Transcriptional co-regulators and macrophage gene expression

University Of California, San Diego, La Jolla CA

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Abstract

Liver X receptors (LXRs) a and b are members of the steroid and thyroid hormone receptor superfamily of ligand- dependent transcription factors that regulate lipid metabolism and inflammation in macrophages and other cell types. Synthetic ligands that activate LXRs have been shown to have protective effects in mouse models of cardiovascular, metabolic and neurodegenerative diseases. However, nearly all synthetic LXR agonists developed to date cause unacceptable levels of steatosis and hypertriglyceridemia due to on target induction of the Srebp1c gene in hepatocytes, preventing their clinical application. Studies in our laboratory identified desmosterol as the dominant endogenous LXR agonist in mouse macrophage foam cells and in human atherosclerotic lesions and provided evidence that hepatocyte derived desmosterol regulates Kupffer cell LXR activity in response to a steatosis-inducing diet. Our evaluation of desmosterol and synthetic desmosterol mimetics indicate that they can activate LXR target genes in macrophages without inducing Srebp1c expression in hepatocytes. The mechanistic basis for these effects is unknown, but these observations have significant implications for the understanding of cell specific regulation of LXR target genes in homeostasis and disease and suggest a path towards the development of physiologically inspired agonists for therapeutic applications. A major knowledge gap limiting understanding of LXR biology is that nearly all systematic in vivo studies of LXRs and LXR ligands have been performed in a single strain of mice; C57Bl/6. Our preliminary data reveals substantial differences in responses of different inbred strains of mice to a prototypic synthetic LXR agonist, supporting the hypothesis that a deep evaluation of the impact of natural genetic variation on LXR function in macrophages and hepatocytes will yield significant insights into mechanisms by which LXRs regulate lipid metabolism and inflammation in these two cell types. Studies proposed in Specific Aim 1 will directly evaluate this hypothesis. In addition, the transcriptomic and epigenetic data obtained in this aim will enable derivation of cell specific transcriptional networks mediating LXR-dependent gene expression in each cell type. Studies proposed in Specific Aim 2 will test the hypothesis that natural LXR agonists and synthetic analogues drive cell- and gene-specific responses in hepatocytes and macrophages at a genome wide level. Parallel studies in human and mouse macrophages and hepatocytes will establish similarities and differences across species. Studies proposed in Specific Aim 3 will investigate roles of transcriptional co-regulators in mediating these effects. Collectively, these studies will qualitatively advance understanding of mechanisms by which LXRs regulate gene expression that are likely to be relevant for understanding signal-dependent gene regulation in general and may also provide insights for development of LXR agonists that retain therapeutic efficacy in cardiovascular, metabolic and neurodegenerative diseases without unacceptable side effects.