title: microRNA-379 couples glucocorticoid hormones to dysfunctional lipid homeostasis.
abstract: In mammals, glucocorticoids (GCs) and their intracellular receptor, the glucocorticoid receptor (GR), represent critical checkpoints in the endocrine control of energy homeostasis. Indeed, aberrant GC action is linked to severe metabolic stress conditions as seen in Cushing's syndrome, GC therapy and certain components of the Metabolic Syndrome, including obesity and insulin resistance. Here, we identify the hepatic induction of the mammalian conserved microRNA (miR)-379/410 genomic cluster as a key component of GC/GR-driven metabolic dysfunction. Particularly, miR-379 was up-regulated in mouse models of hyperglucocorticoidemia and obesity as well as human liver in a GC/GR-dependent manner. Hepatocyte-specific silencing of miR-379 substantially reduced circulating very-low-density lipoprotein (VLDL)-associated triglyceride (TG) levels in healthy mice and normalized aberrant lipid profiles in metabolically challenged animals, mediated through miR-379 effects on key receptors in hepatic TG re-uptake. As hepatic miR-379 levels were also correlated with GC and TG levels in human obese patients, the identification of a GC/GR-controlled miRNA cluster not only defines a novel layer of hormone-dependent metabolic control but also paves the way to alternative miRNA-based therapeutic approaches in metabolic dysfunction.
authors.affiliation: Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance and Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany.
authors.forename: Roldan M
authors.initials: RM
authors.lastname: de Guia
authors.affiliation: Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance and Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Rose
authors.affiliation: Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance and Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Sommerfeld
authors.affiliation: Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance and Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany.
authors.forename: Oksana
authors.initials: O
authors.lastname: Seibert
authors.affiliation: Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance and Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Strzoda
authors.affiliation: Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance and Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Zota
authors.affiliation: Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance and Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Feuchter
authors.affiliation: Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance and Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Krones-Herzig
authors.affiliation: Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance and Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany.
authors.forename: Tjeerd
authors.initials: T
authors.lastname: Sijmonsma
authors.affiliation: Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance and Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany.
authors.forename: Milen
authors.initials: M
authors.lastname: Kirilov
authors.affiliation: Medical Research Center, Klinikum Mannheim, Mannheim, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Sticht
authors.affiliation: Medical Research Center, Klinikum Mannheim, Mannheim, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Gretz
authors.affiliation: Department of Vascular Medicine, AMC Amsterdam, Amsterdam, The Netherlands.
authors.forename: Geesje
authors.initials: G
authors.lastname: Dallinga-Thie
authors.affiliation: Helmholtz-University-Group Molecular RNA Biology and Cancer DKFZ, Heidelberg, Germany Institute of Pathology Heidelberg University, Heidelberg, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Diederichs
authors.affiliation: Department of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Nora
authors.initials: N
authors.lastname: Klöting
authors.affiliation: Department of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Blüher
authors.affiliation: Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance and Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Berriel Diaz
authors.affiliation: Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance and Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany s.herzig@dkfz.de.
authors.forename: Stephan
authors.initials: S
authors.lastname: Herzig
mesh_terms: D000818:Animals; D002460:Cell Line; D005260:Female; D020868:Gene Silencing; D005938:Glucocorticoids / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism; D008079:Lipoproteins, VLDL / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008820:Mice, Obese; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000235:genetics / Q000378:metabolism
chemical_list: D005938:Glucocorticoids; D008079:Lipoproteins, VLDL; C561022:MIRN379 microRNA, human; D035683:MicroRNAs; D014280:Triglycerides
keywords: LDLR; LSR; VLDL triglyceride; glucocorticoid signalling; miRNA‐379