In vivo bioluminescence imaging reveals copper deficiency in a murine model of nonalcoholic fatty liver disease

Marie Heffern, Hyo Min Park, Ho Yu Au-Yeung, Genevieve C. Van De Bittner, Cheri M. Ackerman, Andreas Stahl, Christopher J. Chang

Research output: Contribution to journalArticle

59 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)14219-14224
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number50
DOIs
StatePublished - Dec 13 2016
Externally publishedYes

Keywords

  • Copper
  • Luciferin
  • Metabolic liver disease
  • Metal homeostasis
  • Molecular imaging

ASJC Scopus subject areas

  • General

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