Abstract
As a mediator of insulin-regulated gene expression, the FoxO1 transcription factor represents a master regulator of liver glucose metabolism. We previously reported that the high-mobility group AT-hook 1 (HMGA1) protein, a molecular switch for the insulin receptor gene, functions also as a downstream target of the insulin receptor signaling pathway, representing a critical nuclear mediator of insulin function. Here, we investigated whether a functional relationship existed between FoxO1 and HMGA1, which might help explain insulin-mediated gene transcription in the liver. To this end, as a model study, we investigated the canonical FoxO1-HMGA1-responsive IGFBP1 gene, whose hepatic expression is regulated by insulin. By using a conventional GST-pull down assay combined with co-immunoprecipitation and Fluorescence Resonance Energy Transfer (FRET) analyses, we provide evidence of a physical interaction between FoxO1 and HMGA1. Further investigation with chromatin immunoprecipitation, confocal microscopy, and Fluorescence Recovery After Photobleaching (FRAP) technology indicated a functional significance of this interaction, in both basal and insulin-stimulated states, providing evidence that, by modulating FoxO1 transactivation, HMGA1 is essential for FoxO1-induced IGFBP1 gene expression, and thereby a critical modulator of insulin-mediated FoxO1 regulation in the liver. Collectively, our findings highlight a novel FoxO1/HMGA1-mediated mechanism by which insulin may regulate gene expression and metabolism.
Highlights
The regulation of glucose metabolism and homeostasis is a central component of living systems
The observation that an interplay among high-mobility group A1 (HMGA1) and forkhead box protein O1 (FoxO1) can be a component of the insulin/FoxO1 signaling pathway constitutes a novel point of the present study, which may help in understanding the molecular basis of certain disorders where insulin action becomes compromised
For the first time in the present work, we demonstrate that HMGA1 physically and functionally interacts with FoxO1, thereby regulating both FoxO1-DNA binding and insulin-mediated FoxO1 gene transcription
Summary
The regulation of glucose metabolism and homeostasis is a central component of living systems In mammals, this function is performed through distinct but interrelated cell signaling pathways that mediate the transduction of hormonal and nutrient stimuli to the nucleus, resulting in modifications of nuclear regulatory proteins (transcription factors), which bind to specific sites on the DNA and cause the activation or repression of genes and gene networks involved in these metabolic processes. HMGA1 has no intrinsic transcriptional activity; rather, it can transactivate promoters by facilitating the assembly and stability of higher-order transcriptional complexes – so-called enhanceosomes – that drive gene transcription in response to extracellular and intracellular signals[20,21] Such signals may affect HMGA1 function by inducing changes in post-translational protein modifications that markedly influence www.nature.com/scientificreports/. On the base of the above considerations, here we explored the hypothesis that the insulin-mediated FoxO1-regulated metabolic pathway in the liver could be modulated by direct interactions of HMGA1 with FoxO1
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