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Proprotein Convertase Subtilisin/Kexin Type 9: Functional Role in Lipid Metabolism and Its Therapeutic Inhibition

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Therapeutic Lipidology

Part of the book series: Contemporary Cardiology ((CONCARD))

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Abstract

Proprotein convertase/kexin type 9 (PCSK9) is produced and secreted by hepatocytes. Once in the extracellular milieu, PCSK9 can bind to the low-density lipoprotein receptor (LDLR) and regulates its cell surface expression. PCSK9 functions as a chaperone molecule. Though much remains to be elucidated about how PCSK9 orchestrates the intracellular routing of LDL-LDLR complexes within the cell, it is clear that PCSK9 promotes the entry of LDL-LDLR complexes into the lysosome where they are proteolytically catabolized. PCSK9 also regulates the expression of a number of other lipoprotein receptors, such as the apoE2 receptor, the VLDL receptor, the LDLR related protein 1, the fatty acid transport protein CD 36, and possibly the pathway (yet to be defined) for lipoprotein(a) clearance. Because it downregulates LDLR, PCSK9 reduces hepatocyte LDL-cholesterol (LDL-C) clearance capacity. Persons with gain-of-function mutations in PCSK9 have increased serum levels of LDL-C and increased risk for developing atherosclerotic cardiovascular disease (ASCVD). Persons with loss-of-function mutations in PCSK9 have reduced serum LDL-C and proportionately lower risk for ASCVD. The inhibition of PCSK9 with monoclonal antibodies or with antisense oligonucleotides directed against its mRNA has revolutionized the management of dyslipidemia. Either used as monotherapies or in combination with statins and other lipid-lowering drugs, the inhibition of PCSK9 allows for reductions in serum LDL-C to levels not previously thought possible. The reduction of pCSK9 availability dramatically increases hepatocyte cell surface expression of LDLR. The inhibition of PCSK9 has been shown to be safe and highly efficacious. Prospective, randomized outcomes trails with evolocumab and alirocumab demonstrate the capacity to reduce risk for myocardial infarction, ischemic stroke, revascularization, and hospitalization for unstable angina. In addition to their role in managing primary hyperlipidemia, the PCSK9 monoclonal antibodies have also been shown to be highly efficacious in the management of familial hypercholesterolemia and have the capacity to reduce rates of atherosclerotic plaque progression and induce plaque regression in the coronary tree.

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  1. Cicarrone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Peter P. Toth

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Editors and Affiliations

  1. The University of Chicago Pritzker School of Medicine, Chicago, IL, USA

    Michael H. Davidson

  2. Cicarrone Center for the Prevention of Cardiovascular Disease, Johns Hopkins Univerity School of Medicine, Baltimore, MD, USA

    Peter P. Toth

  3. Department of Applied Health Science, Indiana University School of Public Health, Bloomington, IN, USA

    Kevin C. Maki

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Toth, P.P. (2021). Proprotein Convertase Subtilisin/Kexin Type 9: Functional Role in Lipid Metabolism and Its Therapeutic Inhibition. In: Davidson, M.H., Toth, P.P., Maki, K.C. (eds) Therapeutic Lipidology. Contemporary Cardiology. Humana, Cham. https://doi.org/10.1007/978-3-030-56514-5_14

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  • DOI: https://doi.org/10.1007/978-3-030-56514-5_14

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  • Publisher Name: Humana, Cham

  • Print ISBN: 978-3-030-56513-8

  • Online ISBN: 978-3-030-56514-5

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