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Scholarly Works (3 results)

  • Thesis
  • Peer Reviewed
UC Davis Electronic Theses and Dissertations (2023)

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.

    Cover page: Effects of Diet on Copper Metabolism
    • Article
    • Peer Reviewed
    UC Davis Previously Published Works (2020)
    Alterations of transition metal levels have been associated with obesity, hepatic steatosis, and metabolic syndrome in humans. Studies in animals indicate an association between dietary sugars and copper metabolism. Our group has conducted a study in which young adults consumed beverages sweetened with glucose, fructose, high fructose corn syrup (HFCS), or aspartame for two weeks and has reported that consumption of both fructose- and HFCS-sweetened beverages increased cardiovascular disease risk factors. Baseline and intervention serum samples from 107 participants of this study were measured for copper metabolism (copper, ceruloplasmin ferroxidase activity, ceruloplasmin protein), zinc levels, and iron metabolism (iron, ferritin, and transferrin) parameters. Fructose and/or glucose consumption were associated with decreased ceruloplasmin ferroxidase activity and serum copper and zinc concentrations. Ceruloplasmin protein levels did not change in response to intervention. The changes in copper concentrations were correlated with zinc, but not with iron. The decreases in copper, ceruloplasmin ferroxidase activity, ferritin, and transferrin were inversely associated with the increases in metabolic risk factors associated with sugar consumption, specifically, apolipoprotein CIII, triglycerides, or post-meal glucose, insulin, and lactate responses. These findings are the first evidence that consumption of sugar-sweetened beverages can alter clinical parameters of transition metal metabolism in healthy subjects.
      Cover page: Effects of Dietary Glucose and Fructose on Copper, Iron, and Zinc Metabolism Parameters in Humans
      • Article
      • Peer Reviewed
      UC Davis Previously Published Works (2023)

      Background

      The clinical manifestations of Wilson disease (WD) are related to copper accumulation in the liver and the brain, but little is known about other tissue involvement regarding metabolic changes in WD. In vitro studies suggested that the loss of intestinal ATP7B affects metabolic dysregulation in WD. We tested this hypothesis by evaluating the gut microbiota and lipidome in 2 mouse models of WD and by characterizing a new mouse model with a targeted deletion of Atp7b in the intestine.

      Methods

      Cecal content 16S sequencing and untargeted hepatic and plasma lipidome analyses in the Jackson Laboratory toxic-milk and the Atp7b null global knockout mouse models of WD were profiled and integrated. Intestine-specific Atp7b knockout mice (Atp7bΔIEC) were generated and characterized using targeted lipidome analysis following a high-fat diet challenge.

      Results

      Gut microbiota diversity was reduced in animal models of WD. Comparative prediction analysis revealed amino acid, carbohydrate, and lipid metabolism functions to be dysregulated in the WD gut microbial metagenome. Liver and plasma lipidomic profiles showed dysregulated triglyceride and diglyceride, phospholipid, and sphingolipid metabolism in WD models. However, Atp7bΔIEC mice did not show gut microbiome differences compared to wild type. When challenged with a high-fat diet, Atp7bΔIEC mice exhibited profound alterations to fatty acid desaturation and sphingolipid metabolism pathways as well as altered APOB48 distribution in intestinal epithelial cells.

      Conclusions

      Gut microbiome and lipidome underlie systemic metabolic manifestations in murine WD. Intestine-specific ATP7B deficiency affected both intestinal and systemic response to a high-fat challenge but not the microbiome profile, at least at early stages. WD is a systemic disease in which intestinal-specific ATP7B loss and diet influence the phenotype and the lipidome profile.
        Cover page: The role of intestine in metabolic dysregulation in murine Wilson disease
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