AIM: Hepatic insulin resistance is a hallmark of type 2 diabetes and non-alcoholic fatty liver disease. Dysregulation of microRNA (miRNA) expression in insulin resistant livers may coordinate impaired hepatic metabolic function. Here, we aimed to discover miRNAs and their downstream targets involved in hepatic insulin resistance.

METHODS: We determined miRNA expression profiles by small RNA sequencing of two mouse models of impaired hepatic insulin action; high-fat diet-induced obesity and liver-specific insulin receptor knockout (LIRKO). Conversely, we assessed the hepatic miRNA expression profile after treatment with the anti-diabetic hormone Fibroblast Growth Factor 21 (FGF21). Ontology analysis of predicted miRNA gene targets was performed to identify regulated gene pathways. Target enrichment analysis and miRNA mimic overexpression in vitro were used to identify unified protein targets of nodes of regulated miRNAs.

RESULTS: We identified an array of miRNA species regulated by impaired liver insulin action or after FGF21 treatment. Ontology analysis of predicted miRNA-gene targets identified pathways controlling hepatic energy metabolism and insulin sensitivity. We identified a node of two miRNAs downregulated in livers of LIRKO mice, miR-883b and miR-205, which positively regulate the expression of transcription factor Zinc Finger E-Box Binding Homeobox 1 (ZEB1). We found another node of two miRNAs upregulated in livers of FGF21-treated mice, miR-155-3p and miR-1968-5p, canonically downregulates caveola component Polymerase I and Transcript Release Factor (PTRF), a gene previously implicated in hepatic energy metabolism.

CONCLUSIONS: Our study identifies two nodes of co-regulated miRNAs that may co-ordinately control hepatic energy metabolism in states of insulin resistance.