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Loss of thymidine phosphorylase activity disrupts adipocyte differentiation and induces insulin-resistant lipoatrophic diabetes.

Authors
  • Gautheron, Jérémie1, 2
  • Lima, Lara3, 4
  • Akinci, Baris5
  • Zammouri, Jamila3, 4
  • Auclair, Martine3, 4
  • Ucar, Sema Kalkan6
  • Ozen, Samim7
  • Altay, Canan8
  • Bax, Bridget E9
  • Nemazanyy, Ivan10
  • Lenoir, Véronique11
  • Prip-Buus, Carina11
  • Acquaviva-Bourdain, Cécile12
  • Lascols, Olivier3, 4, 13
  • Fève, Bruno3, 4, 14
  • Vigouroux, Corinne3, 4, 13, 14
  • Noel, Esther15
  • Jéru, Isabelle16, 17, 18
  • 1 Centre de Recherche Saint-Antoine (CRSA), Sorbonne Université-Inserm UMRS_938, 27 rue Chaligny 75571, 12, Paris Cedex, France. [email protected]. , (France)
  • 2 Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), 75012, Paris, France. [email protected]. , (France)
  • 3 Centre de Recherche Saint-Antoine (CRSA), Sorbonne Université-Inserm UMRS_938, 27 rue Chaligny 75571, 12, Paris Cedex, France. , (France)
  • 4 Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), 75012, Paris, France. , (France)
  • 5 Department of Internal Medicine, Division of Endocrinology and Metabolism, Dokuz Eylul University, 35330, Izmir, Turkey. , (Turkey)
  • 6 Department of Pediatrics, Division of Metabolic Diseases, Ege University, 35100, Izmir, Turkey. , (Turkey)
  • 7 Department of Pediatrics, Division of Pediatric Endocrinology, Ege University, 35100, Izmir, Turkey. , (Turkey)
  • 8 Department of Radiology, Dokuz Eylul University, 35100, Izmir, Turkey. , (Turkey)
  • 9 Institute of Molecular and Clinical Sciences, St George's University of London, London, SW17 0RE, UK.
  • 10 Platform for Metabolic Analyses, Structure Fédérative de Recherche Necker, Inserm, US24/CNRS UMS 3633, 75015, Paris, France. , (France)
  • 11 Institut Cochin, Université Paris Descartes-CNRS UMR8104, Paris, France. , (France)
  • 12 Service de Biochimie et Biologie Moléculaire Grand Est, Hospices Civils, UM Pathologies Héréditaires du Métabolisme et du Globule Rouge, CHU de Lyon, 69500, Bron, France. , (France)
  • 13 Laboratoire commun de Biologie et Génétique Moléculaires, Hôpital Saint-Antoine, AP-HP, 75012, Paris, France. , (France)
  • 14 Centre National de Référence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité (PRISIS), Service de Diabétologie et Endocrinologie de la Reproduction, Hôpital Saint-Antoine, AP-HP, 75012, Paris, France. , (France)
  • 15 Département de Médecine Interne, Centre Hospitalier Universitaire, 67000, Strasbourg, France. , (France)
  • 16 Centre de Recherche Saint-Antoine (CRSA), Sorbonne Université-Inserm UMRS_938, 27 rue Chaligny 75571, 12, Paris Cedex, France. [email protected]. , (France)
  • 17 Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), 75012, Paris, France. [email protected]. , (France)
  • 18 Laboratoire commun de Biologie et Génétique Moléculaires, Hôpital Saint-Antoine, AP-HP, 75012, Paris, France. [email protected]. , (France)
Type
Published Article
Journal
BMC Medicine
Publisher
Springer Science and Business Media LLC
Publication Date
Mar 28, 2022
Volume
20
Issue
1
Pages
95–95
Identifiers
DOI: 10.1186/s12916-022-02296-2
PMID: 35341481
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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. 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. 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. 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. © 2022. The Author(s).

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