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.

Impaired Hepatic Vitamin A Metabolism in NAFLD Mice Leading to Vitamin A Accumulation in Hepatocytes

“…Briefly, age- and sex-matched (8–10 weeks old) C57BL/6J mice were fed either regular chow or an HFC diet (containing 21% fat, with 45% calories from butterfat and 0.2% cholesterol; SAFE [Scientific Animal Food and Engineering], Villemoisson-sur-Orge, France) for a period of 12 or 20 weeks (n = 8), as reported previously. 52 , 53 Both diets contained 20 IU of retinyl acetate/g as a source of vitamin A. Leptin ob mutant (JAX ob/ob) mice (10–12 weeks old; Charles River Laboratories, Wilmington, MA) and appropriate controls (C57BL/6J) were also studied and received chow diet. Animals were kept in a pathogen-free environment with alternating dark-light cycles of 12 hours, and controlled temperature (20–24°C) and relative humidity (55 ± 15%) receiving food and water ad libitum.…”

CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL

“…Liver homogenates prepared as 15% (w/v) solutions in PBS were subjected to lipid extraction according to the Bligh & Dyer method 50 . In short, 600 μl of demi-water was mixed with 200 μl of liver homogenate, and 3 ml of chloroform/methanol was added and mixed.…”

Nuclear COMMD1 Is Associated with Cisplatin Sensitivity in Ovarian Cancer

“…In complex with an E3 ubiquitin ligase, nuclear COMMD1 promotes the proteasomal degradation of the NF-κB subunit p65, which leads to inhibition of transcriptional activity of NF-κB [12–18]. COMMD1 also represses HIF-1 activity [19,20], and elevated nuclear COMMD1 expression augments its inhibitory effect on both NF-Ф06BB and HIF-mediated transcription [10].…”