Zusammenfassung
Die entscheidende Triebkraft für den Gallefluss ist der ATP-abhängige Transport von
Gallebestandteilen (Gallensäuren, reduziertes Glutathion, Bilirubinglucuronide u. a.)
über die kanalikuläre Hepatozytenmembran in die Galle. Die funktionelle Charakterisierung,
die Klonierung und die Lokalisation von Transportproteinen der Hepatozytenmembran
haben entscheidend zum molekularen Verständnis von Gallefluss und intrahepatischer
Cholestase beigetragen. Genetische Defekte in der menschlichen Leber und bei Ratten,
Genausschaltungen bei Mäusen und die direkte Hemmung von Transportproteinen haben
gezeigt, dass die Konjugatexportpumpe MRP2 (Multidrug resistance protein 2; ABCC2)
und die Gallensalzexportpumpe BSEP (Bile salt export pump; ABCB11) den wichtigsten
Beitrag zum Gallensäure-unabhängigen bzw. zum Gallensäure-abhängigen Gallefluss leisten.
In der menschlichen Leber führen bestimmte genetische Varianten zum Verlust der Transportaktivität
der Gallensalzexportpumpe BSEP und zur schweren intrahepatischen Cholestase. Effluxtransporter
in der basolateralen Hepatozytenmembran, insbesondere MRP3 (Multidrug resistance protein
3; ABCC3) und MRP4 (Multidrug resistance protein 4; ABCC4), transportieren Substanzen
vom Hepatozyten in das sinusoidale Blut. Diese Effluxtransporter wurden erst in den
letzten Jahren identifiziert und lokalisiert. Sie kompensieren ein Missverhältnis
zwischen der Aufnahme von Substanzen, z. B. Gallensäuren, über die sinusoidale Membran
in die Hepatozyten und einer unzureichenden kanalikulären Sekretion bei der Cholestase.
Aber auch unter physiologischen Bedingungen wird dieser basolaterale Efflux von Substanzen
beobachtet und ermöglicht nicht nur eine spätere renale Ausscheidung, sondern auch
eine Wiederaufnahme in benachbarte Hepatozyten entlang des Leberazinus.
Abstract
ATP-dependent transport of biliary constituents, such as bile acids, reduced glutathione,
and bilirubin glucuronosides across the hepatocyte canalicular membrane into bile
represents the decisive driving force for the formation of biliary fluid. Functional
characterization, cloning, and localization of hepatocellular transporter proteins
has provided a molecular understanding of the mechanisms underlying bile flow and
intrahepatic cholestasis. Genetic variants in humans and genetic knockout in rodents,
or transporter inhibition have indicated that both the conjugate export pump MRP2
(multidrug resistance protein 2; ABCC2) and the bile salt export pump BSEP (ABCB11)
are major contributors to bile acid-independent and bile acid-dependent bile flow,
respectively. In humans, genetic variants of BSEP, leading to an impaired transport
activity or localization of the protein in the canalicular membrane, are associated
with severe intrahepatic cholestasis. Efflux pumps of the basolateral hepatocyte membrane,
particularly MRP3 (multidrug resistance protein 3; ABCC3) and MRP4 (multidrug resistance
protein 4; ABCC4) pump substances from hepatocytes into sinusoidal blood. These efflux
pumps have been recognized in recent years to play an important compensatory role
in cholestasis and to contribute to the balance between uptake and efflux of substances
during the vectorial transport from sinusoidal blood into bile. This sinusoidal efflux
not only enables subsequent renal elimination, but also re-uptake of substances into
neighboring and more centrally located hepatocytes in the sinusoid.
Schlüsselwörter
ATP-abhängiger Transport - basolaterale Hepatozytenmembran - Cholestase - Gallefluss
- Gallensalz-Exportpumpe (BSEP; ABCB11) - Gallensäuren - intrahepatische Cholestase
Key words
ATP-dependent transport - basolateral hepatocyte membrane - cholestasis - bile flow
- bile salt export pump (BSEP; ABCB11) - bile acids - intrahepatic cholestasis
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Prof. Dr. Dietrich Keppler
German Cancer Research Center (DKFZ)
Im Neuenheimer Feld 280
69120 Heidelberg
Germany
Email: d.keppler@dkfz-heidelberg.de
