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Nat Commun. 2014 Aug 21;5:4699. doi: 10.1038/ncomms5699.

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

Author information

1
Department of Pharmacy-Center for Drug Research and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität, 81377 München, Germany.
2
1] Institute of Laboratory Medicine-University Hospital Munich, 81377 Munich, Germany [2].
3
1] Department of Pharmacy-Center for Drug Research and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität, 81377 München, Germany [2].
4
Department of Pharmacy, Ludwig-Maximilians-Universität München, 81377 München, Germany.
5
2nd Department of Internal Medicine, Klinikum rechts der Isar, Technical University of Munich, 81675 München, Germany.
6
1] Department of Pharmacy-Center for Drug Research and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität, 81377 München, Germany [2] [3].
7
Institute of Biochemistry, Christian-Albrechts-Universität Kiel, 24118 Kiel, Germany.
8
Institute of Laboratory Medicine-University Hospital Munich, 81377 Munich, Germany.
9
Institute for Experimental and Clinical Pharmacology and Toxicology, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
10
1] Max-Planck-Institute for Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany [2].
11
Max-Planck-Institute for Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
12
Institute of Anatomy, Christian-Albrechts-Universität Kiel, 24098 Kiel, Germany.
13
Institute for Cell Biology, Rheinische Friedrich-Wilhelms-Universität Bonn, 53121 Bonn, Germany.
14
Max-Planck-Institute of Neurobiology, Am Klopferspitz 18, 82152 Martinsried, Germany.

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.

PMID:
25144390
DOI:
10.1038/ncomms5699
[Indexed for MEDLINE]

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