title: MicroRNA 33 regulates glucose metabolism.
abstract: Metabolic diseases are characterized by the failure of regulatory genes or proteins to effectively orchestrate specific pathways involved in the control of many biological processes. In addition to the classical regulators, recent discoveries have shown the remarkable role of small noncoding RNAs (microRNAs [miRNAs]) in the posttranscriptional regulation of gene expression. In this regard, we have recently demonstrated that miR-33a and miR33b, intronic miRNAs located within the sterol regulatory element-binding protein (SREBP) genes, regulate lipid metabolism in concert with their host genes. Here, we show that miR-33b also cooperates with SREBP1 in regulating glucose metabolism by targeting phosphoenolpyruvate carboxykinase (PCK1) and glucose-6-phosphatase (G6PC), key regulatory enzymes of hepatic gluconeogenesis. Overexpression of miR-33b in human hepatic cells inhibits PCK1 and G6PC expression, leading to a significant reduction of glucose production. Importantly, hepatic SREBP1c/miR-33b levels correlate inversely with the expression of PCK1 and G6PC upon glucose infusion in rhesus monkeys. Taken together, these results suggest that miR-33b works in concert with its host gene to ensure a fine-tuned regulation of lipid and glucose homeostasis, highlighting the clinical potential of miR-33a/b as novel therapeutic targets for a range of metabolic diseases.
authors.affiliation: Department of Medicine, Leon H. Charney Division of Cardiology and Marc and Ruti Bell Vascular Biology and Disease Program, New York University School of Medicine, New York, New York, USA.
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Ramírez
authors.forename: Leigh
authors.initials: L
authors.lastname: Goedeke
authors.forename: Noemi
authors.initials: N
authors.lastname: Rotllan
authors.forename: Je-Hyun
authors.initials: JH
authors.lastname: Yoon
authors.forename: Daniel
authors.initials: D
authors.lastname: Cirera-Salinas
authors.forename: Julie A
authors.initials: JA
authors.lastname: Mattison
authors.forename: Yajaira
authors.initials: Y
authors.lastname: Suárez
authors.forename: Rafael
authors.initials: R
authors.lastname: de Cabo
authors.forename: Myriam
authors.initials: M
authors.lastname: Gorospe
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernández-Hernando
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D005943:Gluconeogenesis; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008253:Macaca mulatta; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C550416:MIRN33a microRNA, human; D035683:MicroRNAs; D051780:Sterol Regulatory Element Binding Protein 1; D006003:Glycogen; D005952:Glucose-6-Phosphatase; C521898:PCK1 protein, human; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005947:Glucose