MiR-181d-5p ameliorates hypercholesterolemia through targeting PCSK9
Hypercholesterolemia is an independent risk factor for cardiovascular disease. Studies have shown that effectively lowering circulating levels of low-density lipoprotein cholesterol (LDL-C) can prevent and reduce cardiovascular events. MicroRNA-181d(miR-181d) can reduce cell triglycerides and cholesterol esters. However, whether miR-181d-5p can lower LDL-C has not been reported. Herein,we constructed two hypercholesterolemia animal models to analyze the potential relationship between miR-181d-5p and LDL-C. We found that AAV-mediated liver-directed miR-181d-5p over-expressed, the serum cholesterol and serum LDL-C decreased obviously .After miR-181d-5p was over-expressed, the liver cholesterol and liver triglyceride decreased than that of the control mouse.Through Target Scan 8.0, we found PCSK9 was the possible target genes regulated by miR-181d-5p, which was further proved by in vitro experiments. MiR-181d-5p could directly interact with both the PCSK9 3UTR and promoter to inhibit PCSK9 translation and transcription. Furthermore, the result from the DilLDL uptake assay under the knockdown of PCSK9 demonstrated that miR-181d-5p promoting the absorption of LDL-C in Huh7 cells was dependent on PCSK9. Collectively,this study extends miR-181d-5p targets PCSK9 3UTR and inhibits PCSK9 expression and serum LDL-C, suggesting miR-181d-5p might be a new therapeutic target for the development of antihypercholesterolemia drugs.