Abstract
Liver X receptors (LXRs) are ligand-activated transcription factors that coordinate regulation of gene expression involved in several cellular functions but most notably cholesterol homeostasis encompassing cholesterol transport, catabolism, and absorption. WAY-252623 (LXR-623) is a highly selective and orally bioavailable synthetic modulator of LXR, which demonstrated efficacy for reducing lesion progression in the murine LDLR(-/-) atherosclerosis model with no associated increase in hepatic lipogenesis either in this model or Syrian hamsters. In nonhuman primates with normal lipid levels, WAY-252623 significantly reduced total (50-55%) and LDL-cholesterol (LDLc) (70-77%) in a time- and dose-dependent manner as well as increased expression of the target genes ABCA1/G1 in peripheral blood cells. Statistically significant decreases in LDLc were noted as early as day 7, reached a maximum by day 28, and exceeded reductions observed for simvastatin alone (20 mg/kg). Transient increases in circulating triglycerides and liver enzymes reverted to baseline levels over the course of the study. Complementary microarray analysis of duodenum and liver gene expression revealed differential activation of LXR target genes and suggested no direct activation of hepatic lipogenesis. WAY-252623 displays a unique and favorable pharmacological profile suggesting synthetic LXR ligands with these characteristics may be suitable for evaluation in patients with atherosclerotic dyslipidemia.
Highlights
Liver X receptors (LXRs) are ligand-activated transcription factors that coordinate regulation of gene expression involved in several cellular functions but most notably cholesterol homeostasis encompassing cholesterol transport, catabolism, and absorption
WAY-252623 is less potent for inducing SREBP1c and associated triglyceride accumulation in liver cells when compared with more potent dual agonist ligands such as T0901317 or WAY-254011 [19]
WAY-252623 exhibits selective properties when analyzed using coactivator recruitment analysis, which models coactivator/co-repressor exchange associated with LXR response element (LXRE)-bound LXR-RXR heterodimers induced upon ligand binding (Fig. 1)
Summary
Liver X receptors (LXRs) are ligand-activated transcription factors that coordinate regulation of gene expression involved in several cellular functions but most notably cholesterol homeostasis encompassing cholesterol transport, catabolism, and absorption. In nonhuman primates with normal lipid levels, WAY-252623 significantly reduced total (50–55%) and LDL-cholesterol (LDLc) (70–77%) in a time- and dose-dependent manner as well as increased expression of the target genes ABCA1/G1 in peripheral blood cells. As statins primarily limit disease progression through the inhibition of endogenous cholesterol synthesis, newer treatment modalities directed at reversing established atherosclerotic plaque are likely to provide additional benefit and can have important clinical implications for disease management. This is exemplified by the exploratory clinical studies targeting the enhancement of high-density lipoprotein [2]. This article is available online at http://www.jlr.org infusion of apolipoprotein (apo)A-1 milano facilitated coronary atherosclerosis lesion regression as measured by intravascular ultrasound in individuals with acute coronary syndrome suggesting that enhanced cholesterol efflux via the ABCA1 pathway may be a viable mechanistic strategy to provide incremental pharmaceutical benefit
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