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Circulating microRNA signature in non-alcoholic fatty liver disease: from serum non-coding RNAs to liver histology and disease pathogenesis
  1. Carlos J Pirola1,
  2. Tomas Fernández Gianotti1,
  3. Gustavo O Castaño2,
  4. Pablo Mallardi3,
  5. Julio San Martino3,
  6. María Mora Gonzalez Lopez Ledesma4,
  7. Diego Flichman4,
  8. Faridodin Mirshahi5,
  9. Arun J Sanyal5,
  10. Silvia Sookoian2,6
  1. 1Department 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
  2. 2Liver Unit, Medicine and Surgery Department, Hospital Abel Zubizarreta, Ciudad Autónoma de Buenos Aires, Argentina
  3. 3Pathology Department, Hospital Diego Thompson, San Martin, Buenos Aires, Argentina.
  4. 4Department of Virology, School of Pharmacy and Biochemistry, University of Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina
  5. 5Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
  6. 6Department 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
  1. Correspondence to Dr Silvia Sookoian, and Dr Carlos J Pirola, Instituto de Investigaciones Medicas, IDIM-CONICET, Combatientes de Malvinas 3150, CABA-1427, Argentina; sookoian.silvia{at}lanari.fmed.uba.arpirola.carlos@lanari.fmed.uba.ar

Abstract

Objectives 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.

  • Liver
  • Nonalcoholic Steatohepatitis

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