Systems Genetics of Hepatic Metabolome Reveals Octopamine as a Target for Non-Alcoholic Fatty Liver Disease Treatment
| Autor: | Ivo Gut, Nicolas Venteclef, Georg W. Otto, Fawaz Alzaid, Tsz M. Tsang, Christopher P. Day, Mark Lathrop, Marc-Emmanuel Dumas, Jeremy K. Nicholson, Aurélie Le Lay, Jean-Baptiste Cazier, Lyamine Hedjazi, Jane F. Fearnside, Francois Brial, Dominique Gauguier, Alastair D. Burt, Steven P. Wilder |
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| Přispěvatelé: | Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Imperial College London, University of Sheffield [Sheffield], The Weatherall Institute of Molecular Medicine, University of Oxford [Oxford], Institute of Child Health [London], University College of London [London] (UCL), University of Birmingham [Birmingham], Murdoch University, University of Adelaide, Barcelona Institute of Science and Technology (BIST), McGill University and Genome Quebec Innovation Centre, École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU) |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Proton Magnetic Resonance Spectroscopy Quantitative Trait Loci lcsh:Medicine Single-nucleotide polymorphism Type 2 diabetes Biology Quantitative trait locus Diet High-Fat Polymorphism Single Nucleotide Article 03 medical and health sciences 0302 clinical medicine Metabolomics Nutrigenomics Non-alcoholic Fatty Liver Disease Genetic linkage Internal medicine medicine Metabolome Animals lcsh:Science Octopamine Mice Inbred BALB C [SDV.GEN]Life Sciences [q-bio]/Genetics Multidisciplinary Systems Biology Fatty liver lcsh:R food and beverages [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology medicine.disease Chromosomes Mammalian 3. Good health Treatment Outcome 030104 developmental biology Endocrinology Chromosome 4 Genetic linkage study lcsh:Q 030217 neurology & neurosurgery |
| Zdroj: | Scientific Reports Scientific Reports, Nature Publishing Group, 2019, 9, pp.3656. ⟨10.1038/s41598-019-40153-0⟩ Scientific Reports, Vol 9, Iss 1, Pp 1-10 (2019) |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-019-40153-0⟩ |
| Popis: | Non-alcoholic fatty liver disease (NAFLD) is often associated with obesity and type 2 diabetes. To disentangle etiological relationships between these conditions and identify genetically-determined metabolites involved in NAFLD processes, we mapped 1H nuclear magnetic resonance (NMR) metabolomic and disease-related phenotypes in a mouse F2 cross derived from strains showing resistance (BALB/c) and increased susceptibility (129S6) to these diseases. Quantitative trait locus (QTL) analysis based on single nucleotide polymorphism (SNP) genotypes identified diet responsive QTLs in F2 mice fed control or high fat diet (HFD). In HFD fed F2 mice we mapped on chromosome 18 a QTL regulating liver micro- and macrovesicular steatosis and inflammation, independently from glucose intolerance and adiposity, which was linked to chromosome 4. Linkage analysis of liver metabolomic profiling data identified a QTL for octopamine, which co-localised with the QTL for liver histopathology in the cross. Functional relationship between these two QTLs was validated in vivo in mice chronically treated with octopamine, which exhibited reduction in liver histopathology and metabolic benefits, underlining its role as a mechanistic biomarker of fatty liver with potential therapeutic applications. |
| Databáze: | OpenAIRE |
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