MicroRNA‐379 couples glucocorticoid hormones to dysfunctional lipid homeostasis. (15th December 2014)

• Record Type: Journal Article
• Authors: de Guia, Roldan M; Rose, Adam J; Sommerfeld, Anke; Seibert, Oksana; Strzoda, Daniela; Zota, Annika; Feuchter, Yvonne; Krones‐Herzig, Anja; Sijmonsma, Tjeerd; Kirilov, Milen; Sticht, Carsten; Gretz, Norbert; Dallinga‐Thie, Geesje; Diederichs, Sven; Klöting, Nora; Blüher, Matthias; Berriel Diaz, Mauricio; Herzig, Stephan
• Is Part Of: EMBO journal. Volume 34:Number 3(2015)
• Page Start: 344
• Page End: 360
• Publication Date: 2014-12-15
• Subjects: glucocorticoid signalling -- LDLR -- LSR -- miRNA‐379 -- VLDL triglyceride; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.201490464
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract : The discovery of miR‐379 as a direct glucocorticoid receptor target in the liver integrates miRNAs in the physiological control of 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. Synopsis: The discovery of miR‐379 as a direct glucocorticoid receptor target in the liver integrates miRNAs in the physiological control of lipid homeostasis. The conserved microRNA (miR)‐379/410 genomic cluster is a direct GR target. Silencing of miR‐379 ameliorates obesity‐related hypertriglyceridemia. miR‐379 acts through LSR‐ and LDLR‐mediated hepatic lipid uptake. miR‐379 levels correlate with serum cortisol and triglycerides in human obese patients.