title: miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling.
abstract: Cellular imbalances of cholesterol and fatty acid metabolism result in pathological processes, including atherosclerosis and metabolic syndrome. Recent work from our group and others has shown that the intronic microRNAs hsa-miR-33a and hsa-miR-33b are located within the sterol regulatory element-binding protein-2 and -1 genes, respectively, and regulate cholesterol homeostasis in concert with their host genes. Here, we show that miR-33a and -b also regulate genes involved in fatty acid metabolism and insulin signaling. miR-33a and -b target key enzymes involved in the regulation of fatty acid oxidation, including carnitine O-octaniltransferase, carnitine palmitoyltransferase 1A, hydroxyacyl-CoA-dehydrogenase, Sirtuin 6 (SIRT6), and AMP kinase subunit-α. Moreover, miR-33a and -b also target the insulin receptor substrate 2, an essential component of the insulin-signaling pathway in the liver. Overexpression of miR-33a and -b reduces both fatty acid oxidation and insulin signaling in hepatic cell lines, whereas inhibition of endogenous miR-33a and -b increases these two metabolic pathways. Together, these data establish that miR-33a and -b regulate pathways controlling three of the risk factors of metabolic syndrome, namely levels of HDL, triglycerides, and insulin signaling, and suggest that inhibitors of miR-33a and -b may be useful in the treatment of this growing health concern.
authors.affiliation: Department of Medicine and Cell Biology, Leon H Charney Division of Cardiology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Alberto
authors.initials: A
authors.lastname: Dávalos
authors.forename: Leigh
authors.initials: L
authors.lastname: Goedeke
authors.forename: Peter
authors.initials: P
authors.lastname: Smibert
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Ramírez
authors.forename: Nikhil P
authors.initials: NP
authors.lastname: Warrier
authors.forename: Ursula
authors.initials: U
authors.lastname: Andreo
authors.forename: Daniel
authors.initials: D
authors.lastname: Cirera-Salinas
authors.forename: Katey
authors.initials: K
authors.lastname: Rayner
authors.forename: Uthra
authors.initials: U
authors.lastname: Suresh
authors.forename: José Carlos
authors.initials: JC
authors.lastname: Pastor-Pareja
authors.forename: Enric
authors.initials: E
authors.lastname: Esplugues
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
authors.forename: Luiz O F
authors.initials: LO
authors.lastname: Penalva
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Moore
authors.forename: Yajaira
authors.initials: Y
authors.lastname: Suárez
authors.forename: Eric C
authors.initials: EC
authors.lastname: Lai
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernández-Hernando
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004331:Drosophila melanogaster / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007328:Insulin / Q000378:metabolism*; D008055:Lipids / Q000737:chemistry; D035683:MicroRNAs / Q000096:biosynthesis*; D010766:Phosphorylation; D012323:RNA Processing, Post-Transcriptional; D015398:Signal Transduction
chemical_list: D005227:Fatty Acids; D007328:Insulin; D008055:Lipids; C550416:MIRN33a microRNA, human; D035683:MicroRNAs; D002784:Cholesterol