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2014 - High susceptibility to fatty liver disease in two-pore channel 2-deficient mice

icon pap  Port-a-Patch publication in Nature Communications (2014)

Authors: 
Grimm C., Holdt L.M., Chen C.C., Hassan S., Müller C., Jörs S., Cuny H., Kissing S., Schröder B., Butz B., Northoff B., Castonguay J., Luber C.A., Moser M., Spahn S., Lüllmann-Rauch R., Fendel C., Klugbauer N., Griesbeck O., Haas A., Mann M., Bracher F., Teupser D., Saftig P., Biel M., Wahl-Schott C.

 

Journal: 
Nat Commun (2014) 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.


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