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

Area of Science:

• Biochemistry
• Molecular Biology
• Cardiovascular Research

Background:

• Hypercholesterolemia is a major risk factor for cardiovascular disease.
• Lowering low-density lipoprotein cholesterol (LDL-C) reduces cardiovascular events.
• MicroRNA-181d (miR-181d) is known to affect cellular lipid levels, but its role in circulating LDL-C is unclear.

Purpose of the Study:

• To investigate the potential of miR-181d-5p in reducing circulating LDL-C levels.
• To explore the molecular mechanism by which miR-181d-5p might affect LDL-C.
• To assess miR-181d-5p as a therapeutic target for hypercholesterolemia.

Main Methods:

• Generated hypercholesterolemia animal models.
• Utilized adeno-associated virus (AAV)-mediated liver-directed overexpression of miR-181d-5p.
• Performed in vitro experiments including Target Scan 8.0, 3'-UTR and promoter interaction assays, and Dil-LDL uptake assays in PCSK9 knockdown cells.

Main Results:

• Overexpression of miR-181d-5p in hypercholesterolemic mice significantly decreased serum cholesterol, LDL-C, and liver cholesterol and triglyceride levels.
• Proprotein convertase subtilisin/kexin type 9 (PCSK9) was identified as a direct target of miR-181d-5p.
• miR-181d-5p inhibits both the transcription and translation of PCSK9, and this action is crucial for promoting LDL-C uptake.

Conclusions:

• miR-181d-5p directly targets the PCSK9 3'-UTR to inhibit PCSK9 expression.
• This inhibition leads to a reduction in serum LDL-C levels.
• miR-181d-5p represents a promising new therapeutic target for anti-hypercholesterolemia drug development.