Lipid Lowering Therapy and Circulating PCSK9 Concentration

Abstract

Hypercholesterolemia, particularly an increase in low-density lipoprotein cholesterol (LDL-C) levels, contributes substantially to the development of coronary artery disease and the risk for cardiovascular events. As the first-line pharmacotherapy, statins have been shown to reduce both LDL-C levels and cardiovascular events. However, despite intensive statin therapy, a sizable proportion of statin-treated patients are unable to achieve the recommended target LDL-C levels, and not all patients can avoid future cardiovascular events. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis by enhancing the degradation of hepatic low-density lipoprotein receptor (LDLR). Owing to its importance in lipid metabolism, PCSK9 has emerged as a novel pharmacological target for lowering LDL-C levels. In this review, the potential role of circulating PCSK9 as a new biomarker of lipid metabolism is described. Next, previous studies evaluating the effects of lipid-modifying pharmacological agents, particularly statins, on circulating PCSK9 concentrations are summarized. Statins decrease hepatic intracellular cholesterol, resulting in increased LDLRs as well as increased PCSK9 protein. There is a clear dose-response effect of statin treatment on PCSK9 level, as increasing doses of statins also increase the level of circulating PCSK9. Finally, the available therapeutic strategies to inhibit PCSK9 are present. Monoclonal antibodies against PCSK9, in combination with statins, are one of the most promising and novel approaches to achieve further reduction of LDL-C levels and reduce the risk of cardiovascular events.

Reduced plasma PCSK9 response in patients with bacteraemia is associated with mortality

“…In addition to inflammatory conditions, plasma PCSK9 levels are elevated by the use of lipid‐lowering drugs, such as statins . We observed a similar upregulation of plasma PCSK9 in bacteraemia patients using statins, but also identified other factors that were associated with lower plasma PCSK9 levels (male sex, liver disease and alcohol abuse).…”

Pre-germinated brown rice extract ameliorates high-fat diet-induced metabolic syndrome

“…With regard to the proteins involved in lipid metabolism proteins, LDLR is a carrier that removes cholesterol and regulates its amount (Kamisako et al, 2014). PCSK9 binds to LDLR, in which LDL particles cannot be transferred into the cells (Kamisako et al, 2014;Nozue, 2017). The enzyme CYP7α1 is important for the synthesis of bile acid and the regulation of cholesterol levels (Chiu, Chang, Liu, & Chiang, 2017;Mohammadi et al, 2017).…”

Disorders of Lipid Metabolism in Chronic Kidney Disease

“…Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme also accepted as a new biomarker for lipid metabolism, a novel pharmacological target for hypercholesterolemia, since the inhibition of PCSK9 may be one of the management options to decrease CVD risk [42, 43]. PCSK9 is primarily synthesized by the liver, intestine, and kidney as a precursor of the 75 kDa protein; it then undergoes autocatalytic cleavage in the endoplasmic reticulum and secreted as a heterodimer protein [43].…”

“…PCSK9 is primarily synthesized by the liver, intestine, and kidney as a precursor of the 75 kDa protein; it then undergoes autocