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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Transport / genetics
  • Calcium / metabolism
  • Calcium Channels / genetics*
  • Calcium Channels / metabolism
  • Cholesterol / metabolism
  • Cholesterol, LDL / metabolism
  • Endosomes / metabolism
  • ErbB Receptors / metabolism
  • Fatty Liver / etiology
  • Fatty Liver / genetics*
  • Fatty Liver / physiopathology*
  • Genetic Predisposition to Disease
  • Lysosomes / metabolism
  • Male
  • Mice, Knockout

Substances

  • Calcium Channels
  • Cholesterol, LDL
  • TPCN2 protein, mouse
  • Cholesterol
  • ErbB Receptors
  • Calcium