Hepatic FOXO1 Target Genes Are Co-regulated by Thyroid Hormone via RICTOR Protein Deacetylation and MTORC2-AKT Protein Inhibition

Oct 11, 2015The Journal of biological chemistry

Liver Genes Controlled by FOXO1 Are Also Regulated by Thyroid Hormone Through Changes in RICTOR and MTORC2-AKT Protein Activity

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Abstract

FOXO1 knockdown in mice under thyroid hormone influence revealed co-regulation of TH-stimulated FOXO1 target genes.

Thyroid hormone (TH) may activate FOXO1, leading to enhanced interaction with SIRT1-MTORC2 and resulting in decreased phosphorylation of AKT and FOXO1.
Increased nuclear localization and DNA binding of FOXO1 is associated with TH's ability to reduce AKT-dependent phosphorylation.
TH appears to stimulate oxidative phosphorylation and NAD(+) production, indicating potential metabolic effects.
FOXO1 and TH interact to regulate a subset of target genes, suggesting a complex interplay between thyroid hormone signaling and metabolic regulation.

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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.

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Hepatic FOXO1 Target Genes Are Co-regulated by Thyroid Hormone via RICTOR Protein Deacetylation and MTORC2-AKT Protein Inhibition

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