title: Liver X receptor inhibits the synthesis and secretion of apolipoprotein A1 by human liver-derived cells.
abstract: The liver X receptor (LXR) agonist TO901317 inhibited the synthesis of apolipoprotein A1 (apo A1) by human liver-derived cells, including the formation of lipid-poor, prebeta-migrating high-density lipoprotein (HDL). Despite activation of the lipid transporter ABCA1 under these conditions, cellular efflux of PL and cholesterol from liver cells was also reduced. By assaying transcription from full-length and truncated promoters and by site-directed mutagenesis, the effect of LXR and its ligand was localized to a binding site for hepatic nuclear factor-4 (HNF4) in the proximal apo A1 promoter (-132/-119 bp). Chromatin immunoprecipitation analysis of apo A1 transcription complexes from control and ligand-activated cells showed an increase in the binding of reported apo A1 transcriptional inhibitor COUP-TF, which competes with HNF4 for DNA binding. It also identified LXR in the apo A1 transcription complex of TO901317-treated cells. Displacement of HNF4 from the -132/-119 bp promoter DNA sequence in the presence of TO901317 was confirmed by gel shift analysis. These data indicate that LXR can be a significant negative regulator of apo A1 transcription and HDL synthesis.
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, California 94143, USA.
authors.forename: J
authors.initials: J
authors.lastname: Huuskonen
authors.forename: M
authors.initials: M
authors.lastname: Vishnu
authors.forename: P
authors.initials: P
authors.lastname: Chau
authors.forename: P E
authors.initials: PE
authors.lastname: Fielding
authors.forename: C J
authors.initials: CJ
authors.lastname: Fielding
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D016632:Apolipoprotein A-I / Q000096:biosynthesis* / Q000235:genetics; D001693:Biological Transport, Active / Q000235:genetics; D051836:COUP Transcription Factors / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D006845:Hydrocarbons, Fluorinated; D008075:Lipoproteins, HDL / Q000096:biosynthesis; D008099:Liver / Q000166:cytology / Q000378:metabolism; D000071518:Liver X Receptors; D016297:Mutagenesis, Site-Directed; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D014158:Transcription, Genetic; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D051836:COUP Transcription Factors; D002784:Cholesterol; D004268:DNA-Binding Proteins; D051557:Hepatocyte Nuclear Factor 4; D006845:Hydrocarbons, Fluorinated; D008075:Lipoproteins, HDL; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; C577836:ABCA1 protein, human; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides