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Semin Liver Dis 2000; Volume 20(Number 03): 307-322
DOI: 10.1055/s-2000-9386
Copyright © 2000 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Short-Term Regulation of Canalicular Transport

DIETER. HÄUSSINGER, MARCUS. SCHMITT, OLIVER. WEIERGRÄBER, RALF. KUBITZ
  • From the Medizinische Universitätsklinik, Heinrich Heine Universität, Düsseldorf, Germany
Further Information

Publication History

Publication Date:
31 December 2000 (online)

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ABSTRACT

On a short term basis, canalicular secretion is under control of the hepatocellular hydration state, substrates, cytokines, toxins, and hormones. Regulation occurs at the level of substrate availability, covalent modification of transporters, and their regulated exocytic insertion into or endocytic retrieval from the membrane. A variety of signal transduction pathways involving the activation of mitogen-activated protein kinases, protein kinases A and C, participates in these processes. However, much has still to be learned about the crosstalk of different signaling systems and their molecular targets that determine the outcome for canalicular secretion.

KEYWORD

bile secretion - ABC-transporter - cell volume - transporter targeting

REFERENCES

  • 1 Gatmaitan Z C, Arias I M. ATP-dependent transport systems in the canalicular membrane of the hepatocyte.  Physiol Rev . 1995;  75 261-275
    PubMedGoogle Scholar
  • 2 Oude-Elferink R PJ, Meijer D KF, Kuipers F. Hepatobiliary secretion of organic compounds: Molecular mechanisms of membrane transport.  Biochim Biophys Acta . 1995;  1241 215-268
    PubMedGoogle Scholar
  • 3 Meier P J. Molecular mechanisms of hepatic bile salt transport from the sinusoidal blood into bile.  Am J Physiol . 1995;  268 G801-G812
    PubMedGoogle Scholar
  • 4 Keppler D, Arias I M. Transport across the hepatocyte canalicular membrane.  FASEB J . 1997;  11 15-18
    PubMedGoogle Scholar
  • 5 Müller M, Jansen L M. Molecular aspects of hepatobiliary transport.  Am J Physiol . 1997;  272 G1285-G1303
    PubMedGoogle Scholar
  • 6 Keppler D, König J. Expression and localization of the conjugate export pump encoded by the MRP2 (cMRP/cMOAT) gene in liver.  FASEB J . 1997;  11 509-516
    PubMedGoogle Scholar
  • 7 Meijer D KF, Smit J W, Müller M. Hepatobiliary elimination of cationic drugs: The role of P-glycoproteins and other ATP-dependent transporters.  Adv Drug Deliv Rev . 1997;  25 159-200
    CrossrefPubMedGoogle Scholar
  • 8 König J, Nies A T, Cui Y. Conjugate export pumps of the multidrug resistance protein (MRP) family: Localization, substrate specificity, and MRP2-mediated drug resistance.  Biochim Biophys Acta . 1999;  1461 377-394
    PubMedGoogle Scholar
  • 9 Trauner M, Meier P J, Boyer J L. Molecular regulation of hepatocellular transport systems in cholestasis.  J Hepatol . 1999;  31 165-178
    CrossrefPubMedGoogle Scholar
  • 10 Oude-Elferink R PJ, Meijer D KF, Kuipers F. Hepatobiliary secretion of organic compounds: Molecular mechanisms of membrane transport.  Biochim Biophys Acta . 1995;  1241 215-268
    PubMedGoogle Scholar
  • 11 Meier P J, Eckhardt U, Schroeder A. Substrate specifity of sinusoidal bile acid and organic anion uptake systems in rat and human liver.  Hepatology . 1997;  26 1667-1677
    PubMedGoogle Scholar
  • 12 Weinman S A, Carruth M W, Dawson P A. Bile acid uptake via the human apical sodium-bile acid cotransporter is electrogenic.  J Biol Chem . 1998;  273 34691-34695
