MicroRNAs (
miRNAs) control gene expression by reducing mRNA stability and translation. We aimed to identify alterations in human liver
miRNA expression/function in
nonalcoholic fatty liver disease (
NAFLD). Subjects with the highest (median liver fat 30%, n = 15) and lowest (0%, n = 15) liver fat content were selected from >100 obese patients for
miRNA profiling of liver biopsies on microarrays carrying probes for 1438 human
miRNAs (a cross-sectional study). Target mRNAs and pathways were predicted for the
miRNAs most significantly upregulated in
NAFLD, their cell-type-specific expression was investigated by quantitative PCR (qPCR), and the transcriptome of immortalized human hepatocytes (IHH) transfected with the
miRNA with the highest number of predicted targets, miR-576-5p, was studied. The screen revealed 42
miRNAs up- and two downregulated in the
NAFLD as compared to non-
NAFLD liver. The
miRNAs differing most significantly between the groups, miR-103a-2*, miR-106b, miR-576-5p, miRPlus-I137*, miR-892a, miR-1282, miR-3663-5p, and miR-3924, were all upregulated in
NAFLD liver. Target pathways predicted for these
miRNAs included ones involved in
cancer, metabolic regulation,
insulin signaling, and
inflammation. Consistent transcriptome changes were observed in IHH transfected with miR-576-5p, and western analysis revealed a marked reduction of the
RAC1 protein belonging to several miR-576-5p target pathways. To conclude, we identified 44
miRNAs differentially expressed in
NAFLD versus non-
NAFLD liver, 42 of these being novel in the context of
NAFLD. The study demonstrates that by applying a novel study set-up and a broad-coverage array platform one can reveal a wealth of previously undiscovered
miRNA dysregulation in
metabolic disease.