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

Grimm, C., Holdt, L. M., Chen, C.-C., Hassan, S., Müller, C., Jörs, S., et al. (2014). High susceptibility to fatty liver disease in two-pore channel 2-deficient mice. Nature Communications, 5: 4699. doi:10.1038/ncomms5699.

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 Creators:
Grimm, Christian, Author
Holdt, Lesca M., Author
Chen, Cheng-Chang, Author
Hassan, Sami, Author
Müller, Christoph, Author
Jörs, Simone, Author
Cuny, Hartmut, Author
Kissing, Sandra, Author
Schröder, Bernd, Author
Butz, Elisabeth, Author
Northoff, Bernd, Author
Castonguay, Jan, Author
Luber, Christian A., Author
Moser, Markus, Author
Spahn, Saskia, Author
Lüllmann-Rauch, Renate, Author
Fendel, Christina, Author
Klugbauer, Norbert, Author
Griesbeck, Oliver1, Author           
Haas, Albert, Author
Mann, Matthias, AuthorBracher, Franz, AuthorTeupser, Daniel, AuthorSaftig, Paul, AuthorBiel, Martin, AuthorWahl-Schott, Christian, Author more..
Affiliations:
1Research Group: Cellular Dynamics / Griesbeck, MPI of Neurobiology, Max Planck Society, ou_1113560              

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Free keywords: ENDOSOME-LYSOSOME FUSION; NONALCOHOLIC STEATOHEPATITIS; CHOLESTEROL ACCUMULATION; MOLECULAR-MECHANISMS; HEPATIC STEATOSIS; GROWTH-FACTOR; SYNTAXIN 7; TRAFFICKING; RECEPTOR; CALCIUM
 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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Language(s): eng - English
 Dates: 2014-08-21
 Publication Status: Published in print
 Pages: 13
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: ISI: 000341078700003
DOI: 10.1038/ncomms5699
 Degree: -

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Title: Nature Communications
  Abbreviation : Nat. Commun.
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 5 Sequence Number: 4699 Start / End Page: - Identifier: ISSN: 2041-1723
CoNE: https://pure.mpg.de/cone/journals/resource/2041-1723