title: In vivo bioluminescence imaging reveals copper deficiency in a murine model of nonalcoholic fatty liver disease.
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.
authors.affiliation: Department of Chemistry, University of California, Berkeley, CA 94720.
authors.forename: Marie C
authors.initials: MC
authors.lastname: Heffern
authors.affiliation: Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720.
authors.forename: Hyo Min
authors.initials: HM
authors.lastname: Park
authors.affiliation: Department of Chemistry, University of California, Berkeley, CA 94720.
authors.forename: Ho Yu
authors.initials: HY
authors.lastname: Au-Yeung
authors.affiliation: Department of Chemistry, University of California, Berkeley, CA 94720.
authors.forename: Genevieve C
authors.initials: GC
authors.lastname: Van de Bittner
authors.affiliation: Department of Chemistry, University of California, Berkeley, CA 94720.
authors.forename: Cheri M
authors.initials: CM
authors.lastname: Ackerman
authors.affiliation: Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720; chrischang@berkeley.edu astahl@berkeley.edu.
authors.forename: Andreas
authors.initials: A
authors.lastname: Stahl
authors.affiliation: Department of Chemistry, University of California, Berkeley, CA 94720; chrischang@berkeley.edu astahl@berkeley.edu.|Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720.|Helen Wills Neuroscience Institute, University of California, Berkeley, CA 94720.|Howard Hughes Medical Institute, University of California, Berkeley, CA 94720.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Chang
mesh_terms: D000818:Animals; D003300:Copper / Q000172:deficiency*; D059305:Diet, High-Fat / Q000009:adverse effects; D049454:Firefly Luciferin; D049408:Luminescent Agents; D008163:Luminescent Measurements / Q000379:methods; D008297:Male; D056511:Metallochaperones / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D057054:Molecular Imaging / Q000379:methods; D065626:Non-alcoholic Fatty Liver Disease / Q000000981:diagnostic imaging / Q000209:etiology / Q000378:metabolism*
chemical_list: D049408:Luminescent Agents; D056511:Metallochaperones; D049454:Firefly Luciferin; D003300:Copper
keywords: copper; luciferin; metabolic liver disease; metal homeostasis; molecular imaging