title: A potent synthetic LXR agonist is more effective than cholesterol loading at inducing ABCA1 mRNA and stimulating cholesterol efflux.
abstract: The LXR nuclear receptors are intracellular sensors of cholesterol excess and are activated by various oxysterols. LXRs have been shown to regulate multiple genes of lipid metabolism, including ABCA1 (formerly known as ABC1). ABCA1 is a lipid pump that effluxes cholesterol and phospholipid out of cells. ABCA1 deficiency causes extremely low high density lipoprotein (HDL) levels, demonstrating the importance of ABCA1 in the formation of HDL. The present work shows that the acetyl-podocarpic dimer (APD) is a potent, selective agonist for both LXRalpha (NR1H3) and LXRbeta (NR1H2). In transient transactivation assays, APD was approximately 1000-fold more potent, and yielded approximately 6-fold greater maximal stimulation, than the widely used LXR agonist 22-(R)-hydroxycholesterol. APD induced ABCA1 mRNA levels, and increased efflux of both cholesterol and phospholipid, from multiple cell types. Gas chromatography-mass spectrometry measurements demonstrated that APD stimulated efflux of endogenous cholesterol, eliminating any possible artifacts of cholesterol labeling. For both mRNA induction and stimulation of cholesterol efflux, APD was found to be more effective than was cholesterol loading. Taken together, these data show that APD is a more effective LXR agonist than endogenous oxysterols. LXR agonists may therefore be useful for the prevention and treatment of atherosclerosis, especially in the context of low HDL levels.
authors.affiliation: Merck Research Laboratories, Rahway, New Jersey 07065, USA. Carl_Sparrow@Merck.com
authors.forename: Carl P
authors.initials: CP
authors.lastname: Sparrow
authors.forename: Joanne
authors.initials: J
authors.lastname: Baffic
authors.forename: My-Hanh
authors.initials: MH
authors.lastname: Lam
authors.forename: Erik G
authors.initials: EG
authors.lastname: Lund
authors.forename: Alan D
authors.initials: AD
authors.lastname: Adams
authors.forename: Xuan
authors.initials: X
authors.lastname: Fu
authors.forename: Nancy
authors.initials: N
authors.lastname: Hayes
authors.forename: A Brian
authors.initials: AB
authors.lastname: Jones
authors.forename: Karen L
authors.initials: KL
authors.lastname: Macnaul
authors.forename: John
authors.initials: J
authors.lastname: Ondeyka
authors.forename: Sheo
authors.initials: S
authors.lastname: Singh
authors.forename: Jianhua
authors.initials: J
authors.lastname: Wang
authors.forename: Gaochao
authors.initials: G
authors.lastname: Zhou
authors.forename: David E
authors.initials: DE
authors.lastname: Moller
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Wright
authors.forename: John G
authors.initials: JG
authors.lastname: Menke
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D045784:Abietanes; D001692:Biological Transport; D002460:Cell Line; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism* / Q000494:pharmacology*; D004268:DNA-Binding Proteins; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008024:Ligands; D008075:Lipoproteins, HDL / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism; D008956:Models, Chemical; D057093:Orphan Nuclear Receptors; D010616:Phenanthrenes / Q000737:chemistry* / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D045784:Abietanes; D004268:DNA-Binding Proteins; D008024:Ligands; D008075:Lipoproteins, HDL; D000071518:Liver X Receptors; C000605210:NR1H2 protein, human; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D010616:Phenanthrenes; D010743:Phospholipids; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; C452852:acetylpodocarpic dimer; D002784:Cholesterol