title: Circulating microRNA signature in non-alcoholic fatty liver disease: from serum non-coding RNAs to liver histology and disease pathogenesis.
abstract: OBJECTIVE
  We used a screening strategy of global serum microRNA (miRNA) profiling, followed by a second stage of independent replication and exploration of liver expression of selected miRNAs to study: (1) the circulating miRNA signature associated with non-alcoholic fatty liver disease (NAFLD) progression and predictive power, (2) the role of miRNAs in disease biology and (3) the association between circulating miRNAs and features of the metabolic syndrome.
  
  
  METHODS
  The study used a case-control design and included patients with NAFLD proven through biopsy and healthy controls.
  
  
  RESULTS
  Among 84 circulating miRNAs analysed, miR-122, miR-192, miR-19a and miR-19b, miR-125b, and miR-375 were upregulated >2-fold (p<0.05) either in simple steatosis (SS) or non-alcoholic steatohepatitis (NASH). The most dramatic and significant fold changes were observed in the serum levels of miR-122 (7.2-fold change in NASH vs controls and 3.1-fold change in NASH vs SS) and miR-192 (4.4-fold change in NASH vs controls); these results were replicated in the validation set. The majority of serum miR-122 circulate in argonaute2-free forms. Circulating miR-19a/b and miR-125b were correlated with biomarkers of atherosclerosis. Liver miR-122 expression was 10-fold (p<0.03) downregulated in NASH compared with SS and was preferentially expressed at the edge of lipid-laden hepatocytes. In vitro exploration showed that overexpression of miR-122 enhances alanine aminotransferase activity.
  
  
  CONCLUSIONS
  miR-122 plays a role of physiological significance in the biology of NAFLD; circulating miRNAs mirror the histological and molecular events occurring in the liver. NAFLD has a distinguishing circulating miRNA profile associated with a global dysmetabolic disease state and cardiovascular risk.
authors: Department of Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires-National Scientific and Technical Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Argentina.
authors: Carlos J
authors: CJ
authors: Pirola
authors: Department of Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires-National Scientific and Technical Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Argentina.
authors: Tomas
authors: T
authors: Fernández Gianotti
authors: Liver Unit, Medicine and Surgery Department, Hospital Abel Zubizarreta, Ciudad Autónoma de Buenos Aires, Argentina.
authors: Gustavo O
authors: GO
authors: Castaño
authors: Pathology Department, Hospital Diego Thompson, San Martin, Buenos Aires, Argentina.
authors: Pablo
authors: P
authors: Mallardi
authors: Pathology Department, Hospital Diego Thompson, San Martin, Buenos Aires, Argentina.
authors: Julio
authors: J
authors: San Martino
authors: Department of Virology, School of Pharmacy and Biochemistry, University of Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.
authors: María
authors: M
authors: Mora Gonzalez Lopez Ledesma
authors: Department of Virology, School of Pharmacy and Biochemistry, University of Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.
authors: Diego
authors: D
authors: Flichman
authors: Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors: Faridodin
authors: F
authors: Mirshahi
authors: Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors: Arun J
authors: AJ
authors: Sanyal
authors: Liver Unit, Medicine and Surgery Department, Hospital Abel Zubizarreta, Ciudad Autónoma de Buenos Aires, Argentina Department of Clinical and Molecular Hepatology, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires- National Scientific and Technical Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Argentina.
authors: Silvia
authors: S
authors: Sookoian
mesh_terms: D000328:Adult; D000886:Anthropometry / Q000379:methods; D060565:Argonaute Proteins / Q000097:blood / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D016022:Case-Control Studies; D002478:Cells, Cultured; D003198:Computer Simulation; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D056726:Genetic Association Studies / Q000379:methods; D020022:Genetic Predisposition to Disease; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008297:Male; D035683:MicroRNAs / Q000097:blood*; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D022661:RNA, Untranslated / Q000097:blood*; D000637:Transaminases / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
chemical_list: C466422:AGO2 protein, human; D060565:Argonaute Proteins; D015415:Biomarkers; C531907:MIRN122 microRNA, human; D035683:MicroRNAs; D022661:RNA, Untranslated; D000637:Transaminases
keywords: Liver; Nonalcoholic Steatohepatitis