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 language | English |
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Pages (from-to) | 2257-2265 |
Number of pages | 9 |
Journal | Biochimica et Biophysica Acta-Molecular Basis of Disease |
Volume | 1842 |
Issue number | 11 |
DOIs | |
Publication status | Published - 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