Cholestasis and the Role of Basolateral Efflux Pumps

 

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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.

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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