PCSK9 Activity Is Potentiated Through HDL Binding.

Area of Science:

• Cardiovascular Biology
• Lipid Metabolism
• Proteomics

Background:

• Proprotein convertase subtilisin/kexin type 9 (PCSK9) exists in free and lipoprotein-bound forms.
• The functional implications of PCSK9's association with high-density lipoprotein (HDL) are largely unknown.

Purpose of the Study:

• To investigate the novel relationship between PCSK9 and HDL in humans.
• To elucidate the functional consequences of PCSK9-HDL interactions.

Main Methods:

• Utilized nuclear magnetic resonance and targeted mass spectrometry in the Bruneck and SAPHIR cohorts.
• Employed crosslinking mass spectrometry (XLMS) and size-exclusion chromatography for HDL-binding confirmation.
• Conducted quantitative proteomics on HDL from coronary artery disease patients and analyzed HDL lipidome.

Main Results:

• Plasma PCSK9 positively correlated with small HDL and apolipoprotein-C3 levels.
• Postprandial lipemia attenuated PCSK9-HDL association, reduced apolipoprotein-C3 on HDL, and decreased small HDL.
• PCSK9 identified as a core component of the HDL proteome, influencing HDL's role in LDL receptor degradation.

Conclusions:

• High-density lipoprotein (HDL) acts as a binder and functional regulator of PCSK9.
• Postprandial lipemia drives the release of PCSK9 and apolipoprotein-C3 from HDL.
• These findings reveal a new mechanism linking lipoprotein metabolism and PCSK9 regulation.