title: Elk1 and SRF transcription factors convey basal transcription and mediate glucose response via their binding sites in the human LXRB gene promoter.
abstract: The nuclear receptors LXRalpha (NR1H3) and LXRbeta (NR1H2) are attractive drug targets for the treatment of diabetes and cardiovascular disease due to their established role as regulators of cholesterol and lipid metabolism. A large body of literature has recently indicated their important roles in glucose metabolism and particularly LXRbeta is important for proper insulin production in pancreas. In this study, we report that glucose induces transcription via the LXRB gene promoter. The transcription start site of the human LXRB gene was determined and we identified two highly conserved, and functional, ETS and Elk1 binding sites, respectively, in the LXRB gene promoter. The Elk1 binding site also bound the serum responsive factor (SRF). Mutation of these sites abolished binding. Furthermore, mutation of the binding sites or siRNA knockdown of SRF and Elk1 significantly reduced the promoter activity and impaired the glucose response. Our results indicate that the human LXRB gene is controlled by glucose, thereby providing a novel mechanism by which glucose regulates cellular functions via LXRbeta.
authors.affiliation: Department of Biosciences and Nutrition at Novum, Karolinska Institutet, S-14157 Huddinge, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Nilsson
authors.forename: Karin
authors.initials: K
authors.lastname: Dahlman-Wright
authors.forename: Charlotta
authors.initials: C
authors.lastname: Karelmo
authors.forename: Martin
authors.initials: M
authors.lastname: Ebeling
authors.forename: Jan-Ake
authors.initials: JA
authors.lastname: Gustafsson
authors.forename: Knut R
authors.initials: KR
authors.lastname: Steffensen
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D017124:Conserved Sequence; D004268:DNA-Binding Proteins / Q000235:genetics*; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D000071518:Liver X Receptors; D051379:Mice; D008969:Molecular Sequence Data; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D026362:Serum Response Factor / Q000378:metabolism*; D024363:Transcription Initiation Site; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; C000605210:NR1H2 protein, human; C000605213:NR1H3 protein, human; C000605211:Nr1h2 protein, mouse; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D026362:Serum Response Factor; D050807:ets-Domain Protein Elk-1; D005947:Glucose