Signal transduction and hepatocellular bile acid transport: Cross talk between bile acids and second messengers
1999; Elsevier BV; Volume: 117; Issue: 2 Linguagem: Inglês
10.1053/gast.1999.0029900433
ISSN1528-0012
AutoresBernard Bouscarel, S Kroll, Hans Fromm,
Tópico(s)Neonatal Health and Biochemistry
Resumoatypical conventional cholic acid (3α,7α,12α,-trihydroxy-5β cholan-24-oic acid) canalicular bile acid transporter chenodeoxycholic acid (3α,7α-dihydroxy-5β cholan-24-oic acid) 1,2-diacylglycerol deoxycholic acid (3α,12α,-dihydroxy-5β cholan-24-oic acid) half-maximal effective concentration ethylene glycol tetraacetate guanosine 5'-triphosphate horseradish peroxidase inositol 1,4,5-trisphosphate lithocholic acid novel Na+/taurocholate–cotransporting polypeptide organic anion transport protein cAMP-dependent protein kinase protein kinase C 12-O-tetradecanoylphorbol 13-acetate taurocholic acid taurolithocholic acid tauroursodeoxycholic acid ursodeoxycholic acid (3α,7β-dihydroxy-5β cholan-24-oic acid) The hepatocyte inhabits a significant position between blood and bile,1Reichen J. Paumgartner G. Excretory functions of the liver.Int Rev Physiol. 1980; 21: 103-118PubMed Google Scholar with distinct sinusoidal (basolateral) and canalicular (apical) membranes. Tight junctions (zonula occludens) between hepatocytes maintain the polarity and prevent the mixing of canalicular and sinusoidal contents.2Powell D. Barrier function of epithelia.Am J Physiol. 1981; 241: G275-G288PubMed Google Scholar, 3Stevenson B. Anderson J. Bullivant J. The epithelial tight junction: structure, function and preliminary biochemical characterization.Mol Cell Biochem. 1988; 83: 129-145Crossref PubMed Google Scholar In addition to being the site of bile acid synthesis, the hepatocyte plays a key role in bile secretion, with the clearance of bile acids from the portal circulation and their transport to the canalicular lumen. The secretion of bile is maintained by two different mechanisms. One is bile acid dependent, with a linear correlation between the secretion of bile and that of bile acids. The other mechanism of bile secretion is bile acid independent and mainly results from the flux of inorganic ions (see Graf4Graf J. Canalicular bile salt-independent bile formation: concepts and clues from electrolyte transport in rat liver.Am J Physiol. 1983; 244: G233-G246PubMed Google Scholar for review). The proportion of the respective bile acid–dependent and–independent components of bile secretion varies with animal species. However, in humans, bile secretion is mainly bile acid driven. Loss or alteration of bile secretion is associated with various cholestatic hepatobiliary disorders, such as primary sclerosing cholangitis, primary biliary cirrhosis, drug-induced cholestasis, autoimmune chronic active hepatitis, and alcoholic liver disease. The morbidity associated with chronic cholestatic conditions is significant and may necessitate liver transplantation.5Tzakis A.G. Carcassonne C. Todo S. Makowka L. Starzl T.E. Liver transplantation for primary biliary cirrhosis.Semin Liver Dis. 1989; 9: 144-147Crossref PubMed Google Scholar, 6Marsh J. Iwatsuki S. Makowka L. Esquivel C.O. Gordon R.D. Todo S. Tzakis A. Miller C. Van Thiel D. Starzl T.E. Or thotopic liver transplantation for primary sclerosing cholangitis.Ann Surg. 1988; 207: 21-25Crossref PubMed Google Scholar Cholic acid (CA) and chenodeoxycholic acid (CDCA) are the two primary bile acids in humans.7Hofmann A.F. Chemistry and enterohepatic circulation of bile acids.Hepatology. 1984; 4: 4S-14SCrossref PubMed Google Scholar After conjugation mainly to glycine (G) and taurine (T), bile acids are secreted into bile. More than 95% of the bile acid pool is reabsorbed from the intestine and transported to the liver bound mainly to albumin and, to a lesser extent, to lipoproteins,8Ceryak S. Bouscarel B. Fromm H. Comparative binding of bile acids to serum lipoproteins and albumin.J Lipid Res. 1993; 34: 1661-1674PubMed Google Scholar, 9Rudman D. Kendall F.E. Bile acid content of human serum. II. The binding of cholanic acids by human plasma proteins.J Clin Invest. 