title: Activation of LDL receptor expression by small RNAs complementary to a noncoding transcript that overlaps the LDLR promoter.
abstract: Low-density lipoprotein receptor (LDLR) is a cell-surface receptor that plays a central role in regulating cholesterol levels. Increased levels of LDLR would lead to reduced cholesterol levels and contribute to strategies designed to treat hypercholesterolemia. We have previously shown that duplex RNAs complementary to transcription start sites can associate with noncoding transcripts and activate gene expression. Here we show that duplex RNAs complementary to the promoter of LDLR activate expression of LDLR and increase the display of LDLR on the surface of liver cells. Activation requires complementarity to the LDLR promoter and can be achieved by chemically modified duplex RNAs. Promoter-targeted duplex RNAs can overcome repression of LDLR expression by 25-hydroxycholesterol and do not interfere with activation of LDLR expression by lovastatin. These data demonstrate that small RNAs can activate LDLR expression and affect LDLR function.
authors.affiliation: Departments of Pharmacology and Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9041, USA.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Matsui
authors.forename: Fuminori
authors.initials: F
authors.lastname: Sakurai
authors.forename: Sayda
authors.initials: S
authors.lastname: Elbashir
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Foster
authors.forename: Muthiah
authors.initials: M
authors.lastname: Manoharan
authors.forename: David R
authors.initials: DR
authors.lastname: Corey
mesh_terms: D020137:Base Pair Mismatch; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology; D008148:Lovastatin / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012330:RNA, Double-Stranded / Q000378:metabolism*; D022661:RNA, Untranslated / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D006888:Hydroxycholesterols; D012330:RNA, Double-Stranded; D022661:RNA, Untranslated; D011973:Receptors, LDL; C007997:25-hydroxycholesterol; D002784:Cholesterol; D008148:Lovastatin