Publication Date
1-28-2020
Journal
Proceedings of the National Academy of Sciences of the United States of America
DOI
10.1073/pnas.1914267117
PMID
31924743
PMCID
PMC6994990
PubMedCentral® Posted Date
1-10-2020
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Animals, Copper-Transporting ATPases, Disease Models, Animal, Female, Glucose, Hepatolenticular Degeneration, Humans, Insulin Resistance, Liver, Male, Metabolome, Mice, Mice, Inbred C57BL, Mice, Knockout, nuclear receptors, liver, copper
Abstract
Inactivating mutations in the copper transporter Atp7b result in Wilson’s disease. The Atp7b−/− mouse develops hallmarks of Wilson’s disease. The activity of several nuclear receptors decreased in Atp7b−/− mice, and nuclear receptors are critical for maintaining metabolic homeostasis. Therefore, we anticipated that Atp7b−/− mice would exhibit altered progression of diet-induced obesity, fatty liver, and insulin resistance. Following 10 wk on a chow or Western-type diet (40% kcal fat), parameters of glucose and lipid homeostasis were measured. Hepatic metabolites were measured by liquid chromatography–mass spectrometry and correlated with transcriptomic data. Atp7b−/− mice fed a chow diet presented with blunted body-weight gain over time, had lower fat mass, and were more glucose tolerant than wild type (WT) littermate controls. On the Western diet, Atp7b−/− mice exhibited reduced body weight, adiposity, and hepatic steatosis compared with WT controls. Atp7b−/− mice fed either diet were more insulin sensitive than WT controls; however, fasted Atp7b−/− mice exhibited hypoglycemia after administration of insulin due to an impaired glucose counterregulatory response, as evidenced by reduced hepatic glucose production. Coupling gene expression with metabolomic analyses, we observed striking changes in hepatic metabolic profiles in Atp7b−/− mice, including increases in glycolytic intermediates and components of the tricarboxylic acid cycle. In addition, the active phosphorylated form of AMP kinase was significantly increased in Atp7b−/− mice relative to WT controls. Alterations in hepatic metabolic profiles and nuclear receptor signaling were associated with improved glucose tolerance and insulin sensitivity as well as with impaired fasting glucose production in Atp7b−/− mice.
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Endocrine System Diseases Commons, Endocrinology, Diabetes, and Metabolism Commons, Medical Sciences Commons
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