New insights into the biological role of COMMD1: from inflammation to steatosis and hypercholesterolemia

The Copper Metabolism MURR1 Domain Protein 1 (COMMD1) is the prototype of the COMMD family of proteins. It has been shown to regulate various cellular processes, like copper homeostasis, inflammatory response, and hypoxia adaptation, and to mediate the cellular localization of numerous proteins. However, the biological role of COMMD1 and the exact molecular mechanisms by which it regulates these processes are still ill-defined. Therefore, this thesis aimed to give more insight into the biological role of COMMD1 in the pathogenesis of inflammatory diseases, including colitis and non-alcoholic fatty liver disease (NAFLD). The results described in this thesis underline the multifunctional nature of COMMD1, and provide novel insights into its biological function. We demonstrate a cell-type-specific role for COMMD1 in suppressing inflammation, and identify COMMD1 as a novel gene in regulating cholesterol homeostasis and a potential hypercholesterolemia risk gene. Our data indicate that COMMD1 delivers the low-density lipoprotein receptor (LDLR) to the right docking station in the cell. We believe that unraveling the mechanistic action of COMMD1 in the LDLR pathway will help us better understand the mechanism by which COMMD1 regulates biliary copper excretion. Furthermore, our results suggest that hepatic Commd1 plays a role in the progression of high-fat, high-cholesterol (HFC) diet-induced microvesicular steatosis to macrovesicular steatosis. We demonstrated here that microvesicular steatosis is associated with a lower inflammatory tone in the liver and with reduced activation of the LXR pathway, which prevents cells from cholesterol overload. However, further research is necessary to elucidate the mechanism behind this observation. In conclusion, this thesis shows that COMMD1 is a relatively novel adaptor protein in sorting various molecules involved in a number of different biological processes, such as cholesterol and copper homeostasis, and that COMMD1’s role in biological processes is cell-type-specific