1957; 36: 538-542Crossref PubMed Google Scholar where they evoke an inhibitory feedback control on bile acid synthesis. Varying amounts of deoxycholic acid (DCA) and lithocholic acid (LCA), formed by bacterial dehydroxylation of CA and CDCA, respectively, are passively reabsorbed from the colon. In humans, approximately 100 mmol of bile acids circulate through the liver in a 24-hour period, corresponding to 4-12 cycles/day of ̃3 g each.10Strange R.C. Hepatic bile flow.Physiol Rev. 1984; 64: 1055-1102PubMed Google Scholar Several studies have implicated hormones, including vasopressin and glucagon, in the regulation of bile secretion. These hormones, through their effect on calcium mobilization,11Exton J.H. Signaling through phosphatidylcholine breakdown.J Biol Chem. 1990; 265: 1-4Abstract Full Text PDF PubMed Google Scholar adenosine 3',5'-cyclic monophosphate (cAMP) synthesis,12Gilman A.G. Guanine nucleotide-binding regulatory proteins and dual control of adenylate cyclase.J Clin Invest. 1984; 73: 1-14Crossref PubMed Google Scholar and/or protein kinase C (PKC) activation,13Nishizuka Y. The role of protein kinase C in cell surface signal transduction and tumor promotion.Nature. 1984; 308: 693-698Crossref PubMed Scopus (5634) Google Scholar tightly regulate hepatocellular functions, including the hepatocellular uptake, transport, and secretion of bile acids. Furthermore, recent studies have shown the hepatocellular regulation of these signal-transduction pathways by bile acids. The purpose of this review is to survey the role that these signal-transduction cascades, which involve calcium, cAMP, and PKC, have in the regulation of bile acid secretion with a particular focus on the transport of bile acids in both the isolated hepatocyte and perfused liver model, as well as the regulation of these signal-transduction mechanisms by bile acids. Although numerous studies have focused on the respective effects of both bile acids on second messengers and the activation of signal-transduction cascades on bile secretion, few attempts have been made to organize this information in an integrative manner. A better understanding of the interplay of second messengers and bile acids, as it relates to hepatic bile secretion, may facilitate a more directed approach in the future treatment of cholestatic liver diseases. Alteration of the hepatic transport of bile acids can result in their accumulation in the liver and potential spillover of bile acids from the liver to the systemic circulation. The accumulation in the liver of potentially toxic and detergent bile acids will lead to cellular damage and liver dysfunction. It is therefore critical that hepatocellular transport of bile acids be tightly regulated. Specific mechanisms have been identified for both sodium-dependent and -independent hepatocellular bile acid uptake. The carrier responsible for sodium-dependent bile acid transport has been identified as a 48/49-kilodalton protein,14Frimmer M. Ziegler K. The transport of bile acids in liver cells.Biochim Biophys Acta. 1988; 947: 75-99Crossref PubMed Google Scholar, 15Kramer W. Bickel U. Buscher H.P. Kurz G. Bile salt-binding polypeptides in plasma membranes of hepatocytes revealed by photoaffinity labeling.Eur J Biochem. 1982; 129: 13-24Crossref PubMed Scopus (24) Google Scholar which has been localized to the sinosoidal plasma membrane and first purified by Levy et al.16Von Dippe P. Ananthanarayanan M. Drain P. Levy D. Purification and reconstitution of the bile acid transport system from hepatocyte sinusoidal plasma membranes.Biochim Biophys Acta. 1986; 862: 352-360Crossref PubMed Google Scholar A 362–amino acid Na+/taurocholate–cotransporting polypeptide (NTCP and ntcp in human and rat, respectively) with a calculated molecular mass of 38 kilodaltons has been cloned from human liver and localized to chromosome 14.17Hagenbuch B. Meier P.J. Molecular cloning, chromosomal localization, and functional characterization of a human liver Na+/bile acid cotransporter.J Clin Invest. 1994; 93: 1326-1331Crossref PubMed Google Scholar, 18Hagenbuch B. Jacquemin E. Meier P.J. Na+-dependent and Na+-independent bile acid uptake systems in the liver.Cell Physiol Biochem. 1994; 4: 198-205Crossref Google Scholar Furthermore, a 50-54-kilodalton protein19Wolkoff A.W. Chung C.T. Identification, purification and partial characterization of an organic anion binding protein from rat liver cell plasma membrane.J Clin Invest. 