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

Significance Like 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.