    CrossrefPubMedGoogle Scholar
  • 13 Kullack-Ublick G A. Regulation of organic anion and drug transporters of the sinusoidal membrane.  J Hepatol . 1999;  31 563-573
    CrossrefPubMedGoogle Scholar
  • 14 Abe T, Kakyo M, Tokui T. Identification of a novel gene family encoding human liver -specific organic anion transporter LST-1.  J Biol Chem . 1999;  274 17159-17163
    CrossrefPubMedGoogle Scholar
  • 15 Li L, Lee T K, Meier P J. Identification of glutathione as a driving force and leukotriene C4 as a substrate for oatp1, the hepatic sinusoidal organic solute transporter.  J Biol Chem . 1998;  273 16184-16191
    CrossrefPubMedGoogle Scholar
  • 16 Paulusma C C, Bosma P J, Zaman G JR. Congenital jaundice in rats with a mutation in a multidrug resistance-associated protein gene.  Science . 1996;  271 1126-1128
    CrossrefPubMedGoogle Scholar
  • 17 Büchler M, König J, Brom M. cDNA cloning of the hepatocyte canalicular isoform of the multidrug resistance protein, cMRP, reveals a novel conjugate export pump deficient in hyperbilirubinemic mutant rats.  J Biol Chem . 1996;  271 15091-15098
    CrossrefPubMedGoogle Scholar
  • 18 Taniguchi K, Wada M, Kohno K. A human canalicular multispecific organic anion transporter (cMOAT) gene is overexpressed in cisplatin-resistant human cancer cell lines with decreased drug accumulation.  Cancer Res . 1996;  56 4124-4129
    PubMedGoogle Scholar
  • 19 Gottesman M M, Hrycyna C A, Schoenlein P V. Genetic analysis of the multidrug transporter.  Annu Rev Genet . 1995;  29 607-649
    CrossrefPubMedGoogle Scholar
  • 20 Gerloff T, Stieger B, Hagenbuch B. The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver.  J Biol Chem . 1998;  273 10046-10050
    CrossrefPubMedGoogle Scholar
  • 21 Kartenbeck J, Leuschner U, Mayer R. Absence of the canalicular isoform of the MRP gene-encoded conjugate export pump from the hepatocytes in Dubin-Johnson syndrome.  Hepatology . 1996;  23 1061-1066
    PubMedGoogle Scholar
  • 22 Deleuze J F, Jacquemin E, Dubuisson C. Defect of multidrug-resistance 3 gene expression in a subtype of progressive familial intrahepatic cholestasis.  Hepatology . 1996;  23 904-908
    CrossrefPubMedGoogle Scholar
  • 23 Smit J JM, Schinkel A H, Oude-Elferink R PJ. Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease.  Cell . 1993;  75 451-462
    CrossrefPubMedGoogle Scholar
  • 24 Koopen N R, Müller M, Vonk R J. Molecular mechanisms of cholestasis: Causes and consequences of impaired bile formation.  Biochim Biophys Acta . 1998;  1408 1-17
    PubMedGoogle Scholar
  • 25 Stieger B, Zhang R, O'Neil B. Differential interaction of bile acids from patients with inborn errors of bile acid synthesis with hepatocellular bile acid transporters.  Eur J Biochem . 1997;  244 39-44
    CrossrefPubMedGoogle Scholar
  • 26 Erlinger S. Intracellular events in bile acid transport by the liver. In: Tavaloni N, Berk PD, eds. Hepatic transport and bile secretion, physiology and pathophysiology New York: Raven Press, 1993: 467-475
    Google Scholar
  • 27 Arias I M, Che M, Gatmaitan Z. The biology of the bile canaliculus.  Hepatology . 1993;  17 318-329
    CrossrefPubMedGoogle Scholar
  • 28 Groen A K, van der Meer R, Westerhoff H V. Control of metabolic fluxes.  In: Sies H, ed. Metabolic compartmentation London: Academic Press 1982: 9-37
    Google Scholar
  • 29 Green R M, Beier D, Gollan J L. Regulation of hepatocyte bile salt transporters by endotoxin and inflammatory cytokines in rodents.  Gastroenterology . 1996;  111 193-198
