title: Selective up-regulation of LXR-regulated genes ABCA1, ABCG1, and APOE in macrophages through increased endogenous synthesis of 24(S),25-epoxycholesterol.
abstract: Liver X receptor (LXR) activation represents a mechanism to prevent macrophage foam cell formation. Previously, we demonstrated that partial inhibition of oxidosqualene:lanosterol cyclase (OSC) stimulated synthesis of the LXR agonist 24(S),25-epoxycholesterol (24(S),25-epoxy) and enhanced ABCA1-mediated cholesterol efflux. In contrast to a synthetic, nonsteroidal LXR activator, TO-901317, triglyceride accumulation was not observed. In the present study, we determined whether endogenous 24(S),25-epoxy synthesis selectively enhanced expression of macrophage LXR-regulated cholesterol efflux genes but not genes that regulate fatty acid metabolism. THP-1 human macrophages incubated with the OSC inhibitor (OSCi) RO0714565 (15 nM) significantly reduced cholesterol synthesis and maximized synthesis of 24(S),25-epoxy. Endogenous 24(S),25-epoxy increased ABCA1, ABCG1, and APOE mRNA abundance and consequently increased cholesterol efflux to apoAI. In contrast, OSCi had no effect on LXR-regulated genes LPL (lipoprotein lipase) and FAS (fatty acid synthase). TO-901317 (>or=10 nM) significantly enhanced expression of all genes examined. OSCi and TO-901317 increased the mRNA and precursor form of SREBP-1c, a major regulator of fatty acid and triglyceride synthesis. However, conversion of the precursor to the active form (nSREBP-1c) was blocked by OSCi-induced 24(S),25-epoxy but not by TO-901317 (>or=10 nm), which instead markedly increased nSREBP-1c. Disruption of nSREBP-1c formation by 24(S),25-epoxy accounted for diminished FAS and LPL expression. In summary, endogenous synthesis of 24(S),25-epoxy selectively up-regulates expression of macrophage LXR-regulated cholesterol efflux genes without stimulating genes linked to fatty acid and triglyceride synthesis.
authors.affiliation: Robarts Research Institute Vascular Biology Group, Department of Biochemistry, University of Western, London, Ontario, Canada.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Beyea
authors.forename: Claire L
authors.initials: CL
authors.lastname: Heslop
authors.forename: Cynthia G
authors.initials: CG
authors.lastname: Sawyez
authors.forename: Jane Y
authors.initials: JY
authors.lastname: Edwards
authors.forename: Janet G
authors.initials: JG
authors.lastname: Markle
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hegele
authors.forename: Murray W
authors.initials: MW
authors.lastname: Huff
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics; D001057:Apolipoproteins E / Q000096:biosynthesis* / Q000235:genetics; D002460:Cell Line; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005227:Fatty Acids / Q000096:biosynthesis; D005487:Foam Cells / Q000378:metabolism*; D006801:Humans; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008071:Lipoprotein Lipase / Q000378:metabolism; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D014280:Triglycerides / Q000096:biosynthesis; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; C028358:24,25-epoxycholesterol; D002784:Cholesterol; D008071:Lipoprotein Lipase; D019751:Intramolecular Transferases; C021924:lanosterol synthase