ADH1B, the adipocyte-enriched alcohol dehydrogenase, plays an essential, cell-autonomous role in human adipogenesis
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Published:2024-06-05
Issue:24
Volume:121
Page:
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ISSN:0027-8424
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Container-title:Proceedings of the National Academy of Sciences
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language:en
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Short-container-title:Proc. Natl. Acad. Sci. U.S.A.
Author:
Gautheron Jérémie12, Elsayed Solaf3, Pistorio Valeria12, Lockhart Sam4, Zammouri Jamila12, Auclair Martine12, Koulman Albert4, Meadows Sarah R.4, Lhomme Marie5, Ponnaiah Maharajah6, Si-Bouazza Redouane7, Fabrega Sylvie7ORCID, Belkadi Abdelaziz8, , Delaunay Jean-Louis12, Aït-Slimane Tounsia12, Fève Bruno129, Vigouroux Corinne129ORCID, Abdel Ghaffar Tawhida Y.10, O’Rahilly Stephen4ORCID, Jéru Isabelle1211, Ismail Said I., Al-Muftah Wadha, Badji Radja, Mbarek Hamdi, Darwish Dima, Fadl Tasnim, Yasin Heba, Ennaifar Maryem, Abdellatif Rania, Alkuwari Fatima, Alvi Muhammad, Al-Sarraj Yasser, Saad Chadi, Althani Asmaa, Fethnou Eleni, Qafoud Fatima, Alkhayat Eiman, Afifi Nahla, Tomei Sara, Liu Wei, Lorenz Stephan, Syed Najeeb, Almabrazi Hakeem, Vempalli Fazulur Rehaman, Temanni Ramzi, Saqri Tariq Abu, Khatib Mohammedhusen, Hamza Mehshad, Zaid Tariq Abu, El Khouly Ahmed, Pathare Tushar, Poolat Shafeeq, Al-Ali Rashid, Albagha Omar, Belkadi Abdelaziz, Al-Khodor Souhaila, Alshafai Mashael, Badii Ramin, Chouchane Lotfi, Estivill Xavier, Fakhro Khalid, Mbarek Hamdi, Mokrab Younes, Puthen Jithesh V., Suhre Karsten, Tatari Zohreh
Affiliation:
1. Centre de Recherche Saint-Antoine, Sorbonne Université-Inserm, Paris 75012, France 2. Foundation for Innovation in Cardiometabolism and Nutrition, Paris 75013, France 3. Medical Genetics Department, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt 4. Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge CB2 1TN, United Kingdom 5. Omics Lipidomics, Foundation for Innovation in Cardiometabolism and Nutrition, Paris 75013, France 6. Data sciences unit, Foundation for Innovation in Cardiometabolism and Nutrition, Paris 75013, France 7. Viral Vector and Gene Transfer Platform, Structure Federative de Recherche Necker, Université Paris Cité, Paris 75015, France 8. Bioinformatics Core, Weill Cornell Medicine-Qatar, Education City, Doha 24144, Qatar 9. Centre National de Référence des Pathologies Rares de l’Insulino-Sécrétion et de l’Insulino-Sensibilité, Service de Diabétologie et Endocrinologie de la Reproduction, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris, Paris 75012, France 10. Yassin Abdelghaffar Center for Liver Disease and Research, Cairo 11566, Egypt 11. Medical Genetics Unit, Biology, Genomics and Hygiene Medical-University Department, Pitié-Salpêtrière Hospital, Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Paris 75013, France
Abstract
Alcohol dehydrogenase 1B (ADH1B) is a primate-specific enzyme which, uniquely among the ADH class 1 family, is highly expressed both in adipose tissue and liver. Its expression in adipose tissue is reduced in obesity and increased by insulin stimulation. Interference with
ADH1B
expression has also been reported to impair adipocyte function. To better understand the role of ADH1B in adipocytes, we used CRISPR/Cas9 to delete
ADH1B
in human adipose stem cells (ASC). Cells lacking ADH1B failed to differentiate into mature adipocytes manifested by minimal triglyceride accumulation and a marked reduction in expression of established adipocyte markers. As ADH1B is capable of converting retinol to retinoic acid (RA), we conducted rescue experiments. Incubation of ADH1B-deficient preadipocytes with 9-cis-RA, but not with all-transretinol, significantly rescued their ability to accumulate lipids and express markers of adipocyte differentiation. A homozygous missense variant in
ADH1B
(p.Arg313Cys) was found in a patient with congenital lipodystrophy of unknown cause. This variant significantly impaired the protein’s dimerization, enzymatic activity, and its ability to rescue differentiation in ADH1B-deficient ASC. The allele frequency of this variant in the Middle Eastern population suggests that it is unlikely to be a fully penetrant cause of severe lipodystrophy. In conclusion, ADH1B appears to play an unexpected, crucial and cell-autonomous role in human adipocyte differentiation by serving as a necessary source of endogenous retinoic acid.
Funder
Agence Nationale de la Recherche Mairie de Paris Société Francophone du Diabète Fondation pour la Recherche Médicale Wellcome Trust
Publisher
Proceedings of the National Academy of Sciences
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