It is currently believed that vitamin A, retinol, is biologically inert and that its myriad of biological functions areexerted by active metabolites: the visual chromophore 11-cis-retinaldehyde, and retinoic acids, which regulategene expression by activating specific nuclear hormone receptors. Surprisingly, our preliminary data suggestthat retinol is a transcriptional regulator in its own right. Retinol circulates in blood bound to serum retinol-binding protein (RBP) but it must dissociate from the protein prior to entering target cells. It was recentlyshown that an integral plasma membrane protein termed STRA6 binds RBP and mediates the uptake ofretinol into cells. Our preliminary results demonstrate however that, in addition to its function as a vitamin Atransporter, STRA6 is a ligand-activated cell surface receptor which activates a JAK/STAT pathway inresponse to binding retinol-RBP. Specifically, the data indicate that, association of STRA6 with retinol-boundRBP results in phosphorylation and activation of STATs, which, in turn, induce the transcription of specificSTAT target genes. Studies proposed here will address the hypothesis that retinol can regulate genetranscription by activating a signalling pathway mediated by an RBP/STRA6/STAT pathway. We furtherpropose to elucidate its involvement of this pathway in regulation of lipid homeostasis and insulin responsesand in control of cell growth and survival. The results of these studies may point at novel targets fortherapeutic approaches in treatment of diabetes and cancer.
Insulin resistance and diabetes are global public health problems of epidemic proportions and there is anurgent need for elucidating the molecular basis of these diseases and for identifying novel therapeutic targets.Vitamin A (retinol) is present in blood bound to a protein termed retinol binding protein (RBP) and is taken upfrom this protein into target cells by a transporter called STRA6. It was recently suggested that RBP is acausative factor in the induction of insulin resistance but it is unknown how the protein may exert such aneffect. A mechanism through which RBP inhibits insulin action is suggested by our preliminary observations.These data show that binding of vitamin A-bound RBP to STRA6 results in activation of a signalling cascadethat culminates in upregulation of the expression of genes that inhibit insulin signalling. The findings thusindicate that vitamin A possesses a previously unsuspected function in regulation of gene expression.Proposed studies will examine the involvement of the novel activity of vitamin A in regulation lipid metabolismand insulin sensitivity as well as in control of cell growth and survival. The results of these studies may pointat novel targets for therapeutic approaches in treatment of diabetes and cancer.
