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Control of Foxo1 gene expression by co-activator P300
Anne R Wondisford1, Lishou Xiong, Evan Chang
1From the Division of Metabolism, Department of Pediatrics and.
Abstract:
FOXO1 is an important downstream mediator of the insulin signaling pathway. In the fed state, elevated insulin phosphorylates FOXO1 via AKT, leading to its nuclear exclusion and degradation. A reduction in nuclear FOXO1 levels then leads to suppression of hepatic glucose production. However, the mechanism leading to expression of Foxo1 gene in the fasted state is less clear. We found that Foxo1 mRNA and FOXO1 protein levels of Foxo1 were increased significantly in the liver of mice after 16 h of fasting. Furthermore, dibutyrl cAMP stimulated the expression of Foxo1 at both mRNA and protein level in hepatocytes. Because cAMP-PKA regulates hepatic glucose production through cAMP-response element-binding protein co-activators, we depleted these co-activators using adenoviral shRNAs. Interestingly, only depletion of co-activator P300 resulted in the decrease of Foxo1 mRNA and FOXO1 protein levels. In addition, inhibition of histone acetyltransferase activity of P300 significantly decreased hepatic Foxo1 mRNA and FOXO1 protein levels in fasted mice, as well as fasting blood glucose levels. By characterization of Foxo1 gene promoter, P300 regulates the Foxo1 gene expression through the binding to tandem cAMP-response element sites in the proximal promoter region of Foxo1 gene.
Insights
During fasting, the protein FOXO1 (Forkhead box protein O1) is upregulated in the liver. The co-activator P300 enhances its expression, impacting glucose production.
Area of Science:
- Biochemistry
- Molecular Biology
- Endocrinology
Background:
- FOXO1 (Forkhead box protein O1) is a key regulator in insulin signaling, suppressing hepatic glucose production when active.
- The precise mechanisms controlling Foxo1 gene expression during fasting remain incompletely understood.
Purpose of the Study:
- To elucidate the molecular mechanisms governing Foxo1 gene expression in the liver during fasting.
- To identify key regulators involved in fasting-induced hepatic Foxo1 upregulation.
Main Methods:
- Quantitative analysis of Foxo1 mRNA and protein levels in fasted mice.
- Hepatocyte culture experiments stimulating Foxo1 expression with dibutyryl cAMP.
- Gene silencing using adenoviral shRNAs to deplete co-activators.
- Chromatin immunoprecipitation and promoter analysis to identify regulatory elements.
- Inhibition of histone acetyltransferase activity.
Main Results:
- Fasting significantly increased hepatic Foxo1 mRNA and protein levels.
- Cyclic AMP (cAMP) stimulated Foxo1 expression in hepatocytes.
- Depletion of the co-activator P300 reduced Foxo1 mRNA and protein levels.
- P300 inhibition decreased hepatic Foxo1 expression and fasting blood glucose levels.
- P300 binds to cAMP-response elements in the Foxo1 promoter to regulate its expression.
Conclusions:
- P300, a histone acetyltransferase, plays a critical role in upregulating hepatic Foxo1 expression during fasting.
- P300-mediated regulation of Foxo1 contributes to the control of fasting blood glucose levels.
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