Intracellular lipid-binding protein genes of zebrafish

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One of the major mechanisms thought to facilitate the increasing complexity of organisms in the evolution of life is duplication of genes and entire genomes. We are investigating the regulation and evolution of duplicated genes belonging to the multigene family coding for the intracellular lipid-binding proteins (iLBP) of zebrafish. This family includes the fatty acid-, retinol-, and retinoic acid-binding proteins. iLBP proteins have been implicated in a myriad of cellular processes from uptake and intracellular transport of long-chain fatty acids, bile salts and retinoids, to modulating gene expression, neurogenesis, and human disease. We chose zebrafish for these studies as it is hardy, disease resistant, easily and inexpensively reared, and useful in the application of both experimental embryology and genetic analysis. Moreover, zebrafish is a model system to study vertebrate development in which stages of embryogenesis are well characterized. To date, we have characterized 20 members of the zebrafish iLBP multigene family. Many zebrafish iLBP genes are duplicated owing to a whole genome duplication event that occurred in the ray-finned fish lineage ~230-400 million years ago. We have shown that transcription of several zebrafish duplicated iLBP genes is differentially induced by dietary fatty acids, i.e., only one duplicated gene is induced by fatty acids, and not the sister duplicate, suggesting evolutionary divergence of the regulatory elements in these genes. In this research progamme, we plan to identify the cis-acting regulatory elements in the zebrafish iLBP gene-promoters. Furthermore, we will determine which nuclear transcription factors and their activating ligands (e.g., fatty acids, retinoids, and clofibrate, a drug known to induce many mammalian genes involved in lipid metabolism) bind these cis-elements to induce specific iLBP genes, and how these cis- and trans-acting factors evolved. In addition, since many of the genes that control normal embryogenesis, growth and reproduction in zebrafish are similar, or the same, in mammals, zebrafish may serve as a model system to provide insights into the roles of the iLBP genes implicated in human development and diseases, such as diabetes, atherosclerosis and obesity.