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  • Title: Hsa-miR-140-5p down-regulates LDL receptor and attenuates LDL-C uptake in human hepatocytes.
    Author: Xu Y, Gao J, Gong Y, Chen M, Chen J, Zhao W, Tan S.
    Journal: Atherosclerosis; 2020 Mar; 297():111-119. PubMed ID: 32109664.
    Abstract:
    BACKGROUND AND AIMS: MicroRNAs (miRs) exert important regulatory effects in cholesterol metabolism. Hepatic low density lipoprotein receptor (LDLR) pathway, as the major mechanism for clearing circulating low density lipoprotein cholesterol (LDL-C) in bloodstream, is a pivotal therapeutic target to treat hypercholesterolemia and atherosclerosis. This study aimed to identify novel miRs that regulate LDLR expression. METHODS AND RESULTS: Hsa-miR-140-5p was predicted by bioinformatics analyses to interact with human LDLR mRNA. To evaluate its functional effects in regulating LDLR, hsa-miR-140-5p and anti-miR-140-5p were transfected into human and mouse liver cells, followed by qRT-PCR, western blot, immunofluorescence, flow cytometry, and LDL-C uptake assays. It was observed that hsa-miR-140-5p over-expression dramatically down-regulated LDLR expression and reduced LDL-C uptake, whereas inhibition of hsa-miR-140-5p significantly up-regulated LDLR expression and enhanced LDL-C uptake in human HepG2 and LO2 cells, but not in mouse Hepa1-6 cells. Luciferase reporter assay and site-directed mutagenesis identified that hsa-miR-140-5p interacts with the predicted seed sequence "AAACCACU" in the 3'-UTR of human LDLR mRNA. Hsa-miR-140-5p over-expression attenuated LDL-C uptake and decreased intracellular cholesterol levels in the presence of 50 μg/ml ox-LDL in HepG2 cells. Additionally, palmitic acid and simvastatin suppressed, whereas LDL-C up-regulated the expression of miR-140-5p in HepG2 cells. CONCLUSIONS: Hsa-miR-140-5p is a negative regulator of LDLR expression in human hepatocytes, but not in mouse hepatocytes. Simvastatin inhibits hsa-miR-140-5p expression in human hepatocytes, which is likely to be a novel mechanism for treating hypercholesterolemia with statins in clinic. Antagonism of hsa-miR-140-5p could be a new therapeutic strategy for the treatment of hypercholesterolemia and atherosclerosis.
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