title: USF1 and dyslipidemias: converging evidence for a functional intronic variant.
abstract: Upstream transcription factor 1 (USF1), the first gene associated with familial combined hyperlipidemia (FCHL), regulates numerous genes of glucose and lipid metabolism. Phenotypic overlap between FCHL, type 2 diabetes and the metabolic syndrome makes this gene an intriguing candidate in the disease process of these traits as well. As no disease-associated mutations in the coding region of USF1 have been identified, we addressed the functional role of intronic single nucleotide polymorphisms (SNPs) which define the FCHL-risk alleles of USF1, and identified that a 20 bp DNA sequence, containing the critical intronic SNP, binds nuclear protein(s), representing a likely transcriptional regulatory element. This functional role is further supported by the differential expression of USF1-regulated genes in fat biopsy between individuals carrying different allelic variants of USF1. Importantly, apolipoprotein E (APOE) is the most downregulated gene in the risk individuals, linking the potential risk alleles of USF1 with the impaired APOE-dependent catabolism of atherogenic lipoprotein particles.
authors.affiliation: Department of Molecular Medicine, National Public Health Institute, Finland.
authors.forename: Jussi
authors.initials: J
authors.lastname: Naukkarinen
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Gentile
authors.forename: Aino
authors.initials: A
authors.lastname: Soro-Paavonen
authors.forename: Janna
authors.initials: J
authors.lastname: Saarela
authors.forename: Heikki A
authors.initials: HA
authors.lastname: Koistinen
authors.forename: Päivi
authors.initials: P
authors.lastname: Pajukanta
authors.forename: Marja-Riitta
authors.initials: MR
authors.lastname: Taskinen
authors.forename: Leena
authors.initials: L
authors.lastname: Peltonen
mesh_terms: D000818:Animals; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000235:genetics*; D005786:Gene Expression Regulation; D014644:Genetic Variation; D006949:Hyperlipidemias / Q000235:genetics*; D007438:Introns / Q000235:genetics*; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D014157:Transcription Factors / Q000235:genetics*; D051720:Upstream Stimulatory Factors
chemical_list: D004268:DNA-Binding Proteins; D014157:Transcription Factors; D051720:Upstream Stimulatory Factors