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ADH1B, the adipocyte-enriched alcohol dehydrogenase, plays an essential, cell-autonomous role in human adipogenesis.

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Title: ADH1B, the adipocyte-enriched alcohol dehydrogenase, plays an essential, cell-autonomous role in human adipogenesis.
Authors: Gautheron, Jérémie1,2 jeremie.gautheron@inserm.fr, Elsayed, Solaf3, Pistorio, Valeria1,2, Lockhart, Sam4, Zammouri, Jamila1,2, Auclair, Martine1,2, Koulman, Albert4, Meadows, Sarah R.4, Lhomme, Marie5, Ponnaiah, Maharajah6, Si-Bouazza, Redouane7, Fabrega, Sylvie7, Belkadi, Abdelaziz8, Project, Qatar Genome9, Delaunay, Jean-Louis1,2, Aït-Slimane, Tounsia1, Fève, Bruno1,2,10, Vigouroux, Corinne1,2,10, Ghaffar, Tawhida Y. Abdel11, O'Rahilly, Stephen4 so104@cam.ac.uk
Source: Proceedings of the National Academy of Sciences of the United States of America. 6/11/2024, Vol. 121 Issue 24, p1-9. 37p.
Subjects: Alcohol dehydrogenase, Human stem cells, Adipose tissues, Adipogenesis, Missense mutation
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.Arg-313Cys) 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. [ABSTRACT FROM AUTHOR]
Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: ADH1B, the adipocyte-enriched alcohol dehydrogenase, plays an essential, cell-autonomous role in human adipogenesis.
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  Data: <searchLink fieldCode="AR" term="%22Gautheron%2C+Jérémie%22">Gautheron, Jérémie</searchLink><relatesTo>1,2</relatesTo><i> jeremie.gautheron@inserm.fr</i><br /><searchLink fieldCode="AR" term="%22Elsayed%2C+Solaf%22">Elsayed, Solaf</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Pistorio%2C+Valeria%22">Pistorio, Valeria</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Lockhart%2C+Sam%22">Lockhart, Sam</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Zammouri%2C+Jamila%22">Zammouri, Jamila</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Auclair%2C+Martine%22">Auclair, Martine</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Koulman%2C+Albert%22">Koulman, Albert</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Meadows%2C+Sarah+R%2E%22">Meadows, Sarah R.</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Lhomme%2C+Marie%22">Lhomme, Marie</searchLink><relatesTo>5</relatesTo><br /><searchLink fieldCode="AR" term="%22Ponnaiah%2C+Maharajah%22">Ponnaiah, Maharajah</searchLink><relatesTo>6</relatesTo><br /><searchLink fieldCode="AR" term="%22Si-Bouazza%2C+Redouane%22">Si-Bouazza, Redouane</searchLink><relatesTo>7</relatesTo><br /><searchLink fieldCode="AR" term="%22Fabrega%2C+Sylvie%22">Fabrega, Sylvie</searchLink><relatesTo>7</relatesTo><br /><searchLink fieldCode="AR" term="%22Belkadi%2C+Abdelaziz%22">Belkadi, Abdelaziz</searchLink><relatesTo>8</relatesTo><br /><searchLink fieldCode="AR" term="%22Project%2C+Qatar+Genome%22">Project, Qatar Genome</searchLink><relatesTo>9</relatesTo><br /><searchLink fieldCode="AR" term="%22Delaunay%2C+Jean-Louis%22">Delaunay, Jean-Louis</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Aït-Slimane%2C+Tounsia%22">Aït-Slimane, Tounsia</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Fève%2C+Bruno%22">Fève, Bruno</searchLink><relatesTo>1,2,10</relatesTo><br /><searchLink fieldCode="AR" term="%22Vigouroux%2C+Corinne%22">Vigouroux, Corinne</searchLink><relatesTo>1,2,10</relatesTo><br /><searchLink fieldCode="AR" term="%22Ghaffar%2C+Tawhida+Y%2E+Abdel%22">Ghaffar, Tawhida Y. Abdel</searchLink><relatesTo>11</relatesTo><br /><searchLink fieldCode="AR" term="%22O'Rahilly%2C+Stephen%22">O'Rahilly, Stephen</searchLink><relatesTo>4</relatesTo><i> so104@cam.ac.uk</i>
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  Data: <searchLink fieldCode="DE" term="%22Alcohol+dehydrogenase%22">Alcohol dehydrogenase</searchLink><br /><searchLink fieldCode="DE" term="%22Human+stem+cells%22">Human stem cells</searchLink><br /><searchLink fieldCode="DE" term="%22Adipose+tissues%22">Adipose tissues</searchLink><br /><searchLink fieldCode="DE" term="%22Adipogenesis%22">Adipogenesis</searchLink><br /><searchLink fieldCode="DE" term="%22Missense+mutation%22">Missense mutation</searchLink>
– Name: Abstract
  Label: Abstract
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  Data: 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.Arg-313Cys) 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. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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