Real-time noninvasive imaging of fatty acid uptake in vivo.

Detection and quantification of fatty acid fluxes in animal model systems following physiological, pathological, or pharmacological challenges is key to our understanding of complex metabolic networks as these macronutrients also activate transcription factors and modulate signaling cascades including insulin sensitivity. To enable noninvasive, real-time, spatiotemporal quantitative imaging of fatty acid fluxes in animals, we created a bioactivatable molecular imaging probe based on long-chain fatty acids conjugated to a reporter molecule (luciferin). We show that this probe faithfully recapitulates cellular fatty acid uptake and can be used in animal systems as a valuable tool to localize and quantitate in real time lipid fluxes such as intestinal fatty acid absorption and brown adipose tissue activation. This imaging approach should further our understanding of basic metabolic processes and pathological alterations in multiple disease models.

[1]  B. M. Forman,et al.  Specific bile acids inhibit hepatic fatty acid uptake in mice , 2012, Hepatology.

[2]  A. Stahl,et al.  Fatty acid transport proteins, implications in physiology and disease. , 2012, Biochimica et biophysica acta.

[3]  Carolyn R. Bertozzi,et al.  In vivo imaging of hydrogen peroxide production in a murine tumor model with a chemoselective bioluminescent reporter , 2010, Proceedings of the National Academy of Sciences.

[4]  Barbara E Goodman,et al.  Insights into digestion and absorption of major nutrients in humans. , 2010, Advances in physiology education.

[5]  V. Dilsizian,et al.  Imaging Myocardial Metabolic Remodeling , 2010, Journal of Nuclear Medicine.

[6]  G. Lopaschuk,et al.  Metabolic remodeling associated with subchronic doxorubicin cardiomyopathy. , 2010, Toxicology.

[7]  C. Kahn,et al.  Transplantation of adipose tissue and stem cells: role in metabolism and disease , 2010, Nature Reviews Endocrinology.

[8]  M. Trauner,et al.  Fatty liver and lipotoxicity. , 2010, Biochimica et biophysica acta.

[9]  S. Klein,et al.  Obesity and nonalcoholic fatty liver disease: Biochemical, metabolic, and clinical implications , 2010, Hepatology.

[10]  Christopher H Contag,et al.  Guided by the light: visualizing biomolecular processes in living animals with bioluminescence. , 2010, Current opinion in chemical biology.

[11]  Jianghong Rao,et al.  In vivo bioluminescence imaging of furin activity in breast cancer cells using bioluminogenic substrates. , 2009, Bioconjugate chemistry.

[12]  F. Mottaghy,et al.  Method of bioluminescence imaging for molecular imaging of physiological and pathological processes. , 2009, Methods.

[13]  P. Besnard,et al.  Intestinal absorption of long-chain fatty acids: evidence and uncertainties. , 2009, Progress in lipid research.

[14]  C. Contag,et al.  Overcoming multidrug resistance of small-molecule therapeutics through conjugation with releasable octaarginine transporters , 2008, Proceedings of the National Academy of Sciences.

[15]  J. Rao,et al.  A Bioluminogenic Substrate for In Vivo Imaging of β‐Lactamase Activity , 2007 .

[16]  C. Contag,et al.  Real-time analysis of uptake and bioactivatable cleavage of luciferin-transporter conjugates in transgenic reporter mice , 2007, Proceedings of the National Academy of Sciences.

[17]  B. Rice,et al.  Three-dimensional reconstruction of in vivo bioluminescent sources based on multispectral imaging. , 2007, Journal of biomedical optics.

[18]  Rebecca A. Johnson,et al.  Fatty acid transport , 2001, Journal of Molecular Neuroscience.

[19]  J. Rao,et al.  A bioluminogenic substrate for in vivo imaging of beta-lactamase activity. , 2007, Angewandte Chemie.

[20]  A. Thomson,et al.  Aging and the intestine. , 2006, World journal of gastroenterology.

[21]  A. Stahl,et al.  Fatty Acid Transport Protein 1 Is Required for Nonshivering Thermogenesis in Brown Adipose Tissue , 2006, Diabetes.

[22]  K. Feingold,et al.  FATP1 Is an Insulin-Sensitive Fatty Acid Transporter Involved in Diet-Induced Obesity , 2006, Molecular and Cellular Biology.

