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

PIROLA, CARLOS J.; TOMAS FERNANDEZ GIANOTTI; GUSTAVO CASTAÑO; PABLO MALLARDI; JULIO SAN MARTINO; GONZALEZ LOPEZ LEDESMA MM; FLICHMAN, D; MIRSHAHI F; SANYAL AJ; SILVIA C. SOOKOIAN

GUT - AN INTERNATIONAL JOURNAL OF GASTROENTEOROLOGY AND HEPATOLOGY

B M J PUBLISHING GROUP

Lugar: Londres; Año: 2015 vol. 64 p. 810 - 812

0017-5749

  Objectives: We used a screening strategy of global serum 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 nonalcoholic 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 analyzed, miR-122, miR-192, miR-19a and 19b, miR-125b, and miR-375 were up-regulated >2-fold (p<0.05) either in simple steatosis (SS) or nonalcoholic steatohepatitis (NASH). The most dramatic and significant fold changes were observed in the serum levels of miR-122 (7.2-fold change in NASH versus controls and 3.1-fold change in NASH versus SS) and miR-192 (4.4-fold change in NASH versus controls); these results were replicated in the validation set. The majority of serum miR-122 circulates 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) down-regulated 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. Conclusion: miR-122 plays a role of physiological significance in the biology of NAFLD; circulating miRNAs mirror the histologic and molecular events occurring in the liver. NAFLD has a distinguishing circulating miRNA profile associated with a global dysmetabolic disease state and cardiovascular risk.