Journal
CURRENT ATHEROSCLEROSIS REPORTS
Volume 12, Issue 5, Pages 308-315Publisher
CURRENT MEDICINE GROUP
DOI: 10.1007/s11883-010-0123-6
Keywords
PCSK9; Genetic variants; Mutations; LDL receptor; LDL cholesterol; Cholesterol homeostasis; Atherosclerosis; Cerebrovascular disease; Coronary artery disease; Peripheral arterial disease; Berberine; Fibrate; Statin; Lipoprotein metabolism
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Pro-protein-convertase-subtilisin-kexin-9 (PCSK9) enhances the degradation of the low-density lipoprotein receptor (LDLR) that plays a major role in cholesterol homeostasis. Recent advances have revealed a large number of genetic variants of PCSK9 that may modulate plasma cholesterol levels either positively or negatively, therefore influencing the risk of atherosclerosis. Recognition of these mutants may have clinical implication in assessing severity of disease, prognosis, or response to drug therapy. PCSK9's expression, secretion, and plasma levels maybe modulated by the proprotein convertase furin, by natural inhibitors (annexin-A2), or influenced by lipid-altering agents such as statins, fibrates, ezetimibe, and berberine. It is now a prime target for therapy, prompting the development of various approaches to reduce its LDLR degrading activity, including antibody neutralization, anti-sense oligonucleotides such as phosphorothioates, locked nucleic acids, and RNA interference, and eventually small molecule inhibitors. Which one will be clinically applicable will depend on long-term effects, cost, and ease of administration.
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