Inhibition of microRNA‐124a attenuates non‐alcoholic fatty liver disease through upregulation of adipose triglyceride lipase and the effect of liraglutide intervention

Aim Glucagon‐like peptide‐1 receptor agonists (GLP‐1Ras) have been reported to prevent non‐alcoholic fatty liver disease (NAFLD), but the potential mechanisms are still debated. MicroRNAs (miRNAs) play a prominent role in the field of metabolic disorders, including NAFLD. Our study was designed to further evaluate the effect of GLP‐1Ra liraglutide on NAFLD in terms of miRNAs. Methods MicroRNA expression was evaluated by clustering analysis of microRNA arrays in high fat diet‐fed mice. The luciferase reporter assay was carried out to validate the cross‐talk between adipose triglyceride lipase (ATGL) and miR‐124a. MicroRNA‐124a mimics and inhibitor plasmids were transfected to study the role of miR‐124a in palmitate‐treated normal human liver cell line (HL‐7702). Liraglutide treatment was used to observe the effect of GLP‐1Ra on the miR‐124a/ATGL pathway. Results Expression of ATGL decreased and miR‐124a expression increased in hepatosteatosis in vivo and in vitro . Mechanistically, miR‐124a interacted with the 3′‐untranslated region of ATGL mRNA and induced its degradation. MicroRNA‐124a overexpression antagonized the effect of liraglutide on NAFLD by inhibiting ATGL expression, whereas miR‐124a knockdown led to elevated ATGL and sirtuin 1 (Sirt1) expression, and subsequently decreased lipid accumulation and inflammation in cells. Conclusions MicroRNA‐124a overexpression contributes to the progression of NAFLD through reduction of ATGL expression, whereas miR‐124a knockdown can reverse this trend, suggesting that miR‐124a and its downstream target ATGL can be novel therapeutic targets of NAFLD. We reveal a novel mechanism by which liraglutide attenuates NAFLD by the miR‐124a/ATGL/Sirt1 pathway.