    CrossrefPubMedGoogle Scholar
  • 30 Simon F R, Fortune J, Iwahashi M. Ethinylestradiol cholestasis involves alterations in expression of liver sinusoidal transporters.  Am J Physiol . 1996;  34 G1043-G1052
    PubMedGoogle Scholar
  • 31 Bolder U, Non-Tu H-T, Schteingart C D. Hepatocyte transport of bile acids and organic anions in endotoxemixc rats: Impaired uptake and secretion.  Gastroenterology . 1997;  112 214-225
    PubMedGoogle Scholar
  • 32 Grüne S, Engelking L R, Anwer S. Role of intracellular calcium and protein kinases in the activation of hepatic Na+/taurocholate cotransport by cyclic AMP.  J Biol Chem . 1993;  268 17734-17741
    PubMedGoogle Scholar
  • 33 Mukhopadadhyay S, Ananthanarayanan M, Stieger B. Sodium taurocholate cotransporting polypeptide is a serine, threonine phosphoprotein and is dephosphorylated by cyclic adenosine monophosphate.  Hepatology . 1998;  28 1629-1636
    CrossrefPubMedGoogle Scholar
  • 34 Mukhopadadhyay S, Ananthanarayanan M, Stieger B. cAMP increases liver Na+-taurocholate cotransport by translocating transporter to plasma membrane.  Am J Physiol . 1997;  273 G842-G848
    PubMedGoogle Scholar
  • 35 Mukhopadadhyay S, Webster C RL, Anwer M S. Role of protein phosphatases in cyclic AMP-mediated stimulation of hepatic Na+/taurocholate cotransport.  J Biol Chem . 1998;  273 30039-30045
    CrossrefPubMedGoogle Scholar
  • 36 Dranoff J A, McClure M, Burgsthaler A D. Short-term regulation of bile acid uptake by microfilament-dependent translocation of rat ntcp to the plasma membrane.  Hepatology . 1999;  30 223-229
    CrossrefPubMedGoogle Scholar
  • 37 Roelofsen H, Hooifeld G J, Koning H. Glutathione S-conjugate transport in hepatocytes entering the cell cycle is preserved by a switch in expression from the apical MRP2 to the basolateral MRP1 transporting protein.  J Cell Sci . 1999;  112 1395-1404
    PubMedGoogle Scholar
  • 38 Schmitt M, Kubitz R, Wettstein M. Retrieval of the mrp2 gene encoded conjugate export pump from the canalicular membrane contributes to cholestasis induced by t-BOOH and CDNB.  Biol Chem . 2000;  381 487-495
    CrossrefPubMedGoogle Scholar
  • 39 Gottesman M M, Pastan I. Biochemistry of multidrug resistance mediated by the multidrug transporter.  Annu Rev Biochem . 1993;  62 385-427
    CrossrefPubMedGoogle Scholar
  • 40 Vanoye C G, Castro A F, Pourcher T. Phosphorylation of P-glycoprotein by PKA and PKC modulates swelling-activated Cl- currents.  Am J Physiol . 1999;  276 C370-C378
    PubMedGoogle Scholar
  • 41 Bradbury N A, Bridges R J. Role of membrane trafficking in plasma membrane solute transport.  Am J Physiol . 1994;  267 C1-C24
    PubMedGoogle Scholar
  • 42 Burckhardt B C, Burckhardt G. Cellular mechanisms of proximal tubular acidification.  In: Häussinger D, ed. pH homeostasis London: Academic Press 1988: 233-262
    Google Scholar
  • 43 Kubitz R, D'Urso D, Keppler D. Osmodependent dynamic localization of the multidrug resistence protein-2 in the rat hepatocyte canalicular membrane.  Gastroenterology . 1997;  113 1438-1442
    CrossrefPubMedGoogle Scholar
  • 44 Häussinger D, Saha N, Hallbrucker C. Involvement of microtubules in the swelling-induced stimulation of transcellular taurocholate transport in perfused rat liver.  Biochem J . 1993;  291 355-360
    PubMedGoogle Scholar
  • 45 Gatmaitan Z C, Nies A T, Arias I M. Regulation and translocation of ATP-dependent apical membrane proteins in rat liver.  Am J Physiol . 1997;  272 G1041-G1049
