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Circulating microRNA signature in non-alcoholic fatty liver disease: from serum non-coding RNAs to liver histology and disease pathogenesis

Pirola, Carlos J, Fernández Gianotti, Tomas, Castaño, Gustavo O, Mallardi, Pablo, San Martino, Julio, Mora Gonzalez Lopez Ledesma, María, Flichman, Diego, Mirshahi, Faridodin +2 more·2015·Gut
DOI 10.1136/gutjnl-2014-306996PMC PMC4277726
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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.

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  • Elevated serum levels of liver-specific miR-122 have been detected in patients with drug induced liver injury, steatosis, hepatitis-B and -C infections and in patients with hepatocellular carcinoma (23-26).

    “Elevated serum levels of liver-specific miR-122 have been detected in patients with drug induced liver injury, steatosis, hepatitis-B and -C infections and in patients with hepatocellular carcinoma (23–26).”

    From Distribution of miRNA expression across human tissues (2016) · cites this paper as [25]

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Authors
Pirola, C. J., Fernández Gianotti, T., Castaño, G. O., Mallardi, P., San Martino, J., Mora Gonzalez Lopez Ledesma, M., Flichman, D., Mirshahi, F., Sanyal, A. J., & Sookoian, S.
Affiliations
  • 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
  • Liver Unit, Medicine and Surgery Department, Hospital Abel Zubizarreta, Ciudad Autónoma de Buenos Aires, Argentina
  • Pathology Department, Hospital Diego Thompson, San Martin, Buenos Aires, Argentina.
  • Department of Virology, School of Pharmacy and Biochemistry, University of Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina
  • Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
Venue
Gut
Publisher
BMJ
Published
2014-06-27
Volume
64
Issue
5
Pages
800-812
ISSN
  • 0017-5749
  • 1468-3288
DOI
10.1136/gutjnl-2014-306996
PMC
PMC4277726
Cited by
507
References
5
Language
en

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