Molecular regulation of glucose metabolism by orphan nuclear receptors

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The objective of this research program is to identify novel mechanisms by which orphan nuclear receptors control the activation and repression of genes involved in glucose metabolism. Activation of the liver X receptor alpha (LXRa) inhibits the expression of key genes involved in glucose metabolism including the rate-limiting enzyme in glucose synthesis, phosphoenolpyruvate carboxykinase (PEPCK). Preliminary data from this lab have also demonstrated that the liver X receptor beta (LXRb) is required for the glucocorticoid (GC)-mediated upregulation of PEPCK, suggesting that an important and currently unrecognized molecular interplay is occurring between the nuclear receptors glucocorticoid receptor and the LXRs. The first objective will be to determine the molecular mechanism of LXRa-mediated transrepression of genes involved in glucose metabolism. The second objective will be to identify novel mechanisms of interaction between GC and the orphan nuclear receptor LXRb in the control of glucose metabolism. Using sophisticated technology for genomic and proteomic analysis, we will determine whether direct regulation of GC-responsive genes is occurring with LXRs or whether the effect is secondary to altered regulation of another intermediate protein. We will determine whether or not these nuclear receptors are associated with these active promoters and where they are located in the promoter context. This research program has the important function of identifying completely novel molecular mechanisms for GC signaling and glucose regulation with a high probability for uncovering how members of this receptor superfamily converge at the molecular level on metabolic signaling pathways. The benefit to Canada will come not only in the form of an enhanced research environment for trainees and increased visibility in the quality of research in Canada but also in the discovery of new molecular components regulating the critically important process of glucose metabolism.