[23]  C. Contag,et al.  Releasable luciferin-transporter conjugates: tools for the real-time analysis of cellular uptake and release. , 2006, Journal of the American Chemical Society.

[24]  Peter O. Krutzik,et al.  Luminescent imaging of β-galactosidase activity in living subjects using sequential reporter-enzyme luminescence , 2006, Nature Methods.

[25]  W. El-Deiry,et al.  Bioluminescent imaging of TRAIL-induced apoptosis through detection of caspase activation following cleavage of DEVD-aminoluciferin , 2005, Cancer Biology & Therapy.

[26]  R. Weissleder,et al.  In vivo imaging of S-TRAIL-mediated tumor regression and apoptosis. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[27]  P. Herrero,et al.  Imaging of myocardial metabolism , 2005, Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology.

[28]  Xianlin Han,et al.  Transgenic Expression of Fatty Acid Transport Protein 1 in the Heart Causes Lipotoxic Cardiomyopathy , 2005, Circulation research.

[29]  G. Tsujimoto,et al.  Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120 , 2005, Nature Medicine.

[30]  D. Jenkins,et al.  Bioluminescent imaging (BLI) to improve and refine traditional murine models of tumor growth and metastasis , 2004, Clinical & Experimental Metastasis.

[31]  Irving L. Weissman,et al.  Shifting foci of hematopoiesis during reconstitution from single stem cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[32]  Anton P. McCaffrey,et al.  Advancing Molecular Therapies through In Vivo Bioluminescent Imaging , 2003, Molecular imaging.

[33]  S. Gambhir,et al.  Molecular imaging in living subjects: seeing fundamental biological processes in a new light. , 2003, Genes & development.

[34]  H. Lodish,et al.  Insulin causes fatty acid transport protein translocation and enhanced fatty acid uptake in adipocytes. , 2002, Developmental cell.

[35]  H. Hauner.  The mode of action of thiazolidinediones , 2002, Diabetes/metabolism research and reviews.

[36]  E. Emken.  Stable isotope approaches, applications, and issues related to polyunsaturated fatty acid metabolism studies , 2001, Lipids.

[37]  U. Neumann,et al.  Expression cloning , 2001, SIGGRAPH 2001.

[38]  P. Herrero,et al.  A novel mouse model of lipotoxic cardiomyopathy. , 2001, The Journal of clinical investigation.

[39]  G. Keating,et al.  Orlistat: in the prevention and treatment of type 2 diabetes mellitus. , 2001, Drugs.

[40]  J. Holden,et al.  Synthesis and preliminary evaluation of 18F-labeled 4-thia palmitate as a PET tracer of myocardial fatty acid oxidation , 2000 .

[41]  J. Holden,et al.  Synthesis and preliminary evaluation of (18)F-labeled 4-thia palmitate as a PET tracer of myocardial fatty acid oxidation. , 2000, Nuclear medicine and biology.

[42]  H. Lodish,et al.  Identification of the major intestinal fatty acid transport protein. , 1999, Molecular cell.

[43]  W. Stein.  OVERCOMING MULTIDRUG RESISTANCE , 1999 .

[44]  O. Sabri,et al.  Imaging of beta-oxidation by static PET with 14(R,S)-[18F]-fluoro-6-thiaheptadecanoic acid (FTHA) in patients with advanced coronary heart disease: a comparison with 18FDG-PET and 99Tcm-MIBI SPET. , 1996, Nuclear medicine communications.

[45]  J. H. Johnson,et al.  Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: impairment in adipocyte-beta-cell relationships. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[46]  H. Lodish,et al.  Expression cloning and characterization of a novel adipocyte long chain fatty acid transport protein , 1994, Cell.

[47]  H. Lodish,et al.  Cloning of a Rab3 isotype predominantly expressed in adipocytes. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[48]  C. Sweeley,et al.  Fatty acid oxidation by ischemic myocardium. , 1975, Recent advances in studies on cardiac structure and metabolism.

[49]  W D McElroy,et al.  Substrate-binding properties of firefly luciferase. I. Luciferin-binding site. , 1969, Archives of biochemistry and biophysics.