Proprotein Convertase Subtilisin/Kexin Type 9: A View beyond the Canonical Cholesterol-Lowering Impact.

Chiara Macchi, Nicola Ferri, Cesare R Sirtori, Alberto Corsini, Maciej Banach, Massimiliano Ruscica

Journal: The American journal of pathology 2021;191(8):1385-1397

PMID: 34019847

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Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9), mainly synthetized and released by the liver, represents one of the key regulators of low-density lipoprotein cholesterol. Although genetic and interventional studies have demonstrated that lowering PCSK9 levels corresponds to a cardiovascular benefit, identification of non-cholesterol-related processes has emerged since its discovery. Besides liver, PCSK9 is also expressed in many tissues (eg, intestine, endocrine pancreas, and brain). The aim of the present review is to describe and discuss PCSK9 pathophysiology and possible non-lipid-lowering effects whether already extensively characterized (eg, inflammatory burden of atherosclerosis, triglyceride-rich lipoprotein metabolism, and platelet activation), or to be unraveled (eg, in adipose tissue). The identification of novel transcriptional factors in the promoter region of human PCSK9 (eg, ChREBP) characterizes new mechanisms explaining how controlling intrahepatic glucose may be a therapeutic strategy to reduce cardiovascular risk in type 2 diabetes. Finally, the evidence describing PCSK9 as involved in cell proliferation and apoptosis raises the possibility of this protein being involved in cancer risk.

Address: Department of Pharmacological and Biomolecular Sciences, Universita' degli Studi di Milano, Italy. Electronic address: [email protected].; Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padua, Italy.; Department of Pharmacological and Biomolecular Sciences, Universita' degli Studi di Milano, Italy.; Department of Pharmacological and Biomolecular Sciences, Universita' degli Studi di Milano, Italy; Istituti di Ricovero e Cura a Carattere Scientifico MultiMedica, Sesto San Giovanni/Milan, Italy.; Department of Hypertension, Medical University of Lodz, Lodz, Poland; Polish Mother's Memorial Hospital Research Institute, Lodz, Poland; Cardiovascular Research Centre, University of Zielona Góra, Zielona Góra, Poland.; Department of Pharmacological and Biomolecular Sciences, Universita' degli Studi di Milano, Italy. Electronic address: [email protected].

DOI: 10.1016/j.ajpath.2021.04.016