Longitudinal analysis of serum miR-122 in a rat model of Wilson's disease.

Siaj R, Sauer V, Stöppeler S, Gerß J, Spiegel HU, Köhler G, Zibert A, Schmidt HH

Abstract

PURPOSE: MicroRNA-122 (miR-122) has recently been shown to represent a novel biomarker of liver disease. However, the presence of serum miR-122 after liver injury was mostly studied at singular time points. The course of serum miR-122 was determined at consecutive time points during the onset of disease. METHODS: Fulminant hepatitis was induced by a high-copper diet in Long-Evans Cinnamon (LEC) rats that were used as models for Wilson's disease (WD). Levels of serum miR-122, alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, and liver histology were determined. RESULTS: Toxic copper given to isolated hepatocytes induced release of miR-122 into the tissue culture medium. Levels of serum miR-122 were highly elevated (21.9 ± 5) in LEC rats after high-copper diet in fulminant hepatitis, whereas healthy rats showed low (<0.6) baseline levels of miR-122. Levels of miR-122 in the serum of LEC rats after high-copper diet continuously increased for about 4 weeks prior to the onset of fulminant hepatitis. In most of the animals (77.8%), significantly increased levels of miR-122 were detected about 2 weeks (13.7 ± 2 days) earlier as compared to hepatitis-associated serum markers ALT, AST, and bilirubin. Analysis of miR-122 in survivors after cell-based therapy of WD demonstrated a rapid decrease of miR-122 levels following hepatocyte transplantation. miR-122 expression in the serum was normalized to baseline levels in most of the (4/5) survivors. CONCLUSION: Our results suggest that longitudinal analysis of miR-122 allows detection of severe liver disease at an early stage and might be excellently suited to monitor therapy, at least when severe liver disease can be restored as observed after cell-based therapy of WD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12072-012-9348-5) contains supplementary material, which is available to authorized users.