Zusammenfassung
In den letzten Jahren hat sich unser Verständnis der molekularen Mechanismen der Cholestase zunehmend vertieft. Mutationen einzelner Transportergene können angeborene Cholestasesyndrome verursachen, während bei erworbenen Cholestaseformen cholestatische Noxen (wie z. B. Medikamente, Hormone, inflammatorische Zytokine) zu einer veränderten Transporterexpression und -funktion führen. Diese Veränderungen können einerseits die Cholestase verstärken, andererseits werden so hepatoprotektive Mechanismen aktiviert und eine alternative "retrograde" Gallensäureexkretion in die systemische Zirkulation begünstigt. Dies führt zu einer gesteigerten renalen Elimination toxischer gallepflichtiger Substanzen (z. B. Gallensäuren, Bilirubin) bei Cholestase. Zusätzlich werden Gallensäuren in der Leber vermehrt entgiftet. So machen Hydroxylierung, Sulfatierung und Glucuronidierung Gallensäuren hydrophiler und damit weniger toxisch. Diese molekularen Mechanismen werden durch die Wirkung von Kernrezeptoren vermittelt. Die Aktivität dieser Rezeptoren selbst wird durch Gallensäuren, inflammatorische Zytokine, Medikamente und Hormone reguliert. Zusätzlich zu den transkriptionellen Veränderungen, werden auch ein verminderter Einbau und gesteigerter Ausbau von Transporterprotein aus der Zellmembran beobachtet. Störungen der Zellpolarität, des Zytoskeletts und der Zellkontakte sind ebenso involviert. Das genaue Verständnis dieser molekularen Veränderungen sollte es uns in Zukunft ermöglichen, neue Therapieansätze für cholestatische Lebererkrankungen zu entwickeln. Diese Therapieformen könnten darauf abzielen, eine gestörte Transporterexpression wiederherzustellen und die hepatischen Verteidigungsmechanismen gegen toxische Gallensäuren weiter zu stimulieren.
Summary
Recent progress has enhanced our understanding of the pathogenesis of cholestatic liver diseases. Mutations in genes encoding for hepatobiliary transport systems can cause hereditary cholestatic syndromes and exposure to cholestatic agents (drugs, hormones, inflammatory cytokines) can lead to reduced expression and function of hepatic uptake and excretory systems in acquired forms of cholestasis. In addition to transporter changes which cause or maintain cholestasis, some alterations in transporter gene expression can be viewed as hepatoprotective mechanisms aimed at reducing intrahepatic accumulation of toxic biliary constituents such as bile acids and bilirubin. Alternative excretion of bile acids via the basolateral membrane into the systemic circulation facilitates the renal elimination of bile acids into urine. Moreover, increased bile acid hydroxylation, sulfation and glucuronidation by phase I and II metabolizing enzymes renders bile acids more hydrophilic and less toxic. These molecular changes are mediated by specific nuclear receptors which are regulated by bile acids, proinflammatory cytokines, drugs, and hormones. In addition to transcriptional changes, reduced transporter protein insertion to or increased retrieval from the cell membrane as well as other mechanisms such as altered cell polarity, disruption of cell-to-cell junctions and cytoskeletal changes are involved in the pathogenesis of cholestasis. Understanding the detailed mechanisms regulating expression of transport systems and enzymes is essential for the development of novel therapeutic agents. Such future approaches could specifically target nuclear receptors thus restoring defective transporter expression and supporting hepatic defense mechanisms against toxic bile acids.
