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Nuclear receptor corepressors non-canonically drive glucocorticoid receptor-dependent activation of hepatic gluconeogenesis.
Hauck, Amy K; Mehmood, Rashid; Carpenter, Bryce J; Frankfurter, Maxwell T; Tackenberg, Michael C; Inoue, Shin-Ichi; Krieg, Maria K; Cassim Bawa, Fathima N; Midha, Mohit K; Zundell, Delaine M; Batmanov, Kirill; Lazar, Mitchell A.
Afiliación
  • Hauck AK; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Mehmood R; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Carpenter BJ; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Frankfurter MT; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Tackenberg MC; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Inoue SI; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Krieg MK; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Cassim Bawa FN; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Midha MK; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Zundell DM; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Batmanov K; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Lazar MA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. lazar@pennmedicine.upenn.edu.
Nat Metab ; 6(5): 825-836, 2024 May.
Article en En | MEDLINE | ID: mdl-38622413
ABSTRACT
Nuclear receptor corepressors (NCoRs) function in multiprotein complexes containing histone deacetylase 3 (HDAC3) to alter transcriptional output primarily through repressive chromatin remodelling at target loci1-5. In the liver, loss of HDAC3 causes a marked hepatosteatosis largely because of de-repression of genes involved in lipid metabolism6,7; however, the individual roles and contribution of other complex members to hepatic and systemic metabolic regulation are unclear. Here we show that adult loss of both NCoR1 and NCoR2 (double knockout (KO)) in hepatocytes phenocopied the hepatomegalic fatty liver phenotype of HDAC3 KO. In addition, double KO livers exhibited a dramatic reduction in glycogen storage and gluconeogenic gene expression that was not observed with hepatic KO of individual NCoRs or HDAC3, resulting in profound fasting hypoglycaemia. This surprising HDAC3-independent activation function of NCoR1 and NCoR2 is due to an unexpected loss of chromatin accessibility on deletion of NCoRs that prevented glucocorticoid receptor binding and stimulatory effect on gluconeogenic genes. These studies reveal an unanticipated, non-canonical activation function of NCoRs that is required for metabolic health.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores de Glucocorticoides / Ratones Noqueados / Co-Represor 1 de Receptor Nuclear / Co-Represor 2 de Receptor Nuclear / Gluconeogénesis / Histona Desacetilasas / Hígado Límite: Animals Idioma: En Revista: Nat Metab Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Alemania
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores de Glucocorticoides / Ratones Noqueados / Co-Represor 1 de Receptor Nuclear / Co-Represor 2 de Receptor Nuclear / Gluconeogénesis / Histona Desacetilasas / Hígado Límite: Animals Idioma: En Revista: Nat Metab Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Alemania