    PubMedGoogle Scholar
  • 46 Benedetti A, Strazzabosco M, Ng O C. Regulation of activity and apical targeting of the Cl-/HCO3 - exchanger in rat hepatocytes.  Proc Natl Acad Sci USA . 1994;  91 792-796
    PubMedGoogle Scholar
  • 47 Boyer J L, Soroka C J. Vesicle targeting to the apical domain regulates bile excretory function in isolated rat hepatocyte couplets.  Gastroenterology . 1995;  109 1600-1611
    PubMedGoogle Scholar
  • 48 Kubitz R, Wettstein M, Warskulat U. Regulation of the mrp2 gene-encoded conjugate export pump in the hepatocyte canalicular membrane by lipopolysaccharide, dexamethasone and osmolarity.  Gastroenterology . 1999;  116 401-410
    CrossrefPubMedGoogle Scholar
  • 49 Häussinger D. Regulation and functional significance of liver cell volume.  Prog Liv Dis . 1996;  14 29-53
    PubMedGoogle Scholar
  • 50 Häussinger D. The role of cellular hydration in the regulation of cell function.  Biochem J . 1996;  313 697-710
    PubMedGoogle Scholar
  • 51 Häussinger D, Schliess F. Osmotic induction of signalling cascades: Role in regulation of cell function.  Biochem Biophys Res Commun . 1999;  255 551-55
    CrossrefPubMedGoogle Scholar
  • 52 Häussinger D, Hallbrucker C, Saha N. Cell volume and bile acid excretion.  Biochem J . 1992;  288 681-689
    PubMedGoogle Scholar
  • 53 Bruck R, Haddad P, Graf J. Regulatory volume decrease stimulates bile flow, bile acid excretion and exocytosis in isolated perfused rat liver.  Am J Physiol . 1992;  262 G806-G812
    PubMedGoogle Scholar
  • 54 Schliess F, Schreiber R, Häussinger D. Activation of extracellular signal-regulated kinases Erk-1 and Erk-2 by cell swelling in H4IIE hepatoma cells.  Biochem J . 1995;  309 13-17
    PubMedGoogle Scholar
  • 55 Noe B, Schliess F, Wettstein M. Regulation of taurocholate excretion by a hypoosmolarity-activated signal transduction pathway in rat liver.  Gastroenterology . 1996;  110 858-865
    PubMedGoogle Scholar
  • 56 Davis R J. The mitogen-activated protein kinase signal transduction pathway.  J Biol Chem . 1993;  268 14553-14556
    PubMedGoogle Scholar
  • 57 Schaeffer H J, Weber M J. Mitogen-activated protein kinases: Specific messages from ubiquitous messengers.  Mol Cell Biol . 1999;  19 2435-2444
    PubMedGoogle Scholar
  • 58 Schreiber R, Häussinger D. Characterization of the swelling-induced alkalinization of endocytotic vesicles in fluorescein isothiocyanate-dextran loaded rat hepatocytes.  Biochem J . 1995;  309 19-24
    PubMedGoogle Scholar
  • 59 Schliess F, Kurz A K, vom Dahl S. Activation of mitogen-activated protein kinases Erk-1 and Erk-2 mediates the stimulation of bile acid excretion by tauroursodeoxycholate.  Gastroenterology . 1997;  113 1306-1314
    PubMedGoogle Scholar
  • 60 Schliess F, Heinrich S, Kubitz R. Osmosignalling in the liver. In: Häussinger D, Heinrich P, eds Signalling in the liver. Lancaster: Kluwer Academic Press, 1998: 129-151
    Google Scholar
  • 61 Häussinger D, Schliess F, Dombrowski F. Involvement of p38MAPK in the regulation of proteolysis by liver cell hydration.  Gastroenterology . 1999;  116 921-935
    PubMedGoogle Scholar
  • 62 vom Dahl S, Dombrowski F, Schliess F. Cell hydration controls autophagosome formation in rat liver in a microtubule-dependent way downstream from p38MAPK activation.  Biochem J. submitted for publication; 
    PubMedGoogle Scholar
  • 63 Landry J, Huot J. Modulation of actin dynamics during stress and physiological stimulation by a signalling pathway involving p38 MAP kinase and heat shock protein 27.  Biochem Cell Biol . 1995;  73 703-707
