UC Davis

In the thesis presented here, we investigate the effects of dietary changes on copper metabolism. With increases in incidences of metabolic diseases like non-alcoholic fatty liver disease (NAFLD) and diabetes, there is a need to understand the mechanisms that drive metabolic changes to disease pathogenesis. To this end, in the past 10 years, researchers have investigated the roles of diet on changes to metal micronutrient misregulation. The research presented in this thesis builds upon past findings, and focuses on the relationship between diet, copper regulation, and the progression of metabolic diseases. Chapter one offers insight into the state of research on copper metabolism and the interconnectivity of macronutrients, like fats and sugars, to copper biology. The chapter provides background information key to the comprehension of the thesis. Chapter two investigates the effects of a two-week sugar intervention on human serum. We note changes in metal micronutrient markers related to iron, copper, and zinc that point to a connection between the caloric intake of healthy individuals and metal micronutrient metabolism. Focusing on copper, we did not observe significant changes in the concentration of ceruloplasmin, the main serum copper chaperone, but did note changes in copper dependent ceruloplasmin activity pointing to a change in copper loading of the protein. The activity was positively correlated to changes in total serum copper, while the concentration was not. This observation challenges the current methods of clinical copper quantification that are traditionally measured through the concentration of ceruloplasmin. Chapter three builds on the observations in Chapter two, as a structural investigation of the effects of glucose on ceruloplasmin. We probed the effects of glucose-mediated cleavage on ceruloplasmin’s copper status and cleavage sites. Preliminary data shows notable changes resulting in a fragmentation of the protein and loss of copper that may be related to observed changes in copper metabolism in chapter 2. Chapter four focuses on the mechanisms related to decreases in copper concentrations in the livers of mice with fatty livers. We established a cell model to probe the mechanisms that lead to this copper dyshomeostasis. We propose a mechanism for metal misregulation in liver cells through the release of copper from the mitochondria into the cytosol, which leads to activation of export and sequestration mechanisms that help to explain the observed intracellular state of copper deficiency.