title: Stress-activatedmiR-21/miR-21*in hepatocytes promotes lipid and glucose metabolic disorders associated with high-fat diet consumption.
abstract: miR-21is an oncomir highly upregulated in hepatocellular carcinoma and in early stages of liver diseases characterised by the presence of steatosis. Whether upregulation ofmiR-21contributes to hepatic metabolic disorders and their progression towards cancer is unknown. This study aims at investigating the role ofmiR-21/miR-21*in early stages of metabolic liver disorders associated with diet-induced obesity (DIO).
  
  
  
  ConstitutivemiR-21/miR-21*knockout (miR21KO) and liver-specificmiR-21/miR-21*knockout (LImiR21KO) mice were generated. Mice were then fed with high-fat diet (HFD) and alterations of the lipid and glucose metabolism were investigated. Serum andex vivoexplanted liver tissue were analysed.
  
  
  
  Under normal breeding conditions and standard diet,miR-21/miR-21*deletion in mice was not associated with any detectable phenotypic alterations. However, when mice were challenged with an obesogenic diet, glucose intolerance, steatosis and adiposity were improved in mice lackingmiR-21/miR-21*. Deletion ofmiR-21/miR-21*specifically in hepatocytes led to similar improvements in mice fed an HFD, indicating a crucial role for hepaticmiR-21/miR-21*in metabolic disorders associated with DIO. Further molecular analyses demonstrated thatmiR-21/miR-21*deletion in hepatocytes increases insulin sensitivity and modulates the expression of multiple key metabolic transcription factors involved in fatty acid uptake,de novolipogenesis, gluconeogenesis and glucose output.
  
  
  
  HepaticmiR-21/miR-21*deficiency prevents glucose intolerance and steatosis in mice fed an obesogenic diet by altering the expression of several master metabolic regulators. This study points outmiR-21/miR-21* as a potential therapeutic target for non-alcoholic fatty liver disease and the metabolic syndrome.
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Calo
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Ramadori
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
authors.forename: Cyril
authors.initials: C
authors.lastname: Sobolewski
authors.affiliation: Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Romero
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
authors.forename: Christine
authors.initials: C
authors.lastname: Maeder
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
authors.forename: Margot
authors.initials: M
authors.lastname: Fournier
authors.affiliation: MediCity Research Laboratory, University of Turku, Turku, Finland.|Department of Physiology and Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland.
authors.forename: Pia
authors.initials: P
authors.lastname: Rantakari
authors.affiliation: Department of Physiology and Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland.
authors.forename: Fu-Ping
authors.initials: FP
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Poutanen
authors.affiliation: Department of Surgery, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Dufour
authors.affiliation: Hepatology, Department of Clinical Research, University of Berne, Bern, Switzerland.
authors.forename: Bostjan
authors.initials: B
authors.lastname: Humar
authors.affiliation: Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Serge
authors.initials: S
authors.lastname: Nef
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Foti
mesh_terms: D000818:Animals; D059305:Diet, High-Fat; D004041:Dietary Fats / Q000009:adverse effects; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000378:metabolism*; D018149:Glucose Intolerance / Q000378:metabolism; D044882:Glucose Metabolism Disorders / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*
chemical_list: D004041:Dietary Fats; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D005947:Glucose
keywords: FATTY LIVER; GLUCOSE METABOLISM; LIPID METABOLISM