miR-552-3p modulates transcriptional activities of FXR and LXR to ameliorate hepatic glycolipid metabolism disorder.

Abstract Background & Aims The nuclear location of miRNAs has been discovered for more than a decade, but their exact mechanism and function in the nucleus are still not fully elucidated. In light of our previous discovery that intranuclear miR-552-3p has an inhibitory role in gene transcription and its particular AGGTCA-like sequence, the cis-elements of NR1 subfamily, we aim to explore its potential effect on NR1s and possible application in improving hepatic glycolipid metabolism. Methods RNA-seq, mass spectrum and bioinformatics analysis were used to reveal the possible pathways influenced by miR-552-3p. HFHFr mice and db/db mice transfected with AAV2/8-miR-552-3p were established to investigate in vivo effects of miR-552-3p on hepatic glycolipid metabolism. FRET, pulldown, EMSA and ChIP assays were performed to explore the mechanism of miR-552-3p regulating NR1s. RT-PCR was conducted to analyze miR-552-3p levels in liver biopsies from NAFLD patients and normal controls. Results MiR-552-3p could inhibit metabolic genes expression in vitro and display in vivo beneficial effects on glycolipid metabolism. LXRα and FXR were discovered as primarily pathways regulated by intranuclear miR-552-3p, which achieved by its binding to the complementary sequence of AGGTCA to modulate the transcriptional activities of LXRα and FXR. Moreover, the LXRα and FXR ligand could restore the effects of miR-552-3p on gene expression and glycolipid metabolism. Additionally, hepatic miR-552-3p level was significantly decreased in liver samples from NAFLD patients when compared to the normal control. Conclusions The mechanism of miR-552-3p modulating LXRα and FXR provided a new mode of miRNA-mediated gene regulation. In addition, in vivo beneficial effects and clinical relevance of miR-552-3p suggested that it might be a potential therapeutic target for the treatment of glycolipid metabolic disease.