    PubMedGoogle Scholar
  • 64 Häussinger D, Stoll B, vom Dahl S. Microtubule stabilization and induction of tubulin mRNA by cell swelling in isolated rat hepatocytes.  Biochem Cell Biol . 1994;  72 12-19
    PubMedGoogle Scholar
  • 65 Schreiber R, Stoll B, Lang F. Effects of anisotonicity on intracellular pH in isolated rat hepatocytes as assessed by BCECF and FITC-dextran fluorescence.  Biochem J . 1994;  303 113-120
    PubMedGoogle Scholar
  • 66 Tager J M, Aerts J MFG, Oude-Elferink R JA. pH regulation of intracellular membrane flow.  In: Häussinger D, ed. pH homeostasis London: Academic Press 1988: 123-162
    Google Scholar
  • 67 Wehner F. Taurocholate depolarizes rat hepatocytes in primary culture by increasing cell membrane Na+ conductance.  Pflügers Arch . 1993;  424 145-151
    PubMedGoogle Scholar
  • 68 Warskulat U, Kubitz R, Wettstein M. Regulation of bile salt export pump mRNA levels by dexamethasone and osmolarity in cultured rat hepatocytes.  Biol Chem . 1999;  380 1273-1279
    CrossrefPubMedGoogle Scholar
  • 69 Saha N, Stoll B, Lang F. Effect of anisotonic cell volume modulation on glutathione-S-conugate release, t-butylhydroperoxide metabolism and the pentose phosphate shunt in perfused rat liver.  Eur J Biochem . 1992;  209 437-444
    CrossrefPubMedGoogle Scholar
  • 70 Schliess F, Wiese S, Häussinger D. Osmotic regulation of the heat shock response in H4IIE rat hepatoma cells.  FASEB J . 1999;  13 1557-1564
    PubMedGoogle Scholar
  • 71 Wettstein M, Noe B, Häussinger D. Metabolism of cysteinyl leukotrienes in the perfused rat liver: The influence of endotoxin pretreatment and the cellular hydration state.  Hepatology . 1995;  22 235-240
    CrossrefPubMedGoogle Scholar
  • 72 Dombrowski F, Kubitz R, Chittattu A. Electronmicroscopic demonstration of Mrp2 retrieval from the canalicular membrane in response to hyperosmolarity and LPS.  Biochem J . 2000;  348 183-188
    PubMedGoogle Scholar
  • 73 Kubitz R, Warskulat U, Schmitt M. Dexamethasone- and osmolarity-dependent expression of the multidrug resistence protein 2 in cultured rat hepatocytes.  Biochem J . 1999;  340 585-591
    CrossrefPubMedGoogle Scholar
  • 74 Roelofsen H, Schoemaker B, Bakker C. Impaired hepatocanalicular organic anion transport in endotoxinemic rats.  Am J Physiol . 1995;  269 G427-G434
    PubMedGoogle Scholar
  • 75 Trauner M, Arrese M, Soroka C J. The rat canalicular conjugate export pump (Mrp2) is downregulated in intrahepatic and obstructive cholestasis.  Gastroenterology . 1997;  113 255-264
    CrossrefPubMedGoogle Scholar
  • 76 Vos T A, Hooiveld G JEJ, Koning H. Upregulation of the multidrug resistance genes mrp1 and mdr1b and downregulation of the organic anion transporter Mrp2 and the bile salt transporter Spgp in endotoxinemic rat liver.  Hepatology . 1998;  28 1637-1644
    CrossrefPubMedGoogle Scholar
  • 77 Ahmed-Choudhury J, Orsler D J, Coleman R. Hepatobiliary effects of tertiary-butylhydroperoxide (tBOOH) in isolated rat hepatocyte couplets.  Toxicol Appl Pharmacol . 1998;  152 270-275
    CrossrefPubMedGoogle Scholar
  • 78 Silva J M, McGirr L, O'Brien P J. Prevention of nitrofurantoin-induced cytotoxicity in isolated hepatocytes by fructose.  Arch Biochem Biophys . 1991;  289 313-318
    CrossrefPubMedGoogle Scholar
  • 79 Sies H. Glutathione conjugation. Mechanisms and biological significance.  London: Academic Press, 1988: 184-187
    Google Scholar
