High susceptibility to fatty liver disease in two-pore channel 2-deficient mice

Christian Grimm, Lesca M. Holdt, Cheng-Chang Chen, Sami Hassan, Christoph Müller, Simone Jörs, Hartmut Cuny, Sandra Kissing, Bernd Schröder, Elisabeth Butz, Bernd Northoff, Jan Castonguay, Christian A. Luber, Markus Moser, Saskia Spahn, Renate Lüllmann-Rauch, Christina Fendel, Norbert Klugbauer, Oliver Griesbeck, Albert Haas, Matthias Mann, Franz Bracher, Daniel Teupser, Paul Saftig, Martin Biel () and Christian Wahl-Schott ()
Additional contact information
Christian Grimm: Ludwig-Maximilians-Universität
Lesca M. Holdt: Institute of Laboratory Medicine—University Hospital Munich
Cheng-Chang Chen: Ludwig-Maximilians-Universität
Sami Hassan: Ludwig-Maximilians-Universität
Christoph Müller: Ludwig-Maximilians-Universität München
Simone Jörs: Klinikum rechts der Isar, Technical University of Munich
Hartmut Cuny: Ludwig-Maximilians-Universität
Sandra Kissing: Institute of Biochemistry, Christian-Albrechts-Universität Kiel
Bernd Schröder: Institute of Biochemistry, Christian-Albrechts-Universität Kiel
Elisabeth Butz: Ludwig-Maximilians-Universität
Bernd Northoff: Institute of Laboratory Medicine—University Hospital Munich
Jan Castonguay: Institute for Experimental and Clinical Pharmacology and Toxicology, Albert-Ludwigs-Universität Freiburg
Christian A. Luber: Max-Planck-Institute for Biochemistry, Am Klopferspitz 18
Markus Moser: Max-Planck-Institute for Biochemistry, Am Klopferspitz 18
Saskia Spahn: Ludwig-Maximilians-Universität
Renate Lüllmann-Rauch: Institute of Anatomy, Christian-Albrechts-Universität Kiel
Christina Fendel: Institute for Cell Biology, Rheinische Friedrich-Wilhelms-Universität Bonn
Norbert Klugbauer: Institute for Experimental and Clinical Pharmacology and Toxicology, Albert-Ludwigs-Universität Freiburg
Oliver Griesbeck: Max-Planck-Institute of Neurobiology, Am Klopferspitz 18
Albert Haas: Institute for Cell Biology, Rheinische Friedrich-Wilhelms-Universität Bonn
Matthias Mann: Max-Planck-Institute for Biochemistry, Am Klopferspitz 18
Franz Bracher: Ludwig-Maximilians-Universität München
Daniel Teupser: Institute of Laboratory Medicine—University Hospital Munich
Paul Saftig: Institute of Biochemistry, Christian-Albrechts-Universität Kiel
Martin Biel: Ludwig-Maximilians-Universität
Christian Wahl-Schott: Ludwig-Maximilians-Universität

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: Abstract Endolysosomal organelles play a key role in trafficking, breakdown and receptor-mediated recycling of different macromolecules such as low-density lipoprotein (LDL)-cholesterol, epithelial growth factor (EGF) or transferrin. Here we examine the role of two-pore channel (TPC) 2, an endolysosomal cation channel, in these processes. Embryonic mouse fibroblasts and hepatocytes lacking TPC2 display a profound impairment of LDL-cholesterol and EGF/EGF-receptor trafficking. Mechanistically, both defects can be attributed to a dysfunction of the endolysosomal degradation pathway most likely on the level of late endosome to lysosome fusion. Importantly, endolysosomal acidification or lysosomal enzyme function are normal in TPC2-deficient cells. TPC2-deficient mice are highly susceptible to hepatic cholesterol overload and liver damage consistent with non-alcoholic fatty liver hepatitis. These findings indicate reduced metabolic reserve of hepatic cholesterol handling. Our results suggest that TPC2 plays a crucial role in trafficking in the endolysosomal degradation pathway and, thus, is potentially involved in the homoeostatic control of many macromolecules and cell metabolites.

Date: 2014
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DOI: 10.1038/ncomms5699

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