FoxO1 deacetylation regulates thyroid hormone-induced transcription of key hepatic gluconeogenic genes

J Biol Chem. 2013 Oct 18;288(42):30365-30372. doi: 10.1074/jbc.M113.504845. Epub 2013 Aug 30.

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.

Keywords: FoxO; Gene Regulation; Gene Transcription; Gluconeogenesis; Phosphoenolpyruvate Carboxykinase; Sirt1; Thyroid Hormone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism*
  • Gluconeogenesis / physiology*
  • Glucose-6-Phosphatase / biosynthesis
  • Glucose-6-Phosphatase / genetics
  • Hep G2 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / biosynthesis
  • Intracellular Signaling Peptides and Proteins / genetics
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Phosphoenolpyruvate Carboxykinase (GTP) / biosynthesis
  • Phosphoenolpyruvate Carboxykinase (GTP) / genetics
  • Promoter Regions, Genetic / physiology
  • Receptors, Thyroid Hormone / genetics
  • Receptors, Thyroid Hormone / metabolism
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism
  • Thyroid Hormones / genetics
  • Thyroid Hormones / metabolism*
  • Transcription, Genetic / physiology*
  • Transcriptional Activation / physiology*

Substances

  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Foxo1 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Receptors, Thyroid Hormone
  • Thyroid Hormones
  • Glucose-6-Phosphatase
  • SIRT1 protein, human
  • Sirt1 protein, mouse
  • Sirtuin 1
  • PCK1 protein, human
  • Phosphoenolpyruvate Carboxykinase (GTP)