  • 80 Rost D, Kartenbeck J, Keppler D. Changes in the localization of the rat canalicular conjugate export pump Mrp2 in phalloidin-induced cholestasis.  Hepatology . 1999;  29 814-821
    CrossrefPubMedGoogle Scholar
  • 81 Layden T J, Elias E, Boyer J L. Bile formation in the rat: The role of the paracellular shunt pathway.  J Clin Invest . 1978;  62 1375-1385
    PubMedGoogle Scholar
  • 82 Nemchausky B A, Layden T J, Boyer J L. Effects of chronic choleretic infusions of bile acids on the membrane of the bile canaliculus.  Lab Invest . 1977;  36 259-267
    PubMedGoogle Scholar
  • 83 Gartung C, Ananthanarayanan M, Rahman M A. Downregulation of expression and function of the rat liver Na+/bile acid cotransporter in extrahepatic cholestasis.  Gastroenterology . 1996;  110 199-209
    PubMedGoogle Scholar
  • 84 Vlahevic Z R, Stravitz R T, Heuman D M. Regulation of sterol 27-hydroxylase and its role in the regulation of acidic pathway of bile acid biosynthesis. In: Paumgartner G, Stiehl A, Gerok W, eds. Bile acids in hepatobiliary diseases Lancaster: Kluwer, 1997: 48-62
    Google Scholar
  • 85 Zeger M MP, Hoekstra D. Mechanisms and functional features of polarized membrane traffic in epithelial and hepatic cells.  Biochem J . 1998;  336 257-269
    PubMedGoogle Scholar
  • 86 O'Maille E RL, Richards T G, Short A H. Factors determining the maximal rate of organic anion secretion by the liver and further evidence of the hepatic site of action of the hormone secretin.  J Physiol . 1966;  186 424-438
    PubMedGoogle Scholar
  • 87 Boyer J L, Scheig R L, Klatskin G. The effect of sodium taurocholate on the hepatic metabolism of sulfobromophtalein (BSP). The role of bile flow.  J Clin Invest . 1970;  49 206-215
    PubMedGoogle Scholar
  • 88 Vonk R J, Jekel P, Meijer D KF. Choleresis and hepatic transport mechanisms.  Arch Pharmacol . 1975;  290 375-387
    CrossrefPubMedGoogle Scholar
  • 89 Hayakawa T, Ng O C, Ma A. Taurocholate stimulates transcytotic vesicular pathways labelled by horse radish peroxidase in the isolated perfused rat liver.  Gastroenterology . 1990;  99 216-228
    PubMedGoogle Scholar
  • 90 Beuers U, Nathanson M H, Boyer J L. Tauroursodesoxycholic acid stimulates hepatocellular exocytosis and mobilizes extracellular Ca2 +, mechanisms defective in cholestasis.  J Clin Invest . 1993;  92 2984-2993
    PubMedGoogle Scholar
  • 91 Kurz A K, Block C, vom Dahl S. PI3-kinase dependent Ras activation by tauroursodeoxycholate in rat liver.  Biochem J. in press; 
    PubMedGoogle Scholar
  • 92 Cook S J, McCormick F. Inhibition by cAMP of Ras-dependent activation of Raf.  Science . 1993;  262 1069-1072.
    PubMedGoogle Scholar
  • 93 Häussinger D, Kurz A K, vom Dahl S. Stimulation of bile acid secretion by tauroursodeoxycholate and cell swelling involves mitogen-activated protein kinases. In: Paumgartner G, Stiehl A, Gerok W, eds. Bile acids in hepatobiliary diseases Lancaster: Kluwer, 1997: 143-149
    Google Scholar
  • 94 Beuers U, Nathanson M H, Boyer J L. Effects of tauroursode-oxycholic acid on cytosolic Ca2 + signals in isolated rat hepatocytes.  Gastroenterology . 1993;  104 604-612
    PubMedGoogle Scholar
  • 95 Bouscarel B, Kroll S D, Fromm H. Signal transduction and hepatocellular bile acid transport: Cross talk between bile acids and second messenger systems.  Gastroenterology . 1999;  117 433-452
    PubMedGoogle Scholar
  • 96 Burgoyne R D, Morgan A. Regulated exocytosis.  Biochem J . 1993;  293 305-316
    PubMedGoogle Scholar
