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LXR ligand lowers LDL cholesterol in primates, is lipid neutral in hamster, and reduces atherosclerosis in mouse.
- Source :
-
Journal of lipid research [J Lipid Res] 2009 Dec; Vol. 50 (12), pp. 2358-70. Date of Electronic Publication: 2009 Mar 24. - Publication Year :
- 2009
-
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.
- Subjects :
- Animals
Atherosclerosis metabolism
Caco-2 Cells
Cricetinae
Disease Models, Animal
Humans
Indazoles blood
Indazoles chemistry
Ligands
Liver enzymology
Liver metabolism
Liver X Receptors
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Orphan Nuclear Receptors metabolism
Atherosclerosis drug therapy
Cholesterol, LDL drug effects
Cholesterol, LDL metabolism
Indazoles pharmacology
Lipid Metabolism drug effects
Macaca fascicularis metabolism
Orphan Nuclear Receptors agonists
Subjects
Details
- Language :
- English
- ISSN :
- 1539-7262
- Volume :
- 50
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Journal of lipid research
- Publication Type :
- Academic Journal
- Accession number :
- 19318684
- Full Text :
- https://doi.org/10.1194/jlr.M900037-JLR200