FTO-Catalysed Demethylation of LUR1 mRNA Suppresses Macrophage Lipid Accumulation and Aortic Atherosclerosis

Lipid deposition and foam cell formation drive atherogenesis. Lipid uptake regulator 1 (LUR1) and N6-methyladenosine (m6A) modification play key roles in systemic lipid homeostasis. Bioinformatic analyses revealed a negative correlation between fat mass and obesity-associated protein (FTO) and LUR1 expression and abundant m6A sites within the LUR1 mRNA strand. We therefore hypothesized that FTO-catalysed demethylation modulates LUR1 expression and lipid accumulation in macrophages, thereby influencing aortic plaque development. Acetylated low-density lipoprotein-loaded THP-1 macrophages were transduced with recombinant lentiviruses, and FTO and LUR1 expression was determined by Western blotting and qPCR. m6A abundance was measured by methylated RNA immunoprecipitation-qPCR. Intracellular lipids were quantified by ELISA, and lipid droplets (LDs) were quantified using Oil Red O (ORO) staining. The plasma lipid concentration, aortic sinus plaque area and lipid deposition were evaluated by biochemical assays and histological staining in high-fat-fed apoE^-/- mice that received recombinant adeno-associated viruses. The results revealed that elevated FTO expression not only reduced LUR1 expression and its m6A modification and decreased intracellular LD and cholesterol ester contents but also significantly decreased plasma triglyceride (TG) and low-density lipoprotein-cholesterol levels (LDL-C) and decreased the aortic lesion area. Co-overexpression of FTO and LUR1 abolished these protective effects. These findings indicate that FTO-erased m6A modification decreases LUR1 expression in macrophages to inhibit intracellular lipid accumulation and the occurrence of atherosclerosis (AS).