References
Jansen PL, Muller M, Sturm E (2001) Genes and cholestasis. Hepatology 34: 1067–1074
Trauner M, Boyer JL (2003) Bile salt transporters: molecular characterization, function, and regulation. Physiol Rev 83: 633–671
Boyer JL (1996) Bile duct epithelium: frontiers in transport physiology. Am J Physiol 270: G1–G5
Meier PJ, Stieger B (2002) Bile salt transporters. Annu Rev Physiol 64: 635–661
Bull LN, van Eijk MJ, Pawlikowska L, DeYoung JA, Juijn JA, Liao M, Klomp LW, Lomri N, Berger R, Scharschmidt BF, Knisely AS, Houwen RH, Freimer NB (1998) A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis. Nat Genet 18: 219–224
Strautnieks SS, Bull LN, Knisely AS, Kocoshis SA, Dahl N, Arnell H, Sokal E, Dahan K, Childs S, Ling V, Tanner MS, Kagalwalla AF, Nemeth A, Pawlowska J, Baker A, Mieli-Vergani G, Freimer NB, Gardiner RM, Thompson RJ (1998) A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Nat Genet 20: 233–238
de Vree JM, Jacquemin E, Sturm E, Cresteil D, Bosma PJ, Aten J, Deleuze JF, Desrochers M, Burdelski M, Bernard O, Oude Elferink RP, Hadchouel M (1998) Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. Proc Natl Acad Sci USA 95: 282–287
Fickert P, Zollner G, Fuchsbichler A, Stumptner C, Weiglein AH, Lammert F, Marschall HU, Tsybrovskyy O, Zatloukal K, Denk H, Trauner M (2002) Ursodeoxycholic acid aggravates bile infarcts in bile duct-ligated and Mdr2 knockout mice via disruption of cholangioles. Gastroenterology 123: 1238–1251
Fickert P, Fuchsbichler A, Wagner M, Zollner G, Kaser A, Tilg H, Krause R, Lammert F, Langner C, Zatloukal K, Marschall HU, Denk H, Trauner M (2004) Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology 127: 261–274
Jacquemin E, de Vree JM, Cresteil D, Sokal EM, Sturm E, Dumont M, Scheffer GL, Paul M, Burdelski M, Bosma PJ, Bernard O, Hadchouel M, Elferink RP (2001) The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood. Gastroenterology 120: 1448–1458
Jacquemin E (2001) Role of multidrug resistance 3 deficiency in pediatric and adult liver disease: one gene for three diseases. Semin Liver Dis 21: 551–562
Balistreri WF (1999) Inborn errors of bile acid biosynthesis and transport. Novel forms of metabolic liver disease. Gastroenterol Clin North Am 28: 145–72, vii
Paulusma CC, Kool M, Bosma PJ, Scheffer GL, ter Borg F, Scheper RJ, Tytgat GN, Borst P, Baas F, Oude Elferink RP (1997) A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin-Johnson syndrome. Hepatology 25: 1539–1542
Sheth S, Shea JC, Bishop MD, Chopra S, Regan MM, Malmberg E, Walker C, Ricci R, Tsui LC, Durie PR, Zielenski J, Freedman SD (2003) Increased prevalence of CFTR mutations and variants and decreased chloride secretion in primary sclerosing cholangitis. Hum Genet 113: 286–292
Stieger B, Fattinger K, Madon J, Kullak-Ublick GA, Meier PJ (2000) Drug- and estrogen-induced cholestasis trough inhibition of the paepatocellular bile salt export pump (Bsep) of rat liver. Gastroenterology 118: 422–430
Zollner G, Fickert P, Zenz R, Fuchsbichler A, Stumptner C, Kenner L, Ferenci P, Stauber RE, Krejs GJ, Denk H, Zatloukal K, Trauner M (2001) Hepatobiliary transporter expression in percutaneous liver biopsies of patients with cholestatic liver diseases. Hepatology 33: 633–646
Zollner G, Fickert P, Silbert D, Fuchsbichler A, Marschall HU, Zatloukal K, Denk H, Trauner M (2003) Adaptive changes in hepatobiliary transporter expression in primary biliary cirrhosis. J Hepatol 38: 717–727
Raedsch R, Lauterburg BH, Hofmann AF (1981) Altered bile acid metabolism in primary biliary cirrhosis. Dig Dis Sci 26: 394–401
