FoxO1 Inhibits Sterol Regulatory Element-binding Protein-1c (SREBP-1c) Gene Expression via Transcription Factors Sp1 and SREBP-1c

Xiong Deng,Wenwei Zhang,Insug O-Sullivan,J Bradley Williams,Qingming Dong,Edwards A Park,Rajendra Raghow,Terry G Unterman,Marshall B Elam

doi:10.1074/jbc.m112.347211

Abstract

Induction of lipogenesis in response to insulin is critically dependent on the transcription factor, sterol regulatory element-binding protein-1c (SREBP-1c). FoxO1, a forkhead box class-O transcription factor, is an important mediator of insulin action, but its role in the regulation of lipid metabolism has not been clearly defined. We examined the effects of FoxO1 on srebp1 gene expression in vivo and in vitro. In vivo studies showed that constitutively active (CA) FoxO1 (CA-FoxO1) reduced basal expression of SREBP-1c mRNA in liver by ∼60% and blunted induction of SREBP-1c in response to feeding. In liver-specific FoxO knock-out mice, SREBP-1c expression was increased ∼2-fold. Similarly, in primary hepatocytes, CA-FoxO1 suppressed SREBP1-c expression and inhibited basal and insulin-induced SREBP-1c promoter activity. SREBP-1c gene expression is induced by the liver X receptor (LXR), but CA-FoxO1 did not block the activation of SREBP-1c by the LXR agonist TO9. Insulin stimulates SREBP-1c transcription through Sp1 and via "feed forward" regulation by newly synthesized SREBP-1c. CA-FoxO1 inhibited SREBP-1c by reducing the transactivational capacity of both Sp1 and SREBP-1c. In addition, chromatin immunoprecipitation assays indicate that FoxO1 can associate with the proximal promoter region of the srebp1 gene and disrupt the assembly of key components of the transcriptional complex of the SREBP-1c promoter. We conclude that FoxO1 inhibits SREBP-1c transcription via combined actions on multiple transcription factors and that this effect is exerted at least in part through reduced transcriptional activity of Sp1 and SREBP-1c and disrupted assembly of the transcriptional initiation complex on the SREBP-1c promoter.

Highlights

FoxO1 regulates expression of lipogenic genes including srebp1
SREBP-1c gene expression is induced by the liver X receptor (LXR), but constitutively active (CA)-FoxO1 did not block the activation of SREBP-1c by the LXR agonist TO9
CA-FoxO1 Inhibits Activation of SREBP-1c Transcription by Insulin—Because insulin strongly activates transcription of the srebp1 gene [15, 21] and FoxO1 is a major target of insulin action [1], we examined the effect of CA-FoxO1 on the response of the rat SREBP-1c promoter to insulin

Summary

Background

FoxO1 regulates expression of lipogenic genes including srebp. Results: FoxO1 inhibits transcription of SREBP-1c via coordinated effects on key regulatory factors including Sp1 and SREBP-1c itself. Significance: FoxO1 effectively inhibits SREBP-1c gene expression, a major regulator of hepatic lipogenesis. Insulin suppresses the expression of gluconeogenic enzymes at least in part by promoting nuclear export of FoxO1 via AKT/ PKB-mediated phosphorylation [4] while coordinately inducing hepatic lipid synthesis via SREBP-1c [5]. We have previously shown that in livers of transgenic mice expressing a constitutively active FoxO1 mutant (CAFoxO1), FoxO1 inhibits both SREBP-1c expression and de novo hepatic lipogenesis [6]. This suggests that FoxO1 may play a role in maintaining low levels of SREBP-1c expression during fasting by inhibiting SREBP-1c transcription. The current studies were undertaken to better define the role of FoxO1 in regula-

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EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION