miR-181d-5p ameliorates hypercholesterolemia by targeting PCSK9.

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  • Additional Information
    • Source:
      Publisher: BioScientifica Country of Publication: England NLM ID: 0375363 Publication Model: Electronic-Print Cited Medium: Internet ISSN: 1479-6805 (Electronic) Linking ISSN: 00220795 NLM ISO Abbreviation: J Endocrinol Subsets: MEDLINE
    • Publication Information:
      Publication: Jan. 2011- : Bristol, UK : BioScientifica
      Original Publication: Bristol, UK : Society for Endocrinology
    • Subject Terms:
      Proprotein Convertase 9*/genetics ; Proprotein Convertase 9*/metabolism ; MicroRNAs*/genetics ; MicroRNAs*/metabolism ; Hypercholesterolemia*/genetics ; Hypercholesterolemia*/metabolism; Animals ; Mice ; Humans ; Cholesterol, LDL/blood ; Cholesterol, LDL/metabolism ; Male ; Liver/metabolism ; Mice, Inbred C57BL ; Disease Models, Animal ; Triglycerides/blood ; Triglycerides/metabolism
    • Abstract:
      Hypercholesterolemia is an independent risk factor for cardiovascular disease and lowering circulating levels of low-density lipoprotein cholesterol (LDL-C) can prevent and reduce cardiovascular events. MicroRNA-181d (miR-181d) can reduce the levels of triglycerides and cholesterol esters in cells. However, it is not known whether miR-181d-5p can lower levels of circulating LDL-C. Here, we generated two animal models of hypercholesterolemia to analyze the potential relationship between miR-181d-5p and LDL-C. In hypercholesterolemia model mice, adeno-associated virus (AAV)-mediated liver-directed overexpression of miR-181d-5p decreased the serum levels of cholesterol and LDL-C and the levels of cholesterol and triglyceride in the liver compared with control mice. Target Scan 8.0 indicated Proprotein convertase subtilisin/kexin type 9 (PCSK9) to be a possible target gene of miR-181d-5p, which was confirmed by in vitro experiments. miR-181d-5p could directly interact with both the PCSK9 3'-UTR and promoter to inhibit PCSK9 translation and transcription. Furthermore, Dil-LDL uptake assays in PCSK9 knockdown Huh7 cells demonstrated that miR-181d-5p promotion of LDL-C absorption was dependent on PCSK9. Collectively, our findings show that miR-181d-5p targets the PCSK9 3'-UTR to inhibit PCSK9 expression and to reduce serum LDL-C. miR-181d-5p is therefore a new therapeutic target for the development of anti-hypercholesterolemia drugs.
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    • Contributed Indexing:
      Keywords: LDL-C; PCSK9; hypercholesterolemia; miR-181d-5p
    • Accession Number:
      EC 3.4.21.- (Proprotein Convertase 9)
      0 (MicroRNAs)
      0 (mirn181 microRNA, mouse)
      EC 3.4.21.- (Pcsk9 protein, mouse)
      0 (Cholesterol, LDL)
      EC 3.4.21.- (PCSK9 protein, human)
      0 (Triglycerides)
    • Publication Date:
      Date Created: 20240628 Date Completed: 20240729 Latest Revision: 20241104
    • Publication Date:
      20241104
    • Accession Number:
      PMC11301420
    • Accession Number:
      10.1530/JOE-23-0402
    • Accession Number:
      38940622