1980; 65: 1152-1161Crossref PubMed Google Scholar, 20Berk P.D. Potter B.J. Stremmel W. Role of plasma membrane ligand-binding proteins in the hepatocellular uptake of albumin-bound organic anions.Hepatology. 1987; 7: 165-176Crossref PubMed Google Scholar was identified at the sinusoidal plasma membrane19Wolkoff A.W. Chung C.T. Identification, purification and partial characterization of an organic anion binding protein from rat liver cell plasma membrane.J Clin Invest. 1980; 65: 1152-1161Crossref PubMed Google Scholar and was shown to be involved in hepatocellular uptake of a broad range of organic ions, such as bilirubin, phalloidin, bromsulfophthalein, and ouabain (see Frimmer and Ziegler14Frimmer M. Ziegler K. The transport of bile acids in liver cells.Biochim Biophys Acta. 1988; 947: 75-99Crossref PubMed Google Scholar for review). This chloride-dependent transporter, known as the organic anion transport protein (OATP and oatp in human and rat, respectively), has been cloned and localized in humans to chromosome 12.21Jacquemin E. Hagenbuch B. Stieger B. Wolkoff A.W. Meier P.J. Expression cloning of a rat liver Na+-independent organic anion transporter.Proc Natl Acad Sci USA. 1994; 91: 133-137Crossref PubMed Scopus (461) Google Scholar, 22Kullak Ublick G.A. Beuers U. Meier P.J. Domdey H. Paumgartner G. Assignment of the human organic anion transporting polypeptide (OATP) gene to chromosome 12p12 by fluorescence in situ hybridization.J Hepatol. 1996; 25: 985-987Abstract Full Text PDF PubMed Scopus (21) Google Scholar This transporter may also serve as a sodium-independent bile acid carrier.14Frimmer M. Ziegler K. The transport of bile acids in liver cells.Biochim Biophys Acta. 1988; 947: 75-99Crossref PubMed Google Scholar, 23Von Dippe P. Levy D. Characterization of the bile acid transport system in normal and transformed hepatocytes: photoaffinity labeling of the taurocholate carrier protein.J Biol Chem. 1983; 258: 8896-8901Abstract Full Text PDF PubMed Google Scholar Finally, bile acids (mainly unconjugated) can, to a limited extent, cross the cell membrane passively.24Albalak A. Zeidel M.L. Zucker S.D. Jackson A.A. Donovan J.M. Effects of submicellar bile salt concentrations on biological membrane permeability to low molecular weight non-ionic solutes.Biochemistry. 1996; 35: 7936-7945Crossref PubMed Scopus (24) Google Scholar The net vectorial transport of bile acids from blood to bile is dependent on cellular sodium concentration, pH, and cell volume. Perhaps the most important regulator of this gradient is Na+/K+-adenosine triphosphatase (ATPase) which, through its electrogenic potential, maintains a sodium gradient and a negative membrane potential of approximately −35 mV.25Van Dyke R.W. Scharschmidt B.F. 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Finally, microtubules can be involved in the insertion of the bile acid transporter from pericanalicular vesicles into the canalicular membrane domain. This microtubule-dependent insertion into the canalicular membrane has previously been reported for several transporters, including multidrug-resistance protein MRP243Kubitz R. D'urso D. Keppler D. Haussinger D. Osmodependent dynamic localization of the multidrug resistance protein 2 in the rat hepatocyte canalicular membrane.Gastroenterology. 1997; 113: 1438-1442Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar and ecto-ATPase.44Boyer J.L. Soroka C.J. Vesicle targeting to the apical domain regulates bile excretory function in isolated rat hepatocyte couplets.Gastroenterology. 1995; 109: 1600-1611Abstract Full Text PDF PubMed Scopus (95) Google Scholar This mechanism would support the observation by Gerloff et al.45Gerloff T. Stieger B. Hagenbuch B. Madon J. Landmann L. Roth J. Hofmann A.F. Meier P.J. 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Hansen O.C. Lazrek M.B. Bock E. Obrink B. The cell adhesion molecule Cell-CAM 105 is an ecto-ATPase and a member of the immunoglobulin superfamily.FEBS Lett. 1990; 264: 267-269Crossref PubMed Scopus (63) Google Scholar whereas the canalicular bile acid transporter (cBAT),57Muller M. Jansen P.L. Molecular aspects of hepatobiliary transport.Am J Physiol. 