文章基本信息

标题：In vivo bioluminescence imaging reveals copper deficiency in a murine model of nonalcoholic fatty liver disease
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作者：Marie C. Heffern ; Hyo Min Park ; Ho Yu Au-Yeung 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：50
页码：14219-14224
DOI：10.1073/pnas.1613628113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceLike all essential metals in mammals, deficiency or excess of copper can be detrimental to health. We present a bioluminescent reporter based on copper-dependent uncaging of a D-luciferin substrate for selective, sensitive, and tissue-specific longitudinal imaging of labile copper pools in animal model systems. Application of this technology to monitor a diet-induced mouse model of nonalcoholic fatty liver disease, a disorder affecting ca. 100 million Americans, reveals hepatic copper deficiency and altered expression levels of copper homeostatic proteins that accompany glucose intolerance and weight gain. The results demonstrate the viability of this molecular imaging approach and connect copper dysregulation to metabolic liver disease, providing a platform for designing reactivity-based reporters for cell- and tissue-specific in vivo metal imaging. Copper is a required metal nutrient for life, but global or local alterations in its homeostasis are linked to diseases spanning genetic and metabolic disorders to cancer and neurodegeneration. Technologies that enable longitudinal in vivo monitoring of dynamic copper pools can help meet the need to study the complex interplay between copper status, health, and disease in the same living organism over time. Here, we present the synthesis, characterization, and in vivo imaging applications of Copper-Caged Luciferin-1 (CCL-1), a bioluminescent reporter for tissue-specific copper visualization in living animals. CCL-1 uses a selective copper(I)-dependent oxidative cleavage reaction to release D-luciferin for subsequent bioluminescent reaction with firefly luciferase. The probe can detect physiological changes in labile Cu+ levels in live cells and mice under situations of copper deficiency or overload. Application of CCL-1 to mice with liver-specific luciferase expression in a diet-induced model of nonalcoholic fatty liver disease reveals onset of hepatic copper deficiency and altered expression levels of central copper trafficking proteins that accompany symptoms of glucose intolerance and weight gain. The data connect copper dysregulation to metabolic liver disease and provide a starting point for expanding the toolbox of reactivity-based chemical reporters for cell- and tissue-specific in vivo imaging.
关键词：metal homeostasis ; molecular imaging ; luciferin ; metabolic liver disease ; copper