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Cell-specific discrimination of desmosterol and desmosterol mimetics confers selective regulation of LXR and SREBP pathways in macrophages

ABSTRACT: Activation of liver X receptors (LXRs) with synthetic agonists promotes reverse cholesterol transport and protects against atherosclerosis in mouse models. Most synthetic LXR agonists also cause marked hypertriglyceridemia by inducing the expression of SREBP1c and downstream genes that drive fatty acid biosynthesis. Recent studies demonstrated that desmosterol, an intermediate in the cholesterol biosynthetic pathway that suppresses SREBP processing by binding to SCAP, also binds and activates LXRs and is the dominant LXR ligand in macrophage foam cells. Here, we explore the potential of increasing endogenous desmosterol production or mimicking its activity as a means of inducing LXR activity while simultaneously suppressing SREBP1c induced hypertriglyceridemia. Unexpectedly, while desmosterol strongly activated LXR target genes and suppressed SREBP pathways in mouse and human macrophages, it had almost no activity in mouse or human hepatocytes in vitro. We further demonstrate that sterol-based selective modulators of LXRs have biochemical and transcriptional properties predicted of desmosterol mimetics and selectively regulate LXR function in macrophages in vitro and in vivo. These studies thereby reveal cell-specific discrimination of endogenous and synthetic regulators of LXRs and SREBPs, providing a molecular basis for dissociation of LXR functions in macrophages from those in liver that lead to hypertriglyceridemia.

ORGANISM(S): Mus musculus

PROVIDER: GSE90815 | GEO | 2018/02/12

REPOSITORIES: GEO

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Project description:The objective of the study was to figure out the impact of LXR signaling on human macrophages. Primary human macrophages in an early differentiating and a mature differentiation state were treated with the LXR agonist T091317 for 4 and 24 h and transcriptome-wide expression analysis were performed. As LXRa is highly induced during macrophage differentiation and 68% of all LXRs targets change their expression during this process, we suggest that LXRs have essential functions in macrophage development. More than 238 genes are regulated in early as well as mature macrophages by activation of LXRs; most of them are up-regulated. LXRs administrate differentiation state specific as well as common macrophages functions related primarily to lipid homeostasis, immune response and cell fate. Interestingly, almost only genes related to lipid and cholesterol metabolism are overrepresented among early induced genes, whereas genes related to immune functions respond later, implying the existence of indirect mechanisms of control. Furthermore, in early differentiating macrophages cell proliferation and cell death associated genes are induced after 24 h of LXR activation, whereas in mature macrophages, showing high LXRa expression, the same functional cluster respond far earlier (4 h) after LXR ligand treatment. In conclusion, our data suggest that LXRs are modulators of macrophage differentiation, operating principally as positive transcriptional regulators of genes involved in lipid and cholesterol metabolism and by this indirectly influencing the immunophenotype of macrophages. CD14 positive cells of healthy donors were isolated by magnetic separation and differentiated in the presence of human serum to macrophages. At an early differentiating state (16 h after isolation) and at in mature differentiating state (day 11 after isolation) the cells were treated with the synthetical LXR agonist T091317 respective its solvent DMSO for 4 and 24 h. RNA was isolated and a whole genome microarray was performed.

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Cell-specific discrimination of desmosterol and desmosterol mimetics confers selective regulation of LXR and SREBP pathways in macrophages

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