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Stress-activated miR-21/miR-21* in hepatocytes promotes lipid and glucose metabolic disorders associated with high-fat diet consumption
  1. Nicolas Calo1,
  2. Pierluigi Ramadori1,
  3. Cyril Sobolewski1,
  4. Yannick Romero2,
  5. Christine Maeder1,
  6. Margot Fournier1,
  7. Pia Rantakari3,4,
  8. Fu-Ping Zhang4,
  9. Matti Poutanen4,
  10. Jean-François Dufour5,
  11. Bostjan Humar6,
  12. Serge Nef2,
  13. Michelangelo Foti1
  1. 1Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
  2. 2Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland
  3. 3MediCity Research Laboratory, University of Turku, Turku, Finland
  4. 4Department of Physiology and Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland
  5. 5Department of Surgery, University Hospital Zurich, Zurich, Switzerland
  6. 6Hepatology, Department of Clinical Research, University of Berne, Bern, Switzerland
  1. Correspondence to Professor Michelangelo Foti, Department of Cell Physiology and Metabolism, CMU, 1 rue Michel-Servet, Geneva 1206, Switzerland; Michelangelo.foti{at}unige.ch

Abstract

Objective miR-21 is an oncomir highly upregulated in hepatocellular carcinoma and in early stages of liver diseases characterised by the presence of steatosis. Whether upregulation of miR-21 contributes to hepatic metabolic disorders and their progression towards cancer is unknown. This study aims at investigating the role of miR-21/miR-21* in early stages of metabolic liver disorders associated with diet-induced obesity (DIO).

Design Constitutive miR-21/miR-21* knockout (miR21KO) and liver-specific miR-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 and ex vivo explanted liver tissue were analysed.

Results 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 lacking miR-21/miR-21*. Deletion of miR-21/miR-21* specifically in hepatocytes led to similar improvements in mice fed an HFD, indicating a crucial role for hepatic miR-21/miR-21* in metabolic disorders associated with DIO. Further molecular analyses demonstrated that miR-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 novo lipogenesis, gluconeogenesis and glucose output.

Conclusions Hepatic miR-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 out miR-21/miR-21* as a potential therapeutic target for non-alcoholic fatty liver disease and the metabolic syndrome.

  • FATTY LIVER
  • GLUCOSE METABOLISM
  • LIPID METABOLISM

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