Dietary vitamin A and long chain fatty acids (LCFA) give rise to signaling molecules that control cellular processes by virtue of their ability to modulate the rates of transcription of multiple genes. These activities are mediated by ligand inducible transcription factors known as nuclear hormone receptors. The vitamin A metabolite retinoic acid (RA) governs transcription by activating the nuclear receptors RAR and RXR. The best characterized receptors to mediate the transcriptional activities of LCFA and their derivatives are tenned PPAR. In addition to nuclear receptors, both RA and LCFA associate in cells with members of the family of proteins known as intracellular lipid-binding proteins (iLBP). RA binds to cellular retinoic acid binding proteins (CRABP-I and CRABP-II), while LCFA associate with multiple forms of fatty acid binding proteins (FABP). The mechanisms of action of nuclear receptors have become increasingly clear in recent years. In contrast, while it is generally believed that iLBPs function in solubilization and trafficking of their ligands, the specific roles served by the different iLBP isotypes remain poorly understood. Our previous studies led to the identification of a specific function for CRABP-II. We demonstrated that CRABP-II (but not CRABIP-I) modulates the transcriptional activity of RA through direct interactions with RAR. We recently found further that some FABPs can modulate the transcriptional activities of PPARs, demonstrating that iLBPs other than CRABP-II also participate in the transcriptional activities of their ligands. The goal of this application is to examine the roles of iLBPs as transcriptional co-regulators. To this end we propose to delineate the mechanisms by which iLBPs modulate the ligand-dependent activities of nuclear receptors, and to clarify the functional consequences of the presence of iLBPs for the biological activities of nuclear receptors in cells. In studies outlined under 2 specific aims we propose to clarify the involvement of CRABP-II in the cellular activities of RAR, and to explore the roles of FABPs in regulating the transcriptional activities of PPARs.
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