  • 97 Chao T S, Byron K L, Lee K M. Activation of MAP-kinases by calcium-dependent and calcium-independent pathways. Stimulation by thapsigargin and epidermal growth factor.  J Biol Chem . 1992;  267 19876-19883
    PubMedGoogle Scholar
  • 98 Beuers U, Throckmorton D C, Anderson M S. Tauroursodeoxycholic acid activates protein kinase C in isolated rat hepatocytes.  Gastroenterology . 1996;  110 1553-1563
    CrossrefPubMedGoogle Scholar
  • 99 Stravitz R T, Rao Y P, Vlahevic Z R. Hepatocellular protein kinase C activation by bile acids: Implications for regulation of cholesterol 7α-hydroxylase.  Am J Physiol . 1996;  271 G293-G303
    PubMedGoogle Scholar
  • 100 Ward N E, O'Brian C A. The bile acid analogue fusidic acid can replace phosphatidylserine in the activation of protein kinase C by 12-O-tetradecanoylphorbol-13-acetate in vitro.  Carcinogenesis . 1988;  9 1451-1454
    PubMedGoogle Scholar
  • 101 Rao Y-P, Stravitz R T, Vlahevic Z R. Activation of protein kinase C α and delta by bile acids: Correlation with bile acid structure and diacylglycerol formation.  J Lipid Res . 1997;  38 2446-2454
    PubMedGoogle Scholar
  • 102 Bouscarel B, Gettys T W, Fromm H. Ursodeoxycholic acid inhibits glucagon-induced cAMP formation in hamster hepatocytes: A role for PKC.  Am J Physiol . 1995;  268 G300-G310
    PubMedGoogle Scholar
  • 103 Schliess F, Kurz A K, Häussinger D. Glucagon-induced expression of the MAP kinase phosphatase MKP-1 in rat hepatocytes.  Gastroenterology . 2000;  118 929-936
    PubMedGoogle Scholar
  • 104 Häussinger D, Lang F. Cell volume and hormone action.  Trends Pharmacol Sci . 1992;  13 371-373
    CrossrefPubMedGoogle Scholar
  • 105 Schliess F, vom Dahl S, Häussinger D. Cell volume signalling and insulin resistance in perfused rat liver.  Gastroenterology. in press; 
    PubMedGoogle Scholar
  • 106 Botham K M, Suckling K E, Boyd G S. The effect of glucagon-induced adenosine 3′,5′-monophosphate concentrations on bile acid synthesis in isolated rat liver cells.  FEBS Lett . 1984;  168 317-320
    CrossrefPubMedGoogle Scholar
  • 107 Edmondson J W, Miller B A, Lumeng L. Effect of glucagon on hepatic taurocholate uptake: Relationship to membrane portential.  Am J Physiol . 1985;  249 G427-G433
    PubMedGoogle Scholar
  • 108 Hoshino M, Ohiwa T, Hayakawa T. Effects of dibutyryl cyclic AMP and papaverine on intrahepatocytic bile acid transport. Role of vesicular transport.  Scand J Gastroenterol . 1993;  28 833-838
    PubMedGoogle Scholar
  • 109 Roelofsen H, Soroka C J, Keppler D. Cyclic AMP stimulates sorting of the canalicular organic anion transporter (Mrp2/cMoat) to the apical domain in hepatocyte couplets.  J Cell Sci . 1998;  111 1137-1145
    PubMedGoogle Scholar
  • 110 Hayakawa T, Bruck R, Mg O C. DBcAMP stimulates vesicle transport and HRP excretion in isolated perfused rat liver.  Am J Physiol . 1990;  259 G727-G735
    PubMedGoogle Scholar
  • 111 Lenzen R, Hruby V J, Tavaloni N. Mechanism of glucagon-induced choleresis in guinea pigs.  Am J Physiol . 1990;  259 G736-G744
    PubMedGoogle Scholar
  • 112 Trauner M, Mennone A, Gigliozzi A. Nitric oxide and guanosine 3′,5′-cyclic monophosphate stimulate bile secretion in isolated rat hepatocyte couplets, but not in isolated bile duct units.  Hepatology . 1998;  28 1621-1628
    CrossrefPubMedGoogle Scholar
  • 113 Hamlin S, Rahman K, Carrella M. Modulation of biliary lipid secretion by forskolin and cyclic AMP analogues.  Biochem J . 1990;  265 879-885
    PubMedGoogle Scholar
