A cell-type-specific role for murine Commd1 in liver inflammation

P. Bartuzi, T. Wijshake, D.C. Dekker, A. Fedoseienko, N.J. Kloosterhuis, S.A. Youssef, H. Li, R. Shiri-Sverdlov, J.A. Kuivenhoven, A. Bruin, E. Burstein, M.H. Hofker, B. van de Sluis

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Abstract

The transcription factor NF-kappaB plays a critical role in the inflammatory response and it has been implicated in various diseases, including non-alcoholic fatty liver disease (NAFLD). Although transient NF-kappaB activation may protect tissues from stress, a prolonged NF-kappaB activation can have a detrimental effect on tissue homeostasis and therefore accurate termination is crucial. Copper Metabolism MURR1 Domain-containing 1 (COMMD1), a protein with functions in multiple pathways, has been shown to suppress NF-kappaB activity. However, its action in controlling liver inflammation has not yet been investigated. To determine the cell-type-specific contribution of Commd1 to liver inflammation, we used hepatocyte and myeloid-specific Commd1-deficient mice. We also used a mouse model of NAFLD to study low-grade chronic liver inflammation: we fed the mice a high fat, high cholesterol (HFC) diet, which results in hepatic lipid accumulation accompanied by liver inflammation. Depletion of hepatocyte Commd1 resulted in elevated levels of the NF-kappaB transactivation subunit p65 (RelA) but, surprisingly, the level of liver inflammation was not aggravated. In contrast, deficiency of myeloid Commd1 exacerbated diet-induced liver inflammation. Unexpectedly we observed that hepatic and myeloid Commd1 deficiency in the mice both augmented hepatic lipid accumulation. The elevated levels of proinflammatory cytokines in myeloid Commd1-deficient mice might be responsible for the increased level of steatosis. This increase was not seen in hepatocyte Commd1-deficient mice, in which increased lipid accumulation appeared to be independent of inflammation. Our mouse models demonstrate a cell-type-specific role for Commd1 in suppressing liver inflammation and in the progression of NAFLD.
Original languageEnglish
Pages (from-to)2257-2265
Number of pages9
JournalBiochimica et Biophysica Acta-Molecular Basis of Disease
Volume1842
Issue number11
DOIs
Publication statusPublished - Nov 2014

Keywords

  • COMMD1
  • Inflammation
  • NAFLD
  • Macrophages
  • NF-kappa B inhibitor
  • NF-KAPPA-B
  • EPITHELIAL SODIUM-CHANNEL
  • INSULIN-RESISTANCE
  • NONALCOHOLIC STEATOHEPATITIS
  • TNF-ALPHA
  • ACTIVATION
  • GENE
  • APOPTOSIS
  • DISEASE
  • UBIQUITINATION

Cite this

Bartuzi, P., Wijshake, T., Dekker, D. C., Fedoseienko, A., Kloosterhuis, N. J., Youssef, S. A., Li, H., Shiri-Sverdlov, R., Kuivenhoven, J. A., Bruin, A., Burstein, E., Hofker, M. H., & van de Sluis, B. (2014). A cell-type-specific role for murine Commd1 in liver inflammation. Biochimica et Biophysica Acta-Molecular Basis of Disease, 1842(11), 2257-2265. https://doi.org/10.1016/j.bbadis.2014.06.035