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

Grimm, Christian; Holdt, Lesca M.; Chen, Cheng-Chang; Hassan, Sami; Müller, Christoph; Jörs, Simone; Cuny, Hartmut; Kissing, Sandra; Schröder, Bernd; Butz, Elisabeth; Northoff, Bernd; Castonguay, Jan; Luber, Christian A.; Moser, Markus; Spahn, Saskia; Luellmann-Rauch, Renate; Fendel, Christina; Klugbauer, Norbert; Griesbeck, Oliver; Haas, Albert; Mann, Matthias; Bracher, Franz; Teupser, Daniel; Saftig, Paul; Biel, Martin und Wahl-Schott, Christian (2014): High susceptibility to fatty liver disease in two-pore channel 2-deficient mice. In: Nature Communications, Bd. 5, 4699

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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Chemie und Pharmazie > Department für Pharmazie - Zentrum für Pharmaforschung
• Themengebiete: 500 Naturwissenschaften und Mathematik > 540 Chemie
• ISSN: 2041-1723
• Sprache: Englisch