title: High susceptibility to fatty liver disease in two-pore channel 2-deficient mice.
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.
authors.affiliation: Department of Pharmacy-Center for Drug Research and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität, 81377 München, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Grimm
authors.affiliation: 1] Institute of Laboratory Medicine-University Hospital Munich, 81377 Munich, Germany [2].
authors.forename: Lesca M
authors.initials: LM
authors.lastname: Holdt
authors.affiliation: 1] Department of Pharmacy-Center for Drug Research and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität, 81377 München, Germany [2].
authors.forename: Cheng-Chang
authors.initials: CC
authors.lastname: Chen
authors.affiliation: 1] Department of Pharmacy-Center for Drug Research and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität, 81377 München, Germany [2].
authors.forename: Sami
authors.initials: S
authors.lastname: Hassan
authors.affiliation: Department of Pharmacy, Ludwig-Maximilians-Universität München, 81377 München, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Müller
authors.affiliation: 2nd Department of Internal Medicine, Klinikum rechts der Isar, Technical University of Munich, 81675 München, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Jörs
authors.affiliation: 1] Department of Pharmacy-Center for Drug Research and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität, 81377 München, Germany [2] [3].
authors.forename: Hartmut
authors.initials: H
authors.lastname: Cuny
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-Universität Kiel, 24118 Kiel, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Kissing
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-Universität Kiel, 24118 Kiel, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Schröder
authors.affiliation: Department of Pharmacy-Center for Drug Research and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität, 81377 München, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Butz
authors.affiliation: Institute of Laboratory Medicine-University Hospital Munich, 81377 Munich, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Northoff
authors.affiliation: Institute for Experimental and Clinical Pharmacology and Toxicology, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Castonguay
authors.affiliation: 1] Max-Planck-Institute for Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany [2].
authors.forename: Christian A
authors.initials: CA
authors.lastname: Luber
authors.affiliation: Max-Planck-Institute for Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Moser
authors.affiliation: Department of Pharmacy-Center for Drug Research and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität, 81377 München, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: Spahn
authors.affiliation: Institute of Anatomy, Christian-Albrechts-Universität Kiel, 24098 Kiel, Germany.
authors.forename: Renate
authors.initials: R
authors.lastname: Lüllmann-Rauch
authors.affiliation: Institute for Cell Biology, Rheinische Friedrich-Wilhelms-Universität Bonn, 53121 Bonn, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Fendel
authors.affiliation: Institute for Experimental and Clinical Pharmacology and Toxicology, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Klugbauer
authors.affiliation: Max-Planck-Institute of Neurobiology, Am Klopferspitz 18, 82152 Martinsried, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Griesbeck
authors.affiliation: Institute for Cell Biology, Rheinische Friedrich-Wilhelms-Universität Bonn, 53121 Bonn, Germany.
authors.forename: Albert
authors.initials: A
authors.lastname: Haas
authors.affiliation: Max-Planck-Institute for Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mann
authors.affiliation: Department of Pharmacy, Ludwig-Maximilians-Universität München, 81377 München, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Bracher
authors.affiliation: Institute of Laboratory Medicine-University Hospital Munich, 81377 Munich, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Teupser
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-Universität Kiel, 24118 Kiel, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.affiliation: Department of Pharmacy-Center for Drug Research and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität, 81377 München, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Biel
authors.affiliation: Department of Pharmacy-Center for Drug Research and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität, 81377 München, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Wahl-Schott
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics* / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D008078:Cholesterol, LDL / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005234:Fatty Liver / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology*; D020022:Genetic Predisposition to Disease; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout
chemical_list: D015220:Calcium Channels; D008078:Cholesterol, LDL; C546785:TPCN2 protein, mouse; D002784:Cholesterol; D066246:ErbB Receptors; D002118:Calcium