Contribution of radixin and ezrin to the maintenance of hepatocytes' excretory function in health and disease
Friederike Dellbrügge,
Lena D. Jesse,
Anna Medyukhina,
Na Liu,
Sophie Neugebauer,
Markus Freißmuth,
Stephanie Höppener,
Marc T. Figge,
Helen Morrison,
Lars B. Riecken,
Adrian T. Press
Affiliations
Friederike Dellbrügge
Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Am Klinikum 1, 07740, Jena, Germany; Center for Sepsis Control and Care, Jena University Hospital, Am Klinikum 1, 07740, Jena, Germany
Lena D. Jesse
Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Am Klinikum 1, 07740, Jena, Germany; Center for Sepsis Control and Care, Jena University Hospital, Am Klinikum 1, 07740, Jena, Germany
Anna Medyukhina
Research Group Applied Systems Biology, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute, Beutenbergstraße 11a, 07745, Jena, Germany
Na Liu
Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Am Klinikum 1, 07740, Jena, Germany
Sophie Neugebauer
Department of Clinical Chemistry and Laboratory Diagnostics, Jena University Hospital, Am Klinikum 1, 07740, Jena, Germany
Markus Freißmuth
Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Am Klinikum 1, 07740, Jena, Germany
Stephanie Höppener
Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich-Schiller University, Fürstengraben 1, 07737, Jena, Germany
Marc T. Figge
Research Group Applied Systems Biology, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute, Beutenbergstraße 11a, 07745, Jena, Germany; Faculty of Biological Sciences, Friedrich-Schiller University, Fürstengraben 1, 07737, Jena, Germany
Helen Morrison
Faculty of Biological Sciences, Friedrich-Schiller University, Fürstengraben 1, 07737, Jena, Germany; Leibniz Institute on Aging, Beutenbergstraße 11, 07745, Jena, Germany
Lars B. Riecken
Leibniz Institute on Aging, Beutenbergstraße 11, 07745, Jena, Germany
Adrian T. Press
Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Am Klinikum 1, 07740, Jena, Germany; Center for Sepsis Control and Care, Jena University Hospital, Am Klinikum 1, 07740, Jena, Germany; Medical Faculty, Friedrich-Schiller University, Fürstengraben 1, 07737, Jena, Germany; Corresponding author. Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Am Klinikum 1, 07740, Jena, Germany.
Background & aims: Excretory liver failure is frequently associated with poor prognosis in critically ill patients. It is characterized by the loss of canalicular membrane export pumps at the hepatocyte membrane. The membrane export pump Multidrug resistant-associated protein (MRP) 2 is pivotal in hepatocytes for brushed membrane morphology and transport of various metabolites. In addition, MRP2 anchoring proteins of the Ezrin/Radixin/Moesin (ERM) family are crucial for the correct MRP2 location, integration, and function in different tissues. In hepatocytes, altered ERM signaling is elementary for developing excretory liver failure. Methods: Polarized human HepaRG cells, primary human hepatocytes, and hepatocyte-specific Ezrin knockout mice are employed to investigate ERM expression and function in health and the bile duct ligation model of obstructive cholestasis. Results: ERM-scaffolding protein Ezrin has no relevant function in maintaining the canalicular structure in hepatocytes during health and disease. Conclusions: Homeostasis of the canalicular pole in hepatocytes is maintained exclusively by Radixin but not Ezrin, and Radixin dysfunction promotes cholestasis.
