The morbidity of nonalcoholic fatty liver disease (NAFLD) has increased consistently in recent years. Exenatide could reverse liver fibrosis and lower the occurrence of fatty liver. The aim of the study was to identify and characterize mRNA and miRNA expression to elucidate the mechanism of exenatide in the gerbil model.

Gerbils were fed a high-fat diet for 8 weeks to induce a fibrosis model; then, the gerbil models were treated with exenatide for 4 weeks. The total RNA extracted from the liver tissue samples was used to prepare the library and sequence on a HiSeq 2000. Bioinformatic methods were employed to analyze the sequence data to identify the mRNAs and miRNAs and to acquire the miRNA-mRNA regulatory network.

By RNA-seq, 2344 differentially expressed genes (DEGs) and 72 miRNAs were found in the model group. Compared with the model group, 591 DEGs and 19 miRNAs were found in the quercetin group, whereas 876 DEGs and 18 miRNAs were found in the treatment group. The miRNA-mRNA regulatory network was constructed in a gerbil model. Immunohistochemistry and RNA sequencing confirmed that the therapeutic effect of exenatide may be derived from extrahepatic signal transduction. The key differential genes are CYP3A, CYP4A11, ACAA1, ACSM, PHX1, MAO, FMO, UGT, ACOX2, ABAT, PIK3C and PLCG1. The key miRNAs are miR-15a, miR-27b, miR-532-3P, miR-627, miR-3596, miR-142-3P, Let-7e-5p, miR-214-5, miR-101-3p, miR-378d. New miRNAs, such as novel_127, novel_143, novel_15, novel_204 are associated with liver fibrosis, while novel_127, novel_15, and novel_54 are associated with reverse treated with exenatide.

Our research represents the first description of mRNA/miRNA profiles in a gerbil model of fatty liver fibrosis treated with exenatide, which may provide insights into the pathogenesis or treatment of the metabolic syndrome.