title: A cell-type-specific role for murine Commd1 in liver inflammation.
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.
authors: University of Groningen, University Medical Center Groningen, Department of Pediatrics, Molecular Genetics Section, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors: Paulina
authors: P
authors: Bartuzi
authors: University of Groningen, University Medical Center Groningen, Department of Pediatrics, Molecular Genetics Section, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors: Tobias
authors: T
authors: Wijshake
authors: University of Groningen, University Medical Center Groningen, Department of Pediatrics, Molecular Genetics Section, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors: Daphne C
authors: DC
authors: Dekker
authors: University of Groningen, University Medical Center Groningen, Department of Pediatrics, Molecular Genetics Section, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors: Alina
authors: A
authors: Fedoseienko
authors: University of Groningen, University Medical Center Groningen, Department of Pediatrics, Molecular Genetics Section, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors: Niels J
authors: NJ
authors: Kloosterhuis
authors: Dutch Molecular Pathology Center, Department of Pathology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, De Uithof, 3584 CL Utrecht, The Netherlands.
authors: Sameh A
authors: SA
authors: Youssef
authors: University of Texas Southwestern Medical Center, Departments of Internal Medicine and Molecular Biology, Dallas, TX 75390-9151, USA.
authors: Haiying
authors: H
authors: Li
authors: Department of Molecular Genetics, Maastricht University, 6202 AZ Maastricht, The Netherlands.
authors: Ronit
authors: R
authors: Shiri-Sverdlov
authors: University of Groningen, University Medical Center Groningen, Department of Pediatrics, Molecular Genetics Section, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors: Jan-Albert
authors: JA
authors: Kuivenhoven
authors: Dutch Molecular Pathology Center, Department of Pathology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, De Uithof, 3584 CL Utrecht, The Netherlands.
authors: Alain
authors: A
authors: de Bruin
authors: University of Texas Southwestern Medical Center, Departments of Internal Medicine and Molecular Biology, Dallas, TX 75390-9151, USA.
authors: Ezra
authors: E
authors: Burstein
authors: University of Groningen, University Medical Center Groningen, Department of Pediatrics, Molecular Genetics Section, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors: Marten H
authors: MH
authors: Hofker
authors: 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.
authors: Bart
authors: B
authors: van de Sluis
keywords: COMMD1; Inflammation; Macrophages; NAFLD; NF-κB inhibitor