Loss of lysosomal membrane protein NCU-G1 in mice results in spontaneous liver fibrosis with accumulation of lipofuscin and iron in Kupffer cells

Dis Model Mech. 2014 Mar;7(3):351-62. doi: 10.1242/dmm.014050. Epub 2014 Jan 30.

Abstract

Human kidney predominant protein, NCU-G1, is a highly conserved protein with an unknown biological function. Initially described as a nuclear protein, it was later shown to be a bona fide lysosomal integral membrane protein. To gain insight into the physiological function of NCU-G1, mice with no detectable expression of this gene were created using a gene-trap strategy, and Ncu-g1(gt/gt) mice were successfully characterized. Lysosomal disorders are mainly caused by lack of or malfunctioning of proteins in the endosomal-lysosomal pathway. The clinical symptoms vary, but often include liver dysfunction. Persistent liver damage activates fibrogenesis and, if unremedied, eventually leads to liver fibrosis/cirrhosis and death. We demonstrate that the disruption of Ncu-g1 results in spontaneous liver fibrosis in mice as the predominant phenotype. Evidence for an increased rate of hepatic cell death, oxidative stress and active fibrogenesis were detected in Ncu-g1(gt/gt) liver. In addition to collagen deposition, microscopic examination of liver sections revealed accumulation of autofluorescent lipofuscin and iron in Ncu-g1(gt/gt) Kupffer cells. Because only a few transgenic mouse models have been identified with chronic liver injury and spontaneous liver fibrosis development, we propose that the Ncu-g1(gt/gt) mouse could be a valuable new tool in the development of novel treatments for the attenuation of fibrosis due to chronic liver damage.

Keywords: Fibrosis; Lysosome; NCU-G1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cathepsin D / metabolism
  • Cell Death
  • Collagen / metabolism
  • Female
  • Fluorescence
  • Gene Targeting
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Humans
  • Inflammation / pathology
  • Iron / metabolism*
  • Kupffer Cells / metabolism*
  • Kupffer Cells / pathology
  • Kupffer Cells / ultrastructure
  • Lipofuscin / metabolism*
  • Liver / metabolism
  • Liver / pathology
  • Liver Cirrhosis / metabolism*
  • Liver Cirrhosis / pathology
  • Lysosomes / metabolism*
  • Male
  • Membrane Proteins / metabolism*
  • Mice, Inbred C57BL
  • Oxidative Stress
  • Phenotype
  • Reproducibility of Results
  • Splenomegaly / metabolism
  • Splenomegaly / pathology

Substances

  • Lipofuscin
  • Membrane Proteins
  • NCU-G1 protein, mouse
  • Collagen
  • Iron
  • Cathepsin D