Berge Henegouwen GP, Brandt KH, Eyssen H, Parmentier G (1976) Sulphated and unsulphated bile acids in serum, bile, and urine of patients with cholestasis. Gut 17: 861–869
Phillips MJ, Poucell S, Oda M (1986) Mechanisms of cholestasis. Lab Invest 54: 593–608
Trauner M, Meier PJ, Boyer JL (1998) Molecular pathogenesis of cholestasis. N Engl J Med 339: 1217–1227
Chawla A, Repa JJ, Evans RM, Mangelsdorf DJ (2001) Nuclear receptors and lipid physiology: opening the X-files. Science 294: 1866–1870
Eloranta JJ, Kullak-Ublick GA (2005) Coordinate transcriptional regulation of bile acid homeostasis and drug metabolism. Arch Biochem Biophys 433: 397–412
Trauner M, Graziadei IW (1999) Review article: mechanisms of action and therapeutic applications of ursodeoxycholic acid in chronic liver diseases. Aliment Pharmacol Ther 13: 979–996
Paumgartner G, Beuers U (2004) Mechanisms of action and therapeutic efficacy of ursodeoxycholic acid in cholestatic liver disease. Clin Liver Dis 8: 67–81
Paumgartner G, Beuers U (2002) Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. Hepatology 36: 525–531
Beuers U, Bilzer M, Chittattu A, Kullak-Ublick GA, Keppler D, Paumgartner G, Dombrowski F (2001) Tauroursodeoxycholic acid inserts the apical conjugate export pump, Mrp2, into canalicular membranes and stimulates organic anion secretion by protein kinase C-dependent mechanisms in cholestatic rat liver. Hepatology 33: 1206–1216
Dombrowski F, Stieger B, Beuers U (2006) Tauroursodeoxycholic acid inserts the bile salt export pump into canalicular membranes of cholestatic rat liver. Lab Invest 86: 166–174
Podesta A, Lopez P, Terg R, Villamil F, Flores D, Mastai R, Udaondo CB, Companc JP (1991) Treatment of pruritus of primary biliary cirrhosis with rifampin. Dig Dis Sci 36: 216–220
Bloomer JR, Boyer JL (1975) Phenobarbital effects in cholestatic liver diseases. Ann Intern Med 82: 310–317
Huang W, Zhang J, Moore DD (2004) A traditional herbal medicine enhances bilirubin clearance by activating the nuclear receptor CAR. J Clin Invest 113: 137–143
Marschall HU, Wagner M, Zollner G, Fickert P, Diczfalusy U, Gumhold J, Silbert D, Fuchsbichler A, Benthin L, Grundstrom R, Gustafsson U, Sahlin S, Einarsson C, Trauner M (2005) Complementary stimulation of hepatobiliary transport and detoxification systems by rifampicin and ursodeoxycholic acid in humans. Gastroenterology 129: 476–485
Wagner M, Halilbasic E, Marschall HU, Zollner G, Fickert P, Langner C, Zatloukal K, Denk H, Trauner M (2005) CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice. Hepatology 42: 420–430
Fiorucci S, Antonelli E, Rizzo G, Renga B, Mencarelli A, Riccardi L, Orlandi S, Pellicciari R, Morelli A (2004) The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis. Gastroenterology 127: 1497–1512
Fiorucci S, Clerici C, Antonelli E, Orlandi S, Goodwin B, Sadeghpour BM, Sabatino G, Russo G, Castellani D, Willson TM, Pruzanski M, Pellicciari R, Morelli A (2005) Protective effects of 6-ethyl chenodeoxycholic acid, a farnesoid X receptor ligand, in estrogen-induced cholestasis. J Pharmacol Exp Ther 313: 604–612
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Zollner, G., Trauner, M. Molecular mechanisms of cholestasis. Wien Med Wochenschr 156, 380–385 (2006). https://doi.org/10.1007/s10354-006-0312-7
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/s10354-006-0312-7
Schlüsselwörter
- Cholestase
- Ikterus
- Gallensäuren
- Bilirubin
- ATP-binding Cassette Transporter
- Kernrezeptoren
- Ursodeoxycholsäure
- Rifampicin