Off-campus UNL users: To download campus access dissertations, please use the following link to log into our proxy server with your NU ID and password. When you are done browsing please remember to return to this page and log out.
Non-UNL users: Please talk to your librarian about requesting this dissertation through interlibrary loan.
Copper in Hepatocyte Functions and Fat Metabolism: Protection from Hepatic Lipid Toxicity by Copper Homeostasis
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a progressive liver disorder with comorbidities like obesity, type-2 diabetes, and cardiovascular disease. Given that MAFLD is a widespread and severe health problem with no effective therapeutic, a better understanding of its etiology and unraveling the underlying mechanisms are urgent to combat MAFLD. Substantial evidence indicates that excess fat intake and MAFLD are associated with the dysregulation of copper, an essential micronutrient serving as a cofactor of over a dozen enzymes, including superoxide dismutase (SOD1), ceruloplasmin (Cp), and cytochrome oxidase (CCO). High-fat diet (HFD)-induced inadequate copper uptake and distribution to impair copper-requiring enzyme activities may be critical to the onset and progression of MAFLD. To test this hypothesis, the presented work aimed to (1) investigate copper-related gene expression and cuproenzyme activities in the liver of mice fed a HFD and the effects of surplus fatty acids on copper homeostasis in cultured hepatocytes, (2) characterize lipid metabolism in a mouse strain (Ctr1DHep) in which the Ctr1 copper importer gene is deleted in hepatocytes, and (3) determine the roles of copper-requiring enzymes in fat metabolism to prevent lipid toxicity. Our data revealed that HFD and fatty acids affect the expression and activities of cuproenzymes. Ctr1DHep mice leading to suppressed cuproenzyme activities were susceptible to HFD-induced lipid metabolism disorder, manifesting liver injury, inflammation, and fibrosis. Copper-deficient cultured hepatocytes were likewise sensitive to the toxicity of palmitate, a saturated fatty acid. Fat-soluble antioxidants partially recovered the palmitate sensitivity of hepatocytes. Inhibition of CCO alone mimicked cellular copper deficiency in enhancing palmitate sensitivity. These data indicate that excess fatty acid alters copper homeostasis and copper-dependent cellular metabolic processes, and copper supply to CCO is critical to prevent lipid toxicity. Further studies on the relationship between copper and lipid metabolism are expected to open new opportunities to better understand the etiology of MAFLD and combat MAFLD and its related diseases.
Subject Area
Biochemistry|Epidemiology|Public health
Recommended Citation
Brake, Joseph, "Copper in Hepatocyte Functions and Fat Metabolism: Protection from Hepatic Lipid Toxicity by Copper Homeostasis" (2023). ETD collection for University of Nebraska-Lincoln. AAI30489299.
https://digitalcommons.unl.edu/dissertations/AAI30489299