EPHX1 mutations cause a lipoatrophic diabetes syndrome due to impaired epoxide hydrolysis and increased cellular senescence
Epoxide hydrolases (EHs) regulate cellular homeostasis through hydrolysis of epoxides to less-reactive diols. The first discovered EH was EPHX1, also known as mEH. EH functions remain partly unknown, and no pathogenic variants have been reported in humans. We identified two de novo variants located...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-08-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/68445 |
| _version_ | 1811201487042248704 |
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| author | Jeremie Gautheron Christophe Morisseau Wendy K Chung Jamila Zammouri Martine Auclair Genevieve Baujat Emilie Capel Celia Moulin Yuxin Wang Jun Yang Bruce D Hammock Barbara Cerame Franck Phan Bruno Fève Corinne Vigouroux Fabrizio Andreelli Isabelle Jeru |
| author_facet | Jeremie Gautheron Christophe Morisseau Wendy K Chung Jamila Zammouri Martine Auclair Genevieve Baujat Emilie Capel Celia Moulin Yuxin Wang Jun Yang Bruce D Hammock Barbara Cerame Franck Phan Bruno Fève Corinne Vigouroux Fabrizio Andreelli Isabelle Jeru |
| author_sort | Jeremie Gautheron |
| collection | DOAJ |
| description | Epoxide hydrolases (EHs) regulate cellular homeostasis through hydrolysis of epoxides to less-reactive diols. The first discovered EH was EPHX1, also known as mEH. EH functions remain partly unknown, and no pathogenic variants have been reported in humans. We identified two de novo variants located in EPHX1 catalytic site in patients with a lipoatrophic diabetes characterized by loss of adipose tissue, insulin resistance, and multiple organ dysfunction. Functional analyses revealed that these variants led to the protein aggregation within the endoplasmic reticulum and to a loss of its hydrolysis activity. CRISPR-Cas9-mediated EPHX1 knockout (KO) abolished adipocyte differentiation and decreased insulin response. This KO also promoted oxidative stress and cellular senescence, an observation confirmed in patient-derived fibroblasts. Metreleptin therapy had a beneficial effect in one patient. This translational study highlights the importance of epoxide regulation for adipocyte function and provides new insights into the physiological roles of EHs in humans. |
| first_indexed | 2024-04-12T02:22:28Z |
| format | Article |
| id | doaj.art-9315024a184e4baeacd64e3d01903ed1 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:22:28Z |
| publishDate | 2021-08-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-9315024a184e4baeacd64e3d01903ed12022-12-22T03:52:05ZengeLife Sciences Publications LtdeLife2050-084X2021-08-011010.7554/eLife.68445EPHX1 mutations cause a lipoatrophic diabetes syndrome due to impaired epoxide hydrolysis and increased cellular senescenceJeremie Gautheron0https://orcid.org/0000-0002-7727-9893Christophe Morisseau1Wendy K Chung2Jamila Zammouri3Martine Auclair4Genevieve Baujat5Emilie Capel6Celia Moulin7Yuxin Wang8Jun Yang9Bruce D Hammock10https://orcid.org/0000-0003-1408-8317Barbara Cerame11Franck Phan12Bruno Fève13Corinne Vigouroux14Fabrizio Andreelli15Isabelle Jeru16https://orcid.org/0000-0001-7171-0577Sorbonne Université-Inserm UMRS_938, Centre de Recherche Saint-Antoine (CRSA), Paris, France; Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, FranceDepartment of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, Davis, United StatesDepartment of Pediatrics, Columbia University Irving Medical Center, New York, United States; Deparment of Medicine, Columbia University Irving Medical Center, New York, United StatesSorbonne Université-Inserm UMRS_938, Centre de Recherche Saint-Antoine (CRSA), Paris, France; Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, FranceSorbonne Université-Inserm UMRS_938, Centre de Recherche Saint-Antoine (CRSA), Paris, France; Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, FranceService de Génétique Clinique, Hôpital Necker-Enfants Malades, AP-HP, Paris, FranceSorbonne Université-Inserm UMRS_938, Centre de Recherche Saint-Antoine (CRSA), Paris, France; Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, FranceSorbonne Université-Inserm UMRS_938, Centre de Recherche Saint-Antoine (CRSA), Paris, France; Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, FranceDepartment