High susceptibility to fatty liver disease in two-pore channel 2-deficient mice
2014; Nature Portfolio; Volume: 5; Issue: 1 Linguagem: Inglês
10.1038/ncomms5699
ISSN2041-1723
AutoresChristian Grimm, Lesca M. Holdt, Cheng‐Chang Chen, Sami Hassan, Christoph Müller, Simone Jörs, Hartmut Cuny, Sandra Kissing, Bernd Schröder, Elisabeth Butz, Bernd H. 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 Säftig, Martin Biel, Christian Wahl‐Schott,
Tópico(s)Pancreatic function and diabetes
ResumoEndolysosomal 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.
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