LncRNA MEG3 functions as a ceRNA in regulating hepatic lipogenesis by competitively binding to miR-21 with LRP6

Background: Hepatic lipogenesis dysregulation is essential for the development of non-alcoholic fatty liver disease (NAFLD). Emerging evidence indicates the importance of the involvement of long non-coding RNAs (LncRNAs) in lipogenesis. However, the specific mechanism underlying this process is not clear.

Objective: This study aimed to investigate the functional implication of LncRNA MEG3 (MEG3) in fatty degeneration of hepatocytes and in the pathogenesis of NAFLD.

Methods: The expression of MEG3 was analysed in in vitro and in vivo models of NAFLD, which were established by free fatty acid (FFA)-challenged HepG2 cells and high-fat diet-fed mice, respectively. Endogenous MEG3 was over-expressed by a specific pcDNA3.1-MEG3 to evaluate the regulatory function of MEG3 on triglyceride (TG)- and lipogenesis-related genes. Bioinformatic analysis was used to predict the target genes and binding sites, and the targeted regulatory relationship was verified with a dual luciferase assay. Finally, the possible pathway that regulates MEG3 was also evaluated.

Results: We found that the downregulation of MEG3 in vitro and in vivo models of NAFLD was negatively correlated with lipogenesis-related genes and that overexpression of MEG3 reversed FFA-induced lipid accumulation in HepG2 cells. miR-21 was upregulated in the FFA-challenged HepG2 cells and was physically associated with MEG3 in the process of lipogenesis. Our mechanistic studies demonstrated that MEG3 competitively binds to miR-21 with LRP6, followed by the inhibition of the mTOR pathway, which induces intracellular lipid accumulation.

Conclusion: Our data are the first to document the working model of MEG3 functions as a potential hepatocyte lipid degeneration suppressor. MEG3 helps to alleviate lipid over-deposition, probably by binding to miR-21 to regulate the expression of LRP6. Our results suggest the potency of MEG3 as a biomarker for NAFLD and as a therapeutic target for treatment.