In human and rodent models of insulin resistance, the regulation of gluconeogenesis is altered such that hepatic glucose production is enhanced in the fasted state with reduced suppression in the fed state. In parallel, hepatic de novo lipogenesis is elevated in fasted state and further increased in the fed state. The inability of insulin to suppress hepatic glucose output but still to activate de novo lipogenesis has been referred to as selective insulin resistance. Numerous studies have examined the regulation of DNA binding transcription factors, transcription factor co-activators and co-repressors in the control of liver lipogenic gene expression. Despite the intensive investigation of these trans-factors that control lipogenic gene expression, none of these proteins directly interacts with DNA-dependent RNA polymerase II and it has generally been believed that all of the regulation occurs at the level of the trans-factors. One critical complex termed the Mediator connects multiple trans-factors to the DNA-dependent RNA polymerase II. In mammalians, Mediator is composed of at least 30 individual subunits that are assembled from four sub-complexes, head, middle, tail and kinase sub-modules. In yeast, it was originally suggested that the Mediator is a constitutive component of the expression machinery. However, in drosophila larvae, hepatocyte cultured cells, and liver in vivo we recently demonstrated that the CDK8/CycC complex a component of the kinase sub-module (CDK8/CycC, Med12 and Med13) undergoes dynamic regulation by insulin and nutritional states. Based upon these previous and our new preliminary data that mTORC1 regulates the protein levels of Mediator kinase submodule (CDK8/CycC, MED12 and MED13), we hypothesize that the Mediator complex undergoes structural reorganization from a lipogenic transcriptional repressing state (so called large Mediator complex) in the fasted state to a lipogenic transcriptional activating state (so called small Mediator complex) in the fed state. The dysregulation of the Mediator complex in states of insulin resistance accounts, at least in part, for the elevation of lipogenic gene expression in the fasted state. In this proposal we will determine the physiologic and patho- physiologic alterations of the Mediator complex, the nutritional signals and their dysregulation resulting in the Mediator complex re-organization, and the consequences of these changes on lipogenic gene expression.
In human and rodent models of insulin resistance, the regulation of gluconeogenesis is altered such that hepatic glucose production is enhanced in the fasted state with reduced suppression in the fed state. In parallel, hepatic de novo lipogenesis is elevated in fasted state and further increased in the fed state. The inability of insulin to suppress hepatic glucose output but still to activate de novo lipogenesis has been referred to as selective insulin resistance. Numerous studies have examined changes in insulin signal transduction (insulin receptor isoform and activity, IRS protein expression and phosphorylation, Akt isoform and activity) and cAMP signaling pathways (glucagon and catecholamine receptors, trimeric G protein changes, cAMP production and protein kinase A activity). Moreover, numerous studies have also examined the regulation of DNA binding transcription factors (Foxo1, FxR, USF, XBP1, LxR, SREBP1c and ChREBP) and transcription factor co-activators and co-repressors (DAX1, LCOR, HDAC3) in the control of lipogenic gene expression. Despite the intensive investigator in these trans-factors that control lipogenic gene expression, none of these proteins directly interacts with DNA-dependent RNA polymerase II and it has generally been believed that all of the regulation occurs at the level of the trans-factors. One critical complex termed the Mediator (also referred to as DRIP or TRAP) connects multiple trans-factors to the DNA-dependent RNA polymerase II. In mammalians Mediator is composed of at least 30 individual subunits that are assembled from four sub-complexes, head, middle, tail and kinase sub-modules. For example, SREBP1c was shown to interact with the Med15 subunit in the tail sub-module and this interaction is required for SREBP1c dependent gene expression. In yeast, it was originally suggested that the Mediator is a constitutive component of the expression machinery. However, in drosophila larvae, hepatocyte cultured cells, and liver in vivo we recently demonstrated that the CDK8/CycC complex a component of the kinase sub-module (CDK8/CycC, Med12 and Med13) undergoes dynamic regulation by insulin and nutritional states. Based upon these previous and our new preliminary data that mTORC1 regulates the protein levels of Mediator kinase submodule (CDK8/CycC, MED12 and MED13), we hypothesize that the Mediator complex undergoes structural reorganization from a lipogenic transcriptional repressing state (so called large Mediator complex) in the fasted state to a lipogenic transcriptional activating state (so called small Mediator complex) in the fed state. The dysregulation of the Mediator complex in states of insulin resistance accounts, at least in part, for the elevation of lipogenic gene expression in the fasted state. In this proposal we will determine the physiologic and patho-physiologic alterations of the Mediator complex, the nutritional signals and their dysregulation resulting in the Mediator complex re-organization, and the consequences of these changes on lipogenic gene expression.
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