Abstract
BackgroundLXRs (Liver X Receptor α and β) are nuclear receptors that act as ligand-activated transcription factors. LXR activation causes upregulation of genes involved in reverse cholesterol transport (RCT), including ABCA1 and ABCG1 transporters, in macrophage and intestine. Anti-atherosclerotic effects of synthetic LXR agonists in murine models suggest clinical utility for such compounds.ObjectiveBlood markers of LXR agonist exposure/activity were sought to support clinical development of novel synthetic LXR modulators.MethodsTranscript levels of LXR target genes ABCA1 and ABCG1 were measured using quantitative reverse transcriptase/polymerase chain reaction assays (qRT-PCR) in peripheral blood from mice and rats (following a single oral dose) and monkeys (following 7 daily oral doses) of synthetic LXR agonists. LXRα, LXRβ, ABCA1, and ABCG1 mRNA were measured by qRT-PCR in human peripheral blood mononuclear cells (PBMC), monocytes, T- and B-cells treated ex vivo with WAY-252623 (LXR-623), and protein levels in human PBMC were measured by Western blotting. ABCA1/G1 transcript levels in whole-blood RNA were measured using analytically validated assays in human subjects participating in a Phase 1 SAD (Single Ascending Dose) clinical study of LXR-623.ResultsA single oral dose of LXR agonists induced ABCA1 and ABCG1 transcription in rodent peripheral blood in a dose- and time-dependent manner. Induction of gene expression in rat peripheral blood correlated with spleen expression, suggesting LXR gene regulation in blood has the potential to function as a marker of tissue gene regulation. Transcriptional response to LXR agonist was confirmed in primates, where peripheral blood ABCA1 and ABCG1 levels increased in a dose-dependent manner following oral treatment with LXR-623. Human PBMC, monocytes, T- and B cells all expressed both LXRα and LXRβ, and all cell types significantly increased ABCA1 and ABCG1 expression upon ex vivo LXR-623 treatment. Peripheral blood from a representative human subject receiving a single oral dose of LXR-623 showed significant time-dependent increases in ABCA1 and ABCG1 transcription.ConclusionPeripheral blood cells express LXRα and LXRβ, and respond to LXR agonist treatment by time- and dose-dependently inducing LXR target genes. Transcript levels of LXR target genes in peripheral blood are relevant and useful biological indicators for clinical development of synthetic LXR modulators.
Highlights
LXRs (Liver X Receptor α and β) are nuclear receptors that act as ligand-activated transcription factors
LXRs are expressed in peripheral blood mononuclear cells Expression of LXRα and β in tissue macrophage and differentiated THP-1 cells has been well established [8,15,34,35,36], but scant evidence exists for expression of LXRs in circulating peripheral blood cells
LXR agonists induce gene expression in rodent peripheral blood cells in vivo To determine whether the presence of LXRα and LXRβ in peripheral blood cells would result in regulation of gene expression, a single oral dose of LXR-623 was adminis
Summary
LXRs (Liver X Receptor α and β) are nuclear receptors that act as ligand-activated transcription factors. LXR activation results in the induction of several genes Among these induced genes are those encoding the ATP-binding cassette proteins, such as ABCA1 and ABCG1, which are plasma membraneassociated transport proteins that are responsible for mediating cholesterol efflux as the initial step of the "reverse cholesterol transport" (RCT) process thereby controlling cholesterol mobilization from lipid-laden macrophages [16,17]. This "effluxed" cholesterol is subsequently transferred to plasma acceptor proteins such as high-density lipoprotein (HDL), which delivers excess cholesterol to the liver [17] for eventual excretion. LXRs are expressed in the intestine where they limit dietary cholesterol uptake by regulating the expression of ABC family members ABCA1 and ABCG5/ABCG8 that reside on the apical surface of enterocytes and act as efflux pumps moving cholesterol out of absorptive cells into the intestinal lumen [18]
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