1997; 272: G1285-G1303PubMed Google Scholar also called bile salt export pump45Gerloff T. Stieger B. Hagenbuch B. Madon J. Landmann L. Roth J. Hofmann A.F. Meier P.J. The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver.J Biol Chem. 1998; 273: 10046-10050Crossref PubMed Scopus (636) Google Scholar or sister p-glycoprotein,58Childs S. Yeh R.L. Georges E. Ling V. Identification of a sister gene to P-glycoprotein.Cancer Res. 1995; 55: 2029-2034PubMed Google Scholar is a member of a large superfamily of ATP-binding cassette (ABC) proteins (see Keppler et al.59Keppler D. Kartenbeck J. The canalicular conjugate export pump encoded by the cmrp/cmoat gene.in: Progress in liver diseases. Saunders, Philadelphia1996: 55-67Google Scholar for review). Therefore, the efflux of bile acids is dependent on the cellular level and hydrolysis of Mg2+/ATP, and at least for ecto-ATPase, the cytoplasmic terminal of the protein must be phosphorylated to present transport activity.48Sippel C.J. Suchy F.J. Ananthanarayanan M. Perlmutter D.H. The rat liver ecto-ATPase is also a canalicular bile acid transport protein.J Biol Chem. 1993; 268: 2083-2091Abstract Full Text PDF PubMed Google Scholar Calcium plays a critical role in the regulation of cellular functions. Rapid changes in the cytosolic free (ionized) calcium level result in decreased DNA and protein synthesis as well as stimulated glycogen breakdown. In most cells, including hepatocytes, different mechanisms intervene to control the intracellular cytosolic calcium concentration. In the hepatocyte, the ionized cytosolic calcium concentration is ̃100 nmol/L, whereas the total serum and biliary calcium concentrations are ̃2.5 and 2-7 mmol/L, respectively.60Gertner J.M. Disorders of calcium and phosphorus homeostasis.Pediatr Clin North Am. 1990; 37: 1441-1465PubMed Google Scholar, 61Sutor D.J. Wilkie L.I. Jackson M.J. Ionized calcium in pathological human bile.J Clin Pathol. 1980; 258: C755-C786Google Scholar In the cell, specific organelles, mainly calciosomes (probably localized in the smooth endoplasmic reticulum) and mitochondria, serve as the major intracellular reservoirs of calcium, with a respective calcium concentration of 2-3 mmol/L.62Missiaen L. Wuytack F. Raeymaekers L. De Smedt H. Droog-mans G. Declerck I. Casteels R. Calcium extrusion across plasma membrane and calcium uptake by intracellular stores.Pharmacol Ther. 1991; 50: 191-232Crossref PubMed Google Scholar, 64Gunter T.E. Pfeiffer D.R. 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Whereas the mitochondria also store calcium, this organelle is not involved in IP3-mediated calcium release because of the absence of an IP3 receptor at the surface of its outer membrane (see Missiaen et al.62Missiaen L. Wuytack F. Raeymaekers L. De Smedt H. Droog-mans G. Declerck I. Casteels R. Calcium extrusion across plasma membrane and calcium uptake by intracellular stores.Pharmacol Ther. 1991; 50: 191-232Crossref PubMed Google Scholar for review; Figure 1).Although not proven, the possible role of the mitochondria may be to store the excess of calcium when cytosolic calcium level increases above a certain threshold, and cell viability is compromised.63Meldolesi J. Madeddu L. Pozzan T. Intracellular calcium storage organelles in non-muscle cells: heterogeneity and functional assignment.Biochim Biophys Acta. 1990; 1055: 130-140Crossref PubMed Google Scholar After the increase in cytosolic concentration, calcium will bind to calmodulin and together will activate calcium/calmodulin-dependent protein kinases, such as phosphorylase kinase, and induce biological responses, including, glycogen breakdown, in the liver.68Exton J.H. Phosphoinositide phospholipases and G proteins in hormone action.Annu Rev Physiol. 1994; 56: 349-369Crossref PubMed Google Scholar Once calcium has been released from the specific calcium stores, the cytosolic calcium concentration rapidly returns to basal levels because of the presence of a Ca2+/Mg2+-ATPase (Ca2+ pump) present at the surface of these calciosomes, which pumps the calcium back into these compartments. This increase in cytosolic calcium levels is transient and disappears in <2-3 minutes (see Williamson et al.69Williamson J.R. 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