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Biochim Biophys Acta. 2014 Nov;1842(11):2257-65. doi: 10.1016/j.bbadis.2014.06.035. Epub 2014 Jul 27.

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

Author information

1
University of Groningen, University Medical Center Groningen, Department of Pediatrics, Molecular Genetics Section, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
2
Dutch Molecular Pathology Center, Department of Pathology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, De Uithof, 3584 CL Utrecht, The Netherlands.
3
University of Texas Southwestern Medical Center, Departments of Internal Medicine and Molecular Biology, Dallas, TX 75390-9151, USA.
4
Department of Molecular Genetics, Maastricht University, 6202 AZ Maastricht, The Netherlands.
5
University of Groningen, University Medical Center Groningen, Department of Pediatrics, Molecular Genetics Section, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. Electronic address: A.J.A.van.de.Sluis@umcg.nl.

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.

KEYWORDS:

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

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