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Proprotein convertase subtilisin kexin type 9 and high-density lipoprotein metabolism: experimental animal models and clinical evidence

  • Nicola Ferri
    Correspondence
    Nicola Ferri, Dipartimento di Scienze del Farmaco Largo Meneghetti 2, 35131, Padova, Italy
    Affiliations
    Dipartimento di Scienze del Farmaco, Università di Padova, Padua, Italy
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  • Alberto Corsini
    Affiliations
    Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy

    Multimedica IRCCS, Milan, Italy
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  • Chiara Macchi
    Affiliations
    Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy
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  • Paolo Magni
    Affiliations
    Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy

    Centro per lo Studio delle Malattie Dismetaboliche e delle Iperlipemie–Enrica Grossi Paoletti, Università degli Studi di Milano, Milan, Italy
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  • Massimiliano Ruscica
    Correspondence
    Reprint requests: Massimiliano Ruscica, Dipartimento di Scienze Farmacologiche e Biomolecolari Via Balzaretti 9, 20133, Milano, Italy
    Affiliations
    Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy
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Published:October 21, 2015DOI:https://doi.org/10.1016/j.trsl.2015.10.004
      Proprotein convertase subtilisin kexin type 9 (PCSK9) belongs to the proprotein convertase family. Several studies have demonstrated its involvement in the regulation of low-density lipoprotein (LDL) cholesterol levels by inducing the degradation of the LDL receptor (LDLR). However, experimental, epidemiologic, and pharmacologic data provide important evidence on the role of PCSK9 also on high-density lipoproteins (HDLs). In mice, PCSK9 regulates the HDL cholesterol (HDL-C) levels by the degradation of hepatic LDLR, thus inhibiting the uptake of apolipoprotein (Apo)E–containing HDLs. Several epidemiologic and genetic studies reported positive relationship between PCSK9 and HDL-C levels, likely by reducing the uptake of the ApoE-containing HDL particles. PCSK9 enhances also the degradation of LDLR's closest family members, ApoE receptor 2, very low–density lipoprotein receptor, and LDLR-related protein 1. This feature provides a molecular mechanism by which PCSK9 may affect HDL metabolism. Experimental studies demonstrated that PCSK9 directly interacts with HDL by modulating PCSK9 self-assembly and its binding to the LDLR. Finally, the inhibition of PCSK9 by means of monoclonal antibodies directed to PCSK9 (ie, evolocumab and alirocumab) determines an increase of HDL-C fraction by 7% and 4.2%, respectively. Thus, the understanding of the role of PCSK9 on HDL metabolism needs to be elucidated with a particular focus on the effect of PCSK9 on HDL-mediated reverse cholesterol transport.

      Abbreviations:

      Apo (Apolipoprotein), CHRD (cysteine– and histidine–rich domain), CE (cholesteryl esters), CETP (Cholesterol ester transfer protein), ER (Endoplasmic reticulum), EL (Endothelial lipase), EGF-A (Epidermal growth factor–like repeat homology domain A), HNF-1 (Hepatocyte nuclear factor-1), HDL (High-density lipoprotein), HDL-C (HDL cholesterol), mAb (Monoclonal antibody), Lp(a) (Lipoprotein (a)), LDL (Low-density lipoprotein), LDL-C (LDL cholesterol), LDLR (LDL receptor), PACE4 (paired basic amino acid-cleaving enzyme 4), PC (Proprotein convertase), PCSK9 (Proprotein convertase subtilisin kexin type 9), PRO (prosegment), SP (signal peptide), SRE (Sterol regulatory element), SREBPs (SRE-binding proteins), TG (Triglyceride), VLDL (Very low-density lipoprotein), VLDL-C (VLDL cholesterol)
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