Diabetes mellitus is a significant health problem, affecting over 18 million people in the United States alone.Mutations in several hepatic nuclear factors have been linked to early onset non-insulin dependent diabetesmellitus (MODY), underscoring the importance of the hepatic transcription factors for glucose homeostasis.In the previous grant cycle, we have employed tissue-specific gene ablation to demonstrate the essentialfunction of Foxa2 (previously known as HNF3(3) in the integration of the transcriptional response of thehepatocyte to fasting. In addition, Foxa2 has been proposed as a major mediator of insulin signaling inhepatocytes. We propose the following three Aims:
In Aim 1, which is the direct result of the interactions within the PO1 with Dr. Birnbaum, we will test thehypothesis that Foxa2 is the major mediator of insulin signaling via AKT2 using genetic means. We willderive mice which are deficient for both AKT2 and Foxa2 in hepatocytes to test if Foxa2 is indeed required toestablish the AKT2 mutant phenotype.
In Aim 2, we will collaborate with Dr. Ahima to investigate thecombined role of Foxa1 AND Foxa2 in hepatic metabolism.
This aim i s based on our discovery that Foxaland Foxa2 act jointly to enable the hepatogenic program during fetal devlopment. We hypothesize that thetwo genes also cooperate in transcription in the adult hepatocyte. We will use simulatenous conditional geneablatation for Foxa1 and Foxa2 combined with physiological and genomics approaches to test ourhypothesis that the two genes open chromatin to enable binding of hormone-dependent transcription factorslike CREB and GR.
In Aim 3, we will address a recent controversy concerning the regulation of hepaticgluconeogenesis by cAMP. Currently, two conflicting models exist regarding the regulation of thetranscription factor CREB in hepatocyte. The first proposes that PKA-dependent phosphorylation of CREB isrequired for recruitment of the co-activator CBP/p300 and subsequent activation of target genes, while thesecond invokes PKA-dependent translocation of the novel co-activator TORC2 from the cytoplasm to thenucleus as the central regulator of CREB-dependent transcription. We will address the relative importanceof both pathways in hepatic glucose homeostasis by genetic means. We will develop mouse modelscarrying a Ser/Ala mutation in the PKA-phosphorylation site of CREB or a hepatocyte-specific ablation ofTORC2, and analyze the consequences to glucose metabolism both in vivo and in isolated hepatocytes.Together, these studies will further our understanding of the transcriptional regulation of hepatic metabolismand in insulin action.
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