title: Hepatic FOXO1 Target Genes Are Co-regulated by Thyroid Hormone via RICTOR Protein Deacetylation and MTORC2-AKT Protein Inhibition.
abstract: MTORC2-AKT is a key regulator of carbohydrate metabolism and insulin signaling due to its effects on FOXO1 phosphorylation. Interestingly, both FOXO1 and thyroid hormone (TH) have similar effects on carbohydrate and energy metabolism as well as overlapping transcriptional regulation of many target genes. Currently, little is known about the regulation of MTORC2-AKT or FOXO1 by TH. Accordingly, we performed hepatic transcriptome profiling in mice after FOXO1 knockdown in the absence or presence of TH, and we compared these results with hepatic FOXO1 and THRB1 (TRβ1) ChIP-Seq data. We identified a subset of TH-stimulated FOXO1 target genes that required co-regulation by FOXO1 and TH. TH activation of FOXO1 was directly linked to an increase in SIRT1-MTORC2 interaction and RICTOR deacetylation. This, in turn, led to decreased AKT and FOXO1 phosphorylation. Moreover, TH increased FOXO1 nuclear localization, DNA binding, and target gene transcription by reducing AKT-dependent FOXO1 phosphorylation in a THRB1-dependent manner. These events were associated with TH-mediated oxidative phosphorylation and NAD(+) production and suggested that downstream metabolic effects by TH can post-translationally activate other transcription factors. Our results showed that RICTOR/MTORC2-AKT can integrate convergent hormonal and metabolic signals to provide coordinated and sensitive regulation of hepatic FOXO1-target gene expression.
authors.affiliation: From the Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program and.
authors.forename: Brijesh K
authors.initials: BK
authors.lastname: Singh
authors.affiliation: From the Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program and.
authors.forename: Rohit A
authors.initials: RA
authors.lastname: Sinha
authors.affiliation: From the Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program and.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhou
authors.affiliation: From the Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program and the Stroke Trial Unit, National Neuroscience Institute Singapore, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore.
authors.forename: Madhulika
authors.initials: M
authors.lastname: Tripathi
authors.affiliation: From the Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program and.
authors.forename: Kenji
authors.initials: K
authors.lastname: Ohba
authors.affiliation: From the Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program and the Department of Animal Science and Technology, National Taiwan University, Taipei 10617, Taiwan.
authors.forename: Mu-En
authors.initials: ME
authors.lastname: Wang
authors.affiliation: the Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115, and.
authors.forename: Inna
authors.initials: I
authors.lastname: Astapova
authors.affiliation: From the Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program and Centre for Computational Biology, Duke-National University of Singapore Graduate Medical School, Singapore 169857, Singapore.
authors.forename: Sujoy
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: the Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115, and.
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Hollenberg
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 and paul.yen@duke-nus.edu.sg.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Yen
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D004789:Enzyme Activation / Q000187:drug effects; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D000076225:Mechanistic Target of Rapamycin Complex 2; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013963:Thyroid Hormones / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D002352:Carrier Proteins; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D046912:Multiprotein Complexes; C492571:RICTOR protein, human; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones; C525637:rictor protein, mouse; D009243:NAD; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D056564:Sirtuin 1
keywords: AKT; MTORC2; RICTOR; carbohydrate metabolism; gene regulation; gluconeogenesis; insulin signaling; thyroid hormone; transcription coregulator