出版社：American Society for Biochemistry and Molecular Biology
摘要：Hypercholesterolemia is a major risk factor for coronary arterydisease. Oxysterols are known to inhibit cholesterol biosynthesisand have been explored as potential antihypercholesterolemicagents. The ability of 3ß-hydroxy-5-cholest-8(14)-en-15-one(15-ketosterol) to lower non-HDL cholesterol has been demonstratedin rodent and primate models, but the mechanisms of action remainpoorly understood. Here we show in a coactivator recruitmentassay and cotransfection assays that the 15-ketosterol is apartial agonist for liver X receptor- and -ß (LXRand LXRß). The binding affinity for the LXRs was comparableto those of native oxysterols. In a macrophage cell line ofhuman origin, the 15-ketosterol elevated ATP binding cassettetransporter ABCA1 mRNA in a concentration-dependent fashionwith a potency similar to those of other oxysterols. We furtherfound that in human embryonic kidney HEK 293 cells, the 15-ketosterolsuppressed sterol-responsive element binding protein processingactivity and thus inhibited mRNA expression of 3-hydroxy-3-methylglutaryl-coenzymeA reductase, LDL receptor, and PCSK9. Our data thus providea molecular basis for the hypocholesterolemic activity of the15-ketosterol and further suggest its potential antiatheroscleroticbenefit as an LXR agonist.Supplementary key words hypercholesterolemia • statin • scintillation proximity assay
Abbreviations: LDLR, LDL receptor; LXR, liver X receptor; SPA, scintillation proximity assay; SREBP, sterol-responsive element binding protein
-cholest-8(14)-en-15-one (15-ketosterol) to lower non-HDL cholesterol has been demonstrated in rodent and primate models, but the mechanisms of action remain poorly understood. Here we show in a coactivator recruitment assay and cotransfection assays that the 15-ketosterol is a partial agonist for liver X receptor-
