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

Paulina Bartuzi, Tobias Wijshake, Daphne C. Dekker, Alina Fedoseienko, Niels J. Kloosterhuis, Sameh A. Youssef, Haiying Li, Ronit Shiri-Sverdlov, Jan Albert Kuivenhoven, Alain de Bruin, Ezra Burstein, Marten H. Hofker, Bart van de Sluis

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

The transcription factor NF-κB 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-κB activation may protect tissues from stress, a prolonged NF-κB 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-κB 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-κB 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 (US)
Pages (from-to)2257-2265
Number of pages9
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1842
Issue number11
DOIs
StatePublished - Nov 1 2014

Keywords

  • COMMD1
  • Inflammation
  • Macrophages
  • NAFLD
  • NF-κB inhibitor

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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