of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, Davis, United StatesDepartment of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, Davis, United StatesDepartment of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, Davis, United StatesGoryeb Children’s Hospital, Atlantic Health Systems, Morristown Memorial Hospital, Morristown, United StatesInstitute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Service de Diabétologie-Métabolisme, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France; Sorbonne Université-Inserm UMRS_1269, Paris, FranceSorbonne Université-Inserm UMRS_938, Centre de Recherche Saint-Antoine (CRSA), Paris, France; Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; 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, Paris, FranceSorbonne Université-Inserm UMRS_938, Centre de Recherche Saint-Antoine (CRSA), Paris, France; Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; 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, Paris, France; Laboratoire commun de Biologie et Génétique Moléculaires, Hôpital Saint-Antoine, AP-HP, Paris, FranceInstitute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Service de Diabétologie-Métabolisme, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France; Sorbonne Université-Inserm UMRS_1269, Paris, FranceSorbonne Université-Inserm UMRS_938, Centre de Recherche Saint-Antoine (CRSA), Paris, France; Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Laboratoire commun de Biologie et Génétique Moléculaires, Hôpital Saint-Antoine, AP-HP, Paris, FranceEpoxide hydrolases (EHs) regulate cellular homeostasis through hydrolysis of epoxides to less-reactive diols. The first discovered EH was EPHX1, also known as mEH. EH functions remain partly unknown, and no pathogenic variants have been reported in humans. We identified two de novo variants located in EPHX1 catalytic site in patients with a lipoatrophic diabetes characterized by loss of adipose tissue, insulin resistance, and multiple organ dysfunction. Functional analyses revealed that these variants led to the protein aggregation within the endoplasmic reticulum and to a loss of its hydrolysis activity. CRISPR-Cas9-mediated EPHX1 knockout (KO) abolished adipocyte differentiation and decreased insulin response. This KO also promoted oxidative stress and cellular senescence, an observation confirmed in patient-derived fibroblasts. Metreleptin therapy had a beneficial effect in one patient. This translational study highlights the importance of epoxide regulation for adipocyte function and provides new insights into the physiological roles of EHs in humans.https://elifesciences.org/articles/68445diabetesgeneticsepoxide hydrolaseadipocytecellular senescenceEPHX1 |
| spellingShingle | Jeremie Gautheron Christophe Morisseau Wendy K Chung Jamila Zammouri Martine Auclair Genevieve Baujat Emilie Capel Celia Moulin Yuxin Wang Jun Yang Bruce D Hammock Barbara Cerame Franck Phan Bruno Fève Corinne Vigouroux Fabrizio Andreelli Isabelle Jeru EPHX1 mutations cause a lipoatrophic diabetes syndrome due to impaired epoxide hydrolysis and increased cellular senescence eLife diabetes genetics epoxide hydrolase adipocyte cellular senescence EPHX1 |
| title | EPHX1 mutations cause a lipoatrophic diabetes syndrome due to impaired epoxide hydrolysis and increased cellular senescence |
| title_full | EPHX1 mutations cause a lipoatrophic diabetes syndrome due to impaired epoxide hydrolysis and increased cellular senescence |
| title_fullStr | EPHX1 mutations cause a lipoatrophic diabetes syndrome due to impaired epoxide hydrolysis and increased cellular senescence |
| title_full_unstemmed | EPHX1 mutations cause a lipoatrophic diabetes syndrome due to impaired epoxide hydrolysis and increased cellular senescence |
| title_short | EPHX1 mutations cause a lipoatrophic diabetes syndrome due to impaired epoxide hydrolysis and increased cellular senescence |
| title_sort | ephx1 mutations cause a lipoatrophic diabetes syndrome due to impaired epoxide hydrolysis and increased cellular senescence |
| topic | diabetes genetics epoxide hydrolase adipocyte cellular senescence EPHX1 |
| url | https://elifesciences.org/articles/68445 |
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