  • 114 Bravo E, Ortu G, Cantofora A. The effect of cyclic AMP on the biliary secretion of taurocholic acid in the perfused rat liver.  Biochem Soc Trans . 1995;  23 575S
    PubMedGoogle Scholar
  • 115 vom Dahl S, Hallbrucker C, Lang F. Regulation of liver cell volume by hormones.  Biochem J . 1991;  280 105-109
    PubMedGoogle Scholar
  • 116 Hamada Y, Karjalainen A, Setchell B A. Concomitant stimulation by vasopressin of biliary and perfusate calcium fluxes in the perfused rat liver.  Biochem J . 1992;  281 387-392
    PubMedGoogle Scholar
  • 117 Nathanson M H, Gautam A, Bruck R. Effects of Ca2 + agonists on cytosolic Ca2 + in isolated hepatocytes and on bile secretion in the isolated perfused rat liver.  Hepatology . 1992;  15 107-116
    PubMedGoogle Scholar
  • 118 Krell H, Jaeschke H, Pfaff E. Regulation of canalicular bile formation by α-adrenergic action and external ATP in the perfused rat liver.  Biochem Biophys Res Commun . 1985;  131 139-145
    PubMedGoogle Scholar
  • 119 Beckh K, Kneip S, Arnold R. Direct regulation of bile secretion by prostaglandins in perfused rat liver.  Hepatology . 1994;  19 1208-1213
    CrossrefPubMedGoogle Scholar
  • 120 Beckh K, Arnold A. Regulation of bile secretion by sympathetic nerves in perfused rat liver.  Am J Physiol . 1991;  261 G775-G780
    PubMedGoogle Scholar
  • 121 Tanaka A, Katagiri K, Hoshino M. Endothelin-1 stimulates bile acid secretion and vesicular transport in the isolated perfused rat liver.  Am J Physiol . 1994;  266 G324-G329
    PubMedGoogle Scholar
  • 122 Bruck R, Nathanson M H, Roelofsen H. Effects of protein kinase C and cytosolic Ca2 + on exocytosis in the isolated perfused rat liver.  Hepatology . 1994;  20 1032-1040
    PubMedGoogle Scholar
  • 123 Bouscarel B, Reza S, Dougherty L A. Regulation of taurocholate and ursodeoxycholate uptake in hamster hepatocytes by Ca2 +-mobilizing agents.  Am J Physiol . 1996;  271 G1084-G1095
    PubMedGoogle Scholar
  • 124 Watanabe S, Phillips M J. Ca2 + causes active contraction of bile canaliculi: Direct evidence from microinjection studies.  Proc Natl Acad Sci USA . 1984;  81 6164-6168
    PubMedGoogle Scholar
  • 125 Roma M G, Stone V, Shaw R. Vasopressin-induced disruption of actin cytoskeletal organization and canalicular function in isolated rat hepatocyte couplets: Possible involvement of protein kinase C.  Hepatology . 1998;  28 1031-1041
    CrossrefPubMedGoogle Scholar
  • 126 Corasanti J G, Smith N D, Gordon E R. Protein kinase C agonists inhibit bile secretion independently of effects on the microcirculation in the perfused rat liver.  Hepatology . 1989;  10 8-13
    PubMedGoogle Scholar
  • 127 Nathanson M H, Gautam A, Ng O C. Hormonal regulation of paracellular permeability in isolated rat hepatocyte couplets.  Am J Physiol . 1992;  262 G1079-G1086
    PubMedGoogle Scholar
  • 128 Roelofsen H, Ottenhoff R, Oude-Elferink R PJ. Hepatocanalicular organic anion transport is regulated by protein kinase C.  Biochem J . 1991;  278 637-641
    PubMedGoogle Scholar
  • 129 Büchler M, König J, Brom M. cDNA cloning of the hepatocyte canalicular isoform of the multidrug resistance protein, cMRP, reveals a novel conjugate export pump deficient in hyperbilirubinemic mutant rats.  J Biol Chem . 1996;  271 15091-15098
    CrossrefPubMedGoogle Scholar
  • 130 Zegers M MP, Hoekstra D. Sphingolipid transport to the apical plasma membrane domain in human hepatoma cells is controlled by PKC and PKA activity: A correlation with cell polarity in HepG2 cells.  J Cell Biol . 1997;  138 307-321
    CrossrefPubMedGoogle Scholar