title: FoxO1 deacetylation regulates thyroid hormone-induced transcription of key hepatic gluconeogenic genes.
abstract: Hepatic gluconeogenesis is a concerted process that integrates transcriptional regulation with hormonal signals. A major regulator is thyroid hormone (TH), which acts through its nuclear receptor (TR) to induce the expression of the hepatic gluconeogenic genes, phosphoenolpyruvate carboxykinase (PCK1) and glucose-6-phosphatase (G6PC). Forkhead transcription factor FoxO1 also is an important regulator of these genes; however, its functional interactions with TR are not known. Here, we report that TR-mediated transcriptional activation of PCK1 and G6PC in human hepatic cells and mouse liver was FoxO1-dependent and furthermore required FoxO1 deacetylation by the NAD(+)-dependent deacetylase, SirT1. siRNA knockdown of FoxO1 decreased, whereas overexpression of FoxO1 increased, TH-dependent transcriptional activation of PCK1 and G6PC in cultured hepatic cells. FoxO1 siRNA knockdown also decreased TH-mediated transcription in vivo. Additionally, TH was unable to induce FoxO1 deacetylation or hepatic PCK1 gene expression in TH receptor β-null (TRβ(-/-)) mice. Moreover, TH stimulated FoxO1 recruitment to the PCK1 and G6PC gene promoters in a SirT1-dependent manner. In summary, our results show that TH-dependent deacetylation of a second metabolically regulated transcription factor represents a novel mechanism for transcriptional integration of nuclear hormone action with cellular energy status.
authors.affiliation: From the Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School, Singapore 169857.
authors.forename: Brijesh Kumar
authors.initials: BK
authors.lastname: Singh
authors.affiliation: From the Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School, Singapore 169857.
authors.forename: Rohit Anthony
authors.initials: RA
authors.lastname: Sinha
authors.affiliation: From the Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School, Singapore 169857.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhou
authors.affiliation: From the Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School, Singapore 169857.
authors.forename: Sherwin Ying
authors.initials: SY
authors.lastname: Xie
authors.affiliation: the Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, the Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, and.
authors.forename: Seo-Hee
authors.initials: SH
authors.lastname: You
authors.affiliation: the Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Université Lyon 1, CNRS, Ecole Normale Supérieure de Lyon, 46, allée d'Italie 69364 Lyon Cedex 07, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Gauthier
authors.affiliation: From the Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School, Singapore 169857,. Electronic address: paul.yen@duke-nus.edu.sg.
authors.forename: Paul Michael
authors.initials: PM
authors.lastname: Yen
mesh_terms: D000107:Acetylation; D000818:Animals; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005943:Gluconeogenesis / Q000502:physiology*; D005952:Glucose-6-Phosphatase / Q000096:biosynthesis / Q000235:genetics; D056945:Hep G2 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000096:biosynthesis / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000502:physiology; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D013963:Thyroid Hormones / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology*
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones; D005952:Glucose-6-Phosphatase; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; C521898:PCK1 protein, human; D010729:Phosphoenolpyruvate Carboxykinase (GTP)
keywords: FoxO; Gene Regulation; Gene Transcription; Gluconeogenesis; Phosphoenolpyruvate Carboxykinase; Sirt1; Thyroid Hormone