title: Inhibition of miR-29 has a significant lipid-lowering benefit through suppression of lipogenic programs in liver.
abstract: MicroRNAs (miRNAs) are important regulators and potential therapeutic targets of metabolic disease. In this study we show by in vivo administration of locked nucleic acid (LNA) inhibitors that suppression of endogenous miR-29 lowers plasma cholesterol levels by ~40%, commensurate with the effect of statins, and reduces fatty acid content in the liver by ~20%. Whole transcriptome sequencing of the liver reveals 883 genes dysregulated (612 down, 271 up) by inhibition of miR-29. The set of 612 down-regulated genes are most significantly over-represented in lipid synthesis pathways. Among the up-regulated genes are the anti-lipogenic deacetylase sirtuin 1 (Sirt1) and the anti-lipogenic transcription factor aryl hydrocarbon receptor (Ahr), the latter of which we demonstrate is a direct target of miR-29. In vitro radiolabeled acetate incorporation assays confirm that pharmacologic inhibition of miR-29 significantly reduces de novo cholesterol and fatty acid synthesis. Our findings indicate that miR-29 controls hepatic lipogenic programs, likely in part through regulation of Ahr and Sirt1, and therefore may represent a candidate therapeutic target for metabolic disorders such as dyslipidemia.
authors.affiliation: Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: C Lisa
authors.initials: CL
authors.lastname: Kurtz
authors.affiliation: Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Emily E
authors.initials: EE
authors.lastname: Fannin
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University, Nashville, TN, USA.
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Toth
authors.affiliation: Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Pearson
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University, Nashville, TN, USA.
authors.forename: Kasey C
authors.initials: KC
authors.lastname: Vickers
authors.affiliation: 1] Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA [2] Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, NC, USA.
authors.forename: Praveen
authors.initials: P
authors.lastname: Sethupathy
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000097:blood; D050171:Dyslipidemias / Q000188:drug therapy / Q000378:metabolism; D005260:Female; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D018336:Receptors, Aryl Hydrocarbon / Q000096:biosynthesis*; D056564:Sirtuin 1 / Q000096:biosynthesis*
chemical_list: C547014:MIRN29 microRNA, mouse; D035683:MicroRNAs; D018336:Receptors, Aryl Hydrocarbon; D002784:Cholesterol; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1