Untersuchung des Effektes von Kupferüberladung auf metabolischem Stress im Lebergewebe in vivo und die Bedeutung hiervon auf die Entwicklung von Steatosis
Zusammenfassung der Projektergebnisse
During my two and half years of research at the Johns Hopkins School of Medicine, I was able to study the effects of a Western diet (High fat, high sugar) on wild type mice as well as Wilson disease (ATP7B) knockout mice to try to understand better how the copper- steatosis axis correlate. Wilson disease (WND) is caused by inactivation of the copper transporter ATP7B and copper accumulation in tissues. WND presentations vary from liver steatosis to inflammation, fibrosis, and liver failure. Diets influence the liver phenotype in WND, but findings are inconsistent. To better understand the impact of excess calories on liver phenotype in WND, the study compared C57BL/6J Atp7b−/− and C57BL/6J mice fed for 12 weeks with Western diet or normal chow. Before starting this experiment, in my mind, I would have expected to worsen the phenotype of the Wilson Disease mice and their liver function by feeding them the Western Diet. To the contrary, I was able to improve not just the phenotype in ATP7B ko mice, but also lowered the respective copper levels, both findings which were very surprising. Serum and liver metabolites, body fat content, liver histology, hepatic proteome, and copper content were analyzed. Wild-type and Atp7b−/− livers showed striking similarities in their responses to Western diet, most notably down-regulation of cholesterol biosynthesis, altered nuclear receptor signaling, and changes in cytoskeleton. Western diet increased body fat content and induced liver steatosis in males and females regardless of genotype; however, the effects were less pronounced in Atp7b−/− mice compared with those in the wild type mice. Although hepatic copper remained elevated in Atp7b−/− mice, liver inflammation was reduced. The diet diminished signaling by Rho GTPases, integrin, IL8, and reversed changes in cell cycle machinery and cytoskeleton. Overall, high calories decreased inflammatory response in favor of steatosis without improving markers of cell viability. Similar changes of cellular pathways during steatosis development in wild-type and Atp7b−/− mice explain histologic overlap between WND and nonalcoholic fatty liver disease despite opposite copper changes in these disorders. This experience allowed me to learn so many new skills, which do not just include all the new experimental techniques that I learnt, but also other skills, such as learning how to create full days of work for myself, and planning experiments, being accountable for my own work and daily work motivation. I also learnt how to train others for basic science methods (compared to medical/clinical training). I was able to present the early stages of my project and my idea at the first GAIN Science Slam in 2019 in San Francisco, which I also happened to have won. Additionally, I presented a poster at the AASLD 2020 meeting (virtually due to COVID). I received a Harald Goebell scholarship in 2020 for my ongoing work.
Projektbezogene Publikationen (Auswahl)
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Systemic deletion of Atp7b modifies the hepatocytes’ response to copper overload in the mouse models of Wilson disease. Scientific Reports, 11(1).
Muchenditsi, Abigael; Talbot, C. Conover; Gottlieb, Aline; Yang, Haojun; Kang, Byunghak; Boronina, Tatiana; Cole, Robert; Wang, Li; Dev, Som; Hamilton, James P. & Lutsenko, Svetlana
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Hepatic Steatosis in the Mouse Model of Wilson Disease Coincides with a Muted Inflammatory Response. The American Journal of Pathology, 192(1), 146-159.
Gottlieb, Aline; Dev, Som; DeVine, Lauren; Gabrielson, Kathleen L.; Cole, Robert N.; Hamilton, James P. & Lutsenko, Svetlana
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Oxysterol misbalance critically contributes to Wilson disease pathogenesis. Science Advances, 8(42).
Dev, Som; Muchenditsi, Abigael; Gottlieb, Aline; Deme, Pragney; Murphy, Sean; Gabrielson, Kathleen L.; Dong, Yixuan; Hughes, Robert; Haughey, Norman J.; Hamilton, James P. & Lutsenko, Svetlana
