 68 Clawson G A. Mechanisms of carbon tetrachloride hepatotoxicity.  Pathol Immunopathol Res . 1989;  8 104-112
    CrossrefPubMedGoogle Scholar
  • 69 Mathis G A, Walls S A, Sirica A E. Biochemical characteristics of hyperplastic rat bile ductular epithelial cells cultured ``on top'' and ``inside'' different extracellular matrix substitutes.  Cancer Res . 1988;  48 6145-6153
    PubMedGoogle Scholar
  • 70 Lakehal F, Wendum D, Barbu V. Phase I and phase II drug-metabolizing enzymes are expressed and heterogeneously distributed in the biliary epithelium.  Hepatology . 1999;  30 1498-1506
    CrossrefPubMedGoogle Scholar
  • 71 Parola M, Cheeseman K H, Biocca M E, Dianzani M U, Slater T F. Biochemical studies on bile duct epithelial cells isolated from rat liver [published erratum appears in J Hepatol 1990; 11:397].  J Hepatol . 1990;  10 341-345
    PubMedGoogle Scholar
  • 72 Roomi M W, Ho R K, Sarma D S, Farber E. A common biochemical pattern in preneoplastic hepatocyte nodules generated in four different models in the rat.  Cancer Res . 1985;  45 564-571
    PubMedGoogle Scholar
  • 73 Schrenk D, Eisenmann-Tappe I, Gebhardt R. Drug metabolizing enzyme activities in rat liver epithelial cell lines, hepatocytes and bile duct cells.  Biochem Pharmacol . 1991;  41 1751-1757
    CrossrefPubMedGoogle Scholar
  • 74 Alvaro D, Alpini G, Onori P. Estrogens stimulate proliferation of the intrahepatic biliary epithelium in rats.  Gastroenterology . 2000;  119 1681-1691
    CrossrefPubMedGoogle Scholar
  • 75 Desmet V J, van Eyken P, Roskams T. Histopathology of vanishing bile duct diseases.  Adv Clin Pathol . 1998;  2 87-99
    PubMedGoogle Scholar
  • 76 Desmet V J. Vanishing bile duct disorders.  Prog Liver Dis . 1992;  10 89-121
    PubMedGoogle Scholar
  • 77 Poupon R, Chazouilleres O, Poupon R E. Chronic cholestatic diseases.  J Hepatol . 2000;  32 129-140
    PubMedGoogle Scholar
  • 78 Ludwig J, LaRusso N F, Wiesner R H. The syndrome of primary sclerosing cholangitis.  Prog Liver Dis . 1990;  9 555-566
    PubMedGoogle Scholar
  • 79 Chen L Y, Goldberg H I. Sclerosing cholangitis: broad spectrum of radiographic features.  Gastrointest Radiol . 1984;  1 39-47
    PubMedGoogle Scholar
  • 80 Wee A, Ludwig J. Pericholangitis in chronic ulcerative colitis: primary sclerosing cholangitis of the small bile ducts?.  Ann Intern Med . 1985;  102 581-587
    PubMedGoogle Scholar
  • 81 Ahrendt S A, Nakeeb A, Pitt H A. Cholangiocarcinoma.  Clin Liver Dis . 2001;  5 191-218
    PubMedGoogle Scholar
  • 82 Torok N, Gores G J. Cholangiocarcinoma.  Semin Gastrointest Dis . 2001;  12 125-132
    PubMedGoogle Scholar
  • 83 Alagille D, Odievre M, Gautier M, Dommergues J P. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur.  J Pediatr . 1975;  86 63-71
    CrossrefPubMedGoogle Scholar
  • 84 Alagille D, Estrada A, Hadchouel M, Gautier M, Odievre M, Dommergues J P. Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases.  J Pediatr . 1987;  110 195-200
    PubMedGoogle Scholar
  • 85 Snover D C, Filipovich A H, Ramsay N K, Weisdorf S A, Kersey J H. Graft-versus-host-disease-like histopathological findings in pre-bone-marrow transplantation biopsies of patients with severe T cell deficiency.  Transplantation . 1985;  39 95-97
    PubMedGoogle Scholar
  • 86 Ludwig J. Terminology of hepatic allograft rejection (glossary).  Semin Liver Dis . 1992;  12 89-92
    PubMedGoogle Scholar
  • 87 Tanaka M, Umihara J, Chiba S, Ishikawa E. Intrahepatic bile duct injury following bone marrow transplantation. Analysis of pathological features based on three-dimensional and histochemical observation.  Acta Pathol Jpn . 1986;  36 1793-1806
    PubMedGoogle Scholar
  • 88 Rudzki C, Ishak K G, Zimmerman H J. Chronic intrahepatic cholestasis of sarcoidosis.  Am J Med . 1975;  59 373-387
    CrossrefPubMedGoogle Scholar
  • 89 Maddrey W C. Sarcoidosis and primary biliary cirrhosis. Associated disorders?.  N Engl J Med . 1983;  308 588-590
    PubMedGoogle Scholar
  • 90 Ludwig J, Wiesner R H, LaRusso N F. Idiopathic adulthood ductopenia. A cause of chronic cholestatic liver disease and biliary cirrhosis.  J Hepatol . 1988;  7 193-199
    CrossrefPubMedGoogle Scholar
  • 91 Roskams T, De Vos R, Desmet V. `Undifferentiated progenitor cells' in focal nodular hyperplasia of the liver.  Histopathol . 1996;  28 291-299
    PubMedGoogle Scholar
  • 92 Song Z, Bottjie W G, Cawthon D, Beers K. Biliary glutathione secretion in male single comb white leghorn chickens after inhibition of gamma-glutamyltranspeptidase.  Poult Sci . 2000;  79 1829-1832
    PubMedGoogle Scholar