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

Gautheron, Jérémie and Lima, Lara and Akinci, Baris and Zammouri, Jamila and Auclair, Martine and Ucar, Sema Kalkan and Ozen, Samim and Altay, Canan and Bax, Bridget E. and Nemazanyy, Ivan and Lenoir, Véronique and Prip-Buus, Carina and Acquaviva-Bourdain, Cécile and Lascols, Olivier and Fève, Bruno and Vigouroux, Corinne and Noel, Esther and Jéru, Isabelle (2022) Loss of thymidine phosphorylase activity disrupts adipocyte differentiation and induces insulin-resistant lipoatrophic diabetes. BMC Medicine, 20 (1). ISSN 1741-7015

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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.

Item Type: Article
Subjects: R Medicine > R Medical & Medicine
Depositing User: APLOS Library
Date Deposited: 20 Jun 2022 06:15
Last Modified: 20 Jun 2022 06:15
URI: http://eprints.asianrepository.com/id/eprint/370

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