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

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 cati...

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Published in:Nature communications 2014-08, Vol.5 (1), p.4699, Article 4699
Main Authors: 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, Lüllmann-Rauch, Renate, Fendel, Christina, Klugbauer, Norbert, Griesbeck, Oliver, Haas, Albert, Mann, Matthias, Bracher, Franz, Teupser, Daniel, Saftig, Paul, Biel, Martin, Wahl-Schott, Christian
Format: Article
Language:English
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Animals
Biochemistry
Biological Transport - genetics
Calcium - metabolism
Calcium Channels - genetics
Calcium Channels - metabolism
Cholesterol
Cholesterol - metabolism
Cholesterol, LDL - metabolism
Endosomes - metabolism
Fatty Liver - etiology
Fatty Liver - genetics
Fatty Liver - physiopathology
Genetic Predisposition to Disease
Humanities and Social Sciences
Liver diseases
Lysosomes - metabolism
Male
Metabolism
Metabolites
Mice, Knockout
multidisciplinary
Neurosciences
Proteins
Receptor, Epidermal Growth Factor - metabolism
Science
Science (multidisciplinary)
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Summary: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. Two-pore channel 2 has been implicated in coupling changes in cellular energy status with endolysosomal function. Grimm et al. show that mice lacking this channel display defects in endolysosomal trafficking of LDL-cholesterol and are susceptible to hepatic cholesterol overload and fatty liver disease.
ISSN:2041-1723
2041-1723
DOI:10.1038/ncomms5699