In vivo bioluminescence imaging reveals copper deficiency in a murine model of nonalcoholic fatty liver disease
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...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2016-12, Vol.113 (50), p.14219-14224 |
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| creator | Heffern, Marie C. Park, Hyo Min Au-Yeung, Ho Yu Van de Bittner, Genevieve C. Ackerman, Cheri M. Stahl, Andreas Chang, Christopher J. |
| description | 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. |
| doi_str_mv | 10.1073/pnas.1613628113 |
| format | Article |
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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.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1613628113</identifier><identifier>PMID: 27911810</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animals ; Biological Sciences ; Bioluminescence ; Copper ; Copper - deficiency ; Diet, High-Fat - adverse effects ; Firefly Luciferin ; Homeostasis ; Liver ; Liver diseases ; Luciferin ; Luminescent Agents ; Luminescent Measurements - methods ; Male ; Medical imaging ; Metabolic disorders ; Metallochaperones - metabolism ; Mice ; Mice, Transgenic ; Molecular Imaging - methods ; Non-alcoholic Fatty Liver Disease - diagnostic imaging ; Non-alcoholic Fatty Liver Disease - etiology ; Non-alcoholic Fatty Liver Disease - metabolism ; Physical Sciences ; Vitamin deficiency</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2016-12, Vol.113 (50), p.14219-14224</ispartof><rights>Volumes 1–89 and 106–113, copyright as a collective work only; author(s) retains copyright to individual articles</rights><rights>Copyright National Academy of Sciences Dec 13, 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c509t-d49ccef3870351fede44e2f63bf2940e4b603497da5b5fb1851aa365f0f3aeb53</citedby><cites>FETCH-LOGICAL-c509t-d49ccef3870351fede44e2f63bf2940e4b603497da5b5fb1851aa365f0f3aeb53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/26472819$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/26472819$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27923,27924,53790,53792,58016,58249</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27911810$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Heffern, Marie C.</creatorcontrib><creatorcontrib>Park, Hyo Min</creatorcontrib><creatorcontrib>Au-Yeung, Ho Yu</creatorcontrib><creatorcontrib>Van de Bittner, Genevieve C.</creatorcontrib><creatorcontrib>Ackerman, Cheri M.</creatorcontrib><creatorcontrib>Stahl, Andreas</creatorcontrib><creatorcontrib>Chang, Christopher J.</creatorcontrib><title>In vivo bioluminescence imaging reveals copper deficiency in a murine model of nonalcoholic fatty liver disease</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>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.</description><subject>Animals</subject><subject>Biological Sciences</subject><subject>Bioluminescence</subject><subject>Copper</subject><subject>Copper - deficiency</subject><subject>Diet, High-Fat - adverse effects</subject><subject>Firefly Luciferin</subject><subject>Homeostasis</subject><subject>Liver</subject><subject>Liver diseases</subject><subject>Luciferin</subject><subject>Luminescent Agents</subject><subject>Luminescent Measurements - methods</subject><subject>Male</subject><subject>Medical imaging</subject><subject>Metabolic disorders</subject><subject>Metallochaperones - metabolism</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Molecular Imaging - methods</subject><subject>Non-alcoholic Fatty Liver Disease - diagnostic imaging</subject><subject>Non-alcoholic Fatty Liver Disease - etiology</subject><subject>Non-alcoholic Fatty Liver Disease - metabolism</subject><subject>Physical Sciences</subject><subject>Vitamin deficiency</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkc1r3DAQxUVoSbZpzz21CHp2Ilkfti6FEvoRCPSSnIUsjzZabMmVbMP-95HZNGlPc5jfezOPh9BHSq4oadj1FEy-opIyWbeUsjO0o0TRSnJF3qAdIXVTtbzmF-hdzgdCiBItOUcXdaMobSnZoXgb8OrXiDsfh2X0AbKFYAH70ex92OMEK5ghYxunCRLuwXnrC3HEPmCDxyUVDR5jDwOODocYzGDjYxy8xc7M8xEPft2EPoPJ8B69dcUOPjzPS_Tw4_v9za_q7vfP25tvd5UVRM1Vz5W14FjbECaogx44h9pJ1rlacQK8k4Rx1fRGdMJ1tBXUGCaFI44Z6AS7RF9PvtPSjdCXTHMyg55SyZWOOhqv_98E_6j3cdWCyobKzeDLs0GKfxbIsz7EJZVwWW_XiGql2KjrE2VTzDmBe7lAid4a0ltD-rWhovj872Mv_N9KCvDpBBzyHNPrXvKmOCj2BGz5mas</recordid><startdate>20161213</startdate><enddate>20161213</enddate><creator>Heffern, Marie C.</creator><creator>Park, Hyo Min</creator><creator>Au-Yeung, Ho Yu</creator><creator>Van de Bittner, Genevieve C.</creator><creator>Ackerman, Cheri M.</creator><creator>Stahl, Andreas</creator><creator>Chang, Christopher J.</creator><general>National Academy of Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20161213</creationdate><title>In vivo bioluminescence imaging reveals copper deficiency in a murine model of nonalcoholic fatty liver disease</title><author>Heffern, Marie C. ; Park, Hyo Min ; Au-Yeung, Ho Yu ; Van de Bittner, Genevieve C. ; Ackerman, Cheri M. ; Stahl, Andreas ; Chang, Christopher J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c509t-d49ccef3870351fede44e2f63bf2940e4b603497da5b5fb1851aa365f0f3aeb53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Biological Sciences</topic><topic>Bioluminescence</topic><topic>Copper</topic><topic>Copper - deficiency</topic><topic>Diet, High-Fat - adverse effects</topic><topic>Firefly Luciferin</topic><topic>Homeostasis</topic><topic>Liver</topic><topic>Liver diseases</topic><topic>Luciferin</topic><topic>Luminescent Agents</topic><topic>Luminescent Measurements - methods</topic><topic>Male</topic><topic>Medical imaging</topic><topic>Metabolic disorders</topic><topic>Metallochaperones - metabolism</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Molecular Imaging - methods</topic><topic>Non-alcoholic Fatty Liver Disease - diagnostic imaging</topic><topic>Non-alcoholic Fatty Liver Disease - etiology</topic><topic>Non-alcoholic Fatty Liver Disease - metabolism</topic><topic>Physical Sciences</topic><topic>Vitamin deficiency</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Heffern, Marie C.</creatorcontrib><creatorcontrib>Park, Hyo Min</creatorcontrib><creatorcontrib>Au-Yeung, Ho Yu</creatorcontrib><creatorcontrib>Van de Bittner, Genevieve C.</creatorcontrib><creatorcontrib>Ackerman, Cheri M.</creatorcontrib><creatorcontrib>Stahl, Andreas</creatorcontrib><creatorcontrib>Chang, Christopher J.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Heffern, Marie C.</au><au>Park, Hyo Min</au><au>Au-Yeung, Ho Yu</au><au>Van de Bittner, Genevieve C.</au><au>Ackerman, Cheri M.</au><au>Stahl, Andreas</au><au>Chang, Christopher J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>In vivo bioluminescence imaging reveals copper deficiency in a murine model of nonalcoholic fatty liver disease</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2016-12-13</date><risdate>2016</risdate><volume>113</volume><issue>50</issue><spage>14219</spage><epage>14224</epage><pages>14219-14224</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><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. 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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.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>27911810</pmid><doi>10.1073/pnas.1613628113</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Biological Sciences Bioluminescence Copper Copper - deficiency Diet, High-Fat - adverse effects Firefly Luciferin Homeostasis Liver Liver diseases Luciferin Luminescent Agents Luminescent Measurements - methods Male Medical imaging Metabolic disorders Metallochaperones - metabolism Mice Mice, Transgenic Molecular Imaging - methods Non-alcoholic Fatty Liver Disease - diagnostic imaging Non-alcoholic Fatty Liver Disease - etiology Non-alcoholic Fatty Liver Disease - metabolism Physical Sciences Vitamin deficiency |
| title | In vivo bioluminescence imaging reveals copper deficiency in a murine model of nonalcoholic fatty liver disease |
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