ADH1B, the adipocyte-enriched alcohol dehydrogenase, plays an essential, cell-autonomous role in human adipogenesis
In: ISSN: 0027-8424, 2024
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academicJournal
Zugriff:
International audience ; 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.
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ADH1B, the adipocyte-enriched alcohol dehydrogenase, plays an essential, cell-autonomous role in human adipogenesis
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Autor/in / Beteiligte Person: | Wrote, I, J ; Gautheron, Jérémie ; Elsayed, Solaf ; Pistorio, Valeria ; Lockhart, Sam ; Fabrega, Sylvie ; Auclair, Martine ; Koulman, Albert ; Meadows, Sarah, R ; Lhomme, Marie ; Ponnaiah, Maharajah ; Si-Bouaz, Redouane ; Belkadi, Abdelaziz ; O’rahilly, Stephen ; Delaunay, Jean-Louis ; Aït-Slimane, Tounsia ; Fève, Bruno ; Vigouroux, Corinne ; Ghaffar, Tawhida, y Abdel ; O'Rahilly, Stephen ; Jéru, Isabelle ; Lazar, Mitchell, A ; Zechner, Rudolf ; 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) ; University of Naples Federico II = Università degli studi di Napoli Federico, II ; 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) ; Plateforme Vecteurs Viraux et Transfert de Gènes SFR Necker (VVTG) ; 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)-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) ; Institute of Metabolic Science-Metabolic Research Laboratories ; University of Cambridge UK (CAM) ; CHU Saint-Antoine AP-HP ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU) ; Mitochondrie : Régulations et Pathologie ; Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM) ; Génétique Humaine des Maladies Infectieuses (Inserm U980) ; Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM) ; Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute ; Intégrité du génome et cancers (IGC) ; École Pratique des Hautes Études (EPHE) ; Université Paris Sciences et Lettres (PSL)-Université Paris Sciences et Lettres (PSL)-Institut Gustave Roussy (IGR)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS) ; Sorbonne Université (SU) ; Wellcome Trust-MRC Institute of Metabolic Science ; Graz, Karl-Franzens-Universität ; ANR-21-CE17-0002,DELFAT,Sauver les greffons hépatiques stéatosiques en modulant l'activité de la nécroptose(2021) |
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Zeitschrift: | ISSN: 0027-8424, 2024 |
Veröffentlichung: | HAL CCSD ; National Academy of Sciences, 2024 |
Medientyp: | academicJournal |
DOI: | 10.1073/pnas.2319301121 |
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