دورية أكاديمية
Loss of thymidine phosphorylase activity disrupts adipocyte differentiation and induces insulin-resistant lipoatrophic diabetes
| العنوان: | Loss of thymidine phosphorylase activity disrupts adipocyte differentiation and induces insulin-resistant lipoatrophic diabetes |
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| المؤلفون: | Gautheron, Jérémie, Lima, Lara, Akinci, Baris, Zammouri, Jamila, Auclair, Martine, Ucar, Sema, Kalkan, Ozen, Samim, Altay, Canan, Bax, Bridget, E, Nemazanyy, Ivan, Lenoir, Véronique, Prip-Buus, Carina, Acquaviva-Bourdain, Cécile, Lascols, Olivier, Fève, Bruno, Vigouroux, Corinne, Noel, Esther, Jéru, Isabelle |
| المساهمون: | Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition CHU Pitié Salpêtrière (IHU ICAN), CHU Pitié-Salpêtrière AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Dokuz Eylül Üniversitesi = Dokuz Eylül University Izmir (DEÜ), Ege university, St George's, University of London, Structure Fédérative de Recherche Necker (UAR 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut Cochin Département Endocrinologie, métabolisme, diabète (EMD) (EMD), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Service de Biochimie et Biologie Moléculaire Grand Est HCL, Lyon (Centre de Biologie et de Pathologie), Hospices Civils de Lyon (HCL), CHU Saint-Antoine AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universitaire Strasbourg (CHU Strasbourg), Les Hôpitaux Universitaires de Strasbourg (HUS), ANR-21-CE17-0002,DELFAT,Sauver les greffons hépatiques stéatosiques en modulant l'activité de la nécroptose(2021) |
| المصدر: | ISSN: 1741-7015. |
| بيانات النشر: | HAL CCSD BioMed Central |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | ADRA2A, AGPAT2, AIRE, AKT2, BANF1, BLM, BSCL2, CAV1, CAVIN1, CIDEC, DYRK1B, TP, Thymidine phosphorylase, Lipodystrophy, Insulin resistance, Mutation, Adipose stem cell, CRISPR-Cas9, Mitochondria, Oxidative stress, Diabetes, Genetics, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology |
| الوصف: | International audience ; Background: Thymidine phosphorylase (TP), encoded by the TYMP gene, is a cytosolic enzyme essential for the nucleotide salvage pathway. TP catalyzes the phosphorylation of the deoxyribonucleosides, thymidine and 2′-deoxyuridine, to thymine and uracil. Biallelic TYMP variants are responsible for Mitochondrial NeuroGastroIntestinal Encephalomyopathy (MNGIE), an autosomal recessive disorder characterized in most patients by gastrointestinal and neurological symptoms, ultimately leading to death. Studies on the impact of TYMP variants in cellular systems with relevance to the organs affected in MNGIE are still scarce and the role of TP in adipose tissue remains unexplored. Methods: Deep phenotyping was performed in three patients from two families carrying homozygous TYMP variants and presenting with lipoatrophic diabetes. The impact of the loss of TP expression was evaluated using a CRISPR-Cas9-mediated TP knockout (KO) strategy in human adipose stem cells (ASC), which can be differentiated into adipocytes in vitro. Protein expression profiles and cellular characteristics were investigated in this KO model. Results: All patients had TYMP loss-of-function variants and first presented with generalized loss of adipose tissue and insulin-resistant diabetes. CRISPR-Cas9-mediated TP KO in ASC abolished adipocyte differentiation and decreased insulin response, consistent with the patients' phenotype. This KO also induced major oxidative stress, altered mitochondrial functions, and promoted cellular senescence. This translational study identifies a new role of TP by demonstrating its key regulatory functions in adipose tissue. Conclusions: The implication of TP variants in atypical forms of monogenic diabetes shows that genetic diagnosis of lipodystrophic syndromes should include TYMP analysis. The fact that TP is crucial for adipocyte differentiation and function through the control of mitochondrial homeostasis highlights the importance of mitochondria in adipose tissue biology. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | info:eu-repo/semantics/altIdentifier/pmid/35341481; hal-03873802; https://hal.science/hal-03873802Test; https://hal.science/hal-03873802/documentTest; https://hal.science/hal-03873802/file/Gautheron%20et%20al%20BMC%20Medicine%202022.pdfTest; PUBMED: 35341481; PUBMEDCENTRAL: PMC8958798 |
| DOI: | 10.1186/s12916-022-02296-2 |
| الإتاحة: | https://doi.org/10.1186/s12916-022-02296-2Test https://hal.science/hal-03873802Test https://hal.science/hal-03873802/documentTest https://hal.science/hal-03873802/file/Gautheron%20et%20al%20BMC%20Medicine%202022.pdfTest |
| حقوق: | info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: | edsbas.A375851D |
| قاعدة البيانات: | BASE |
| DOI: | 10.1186/s12916-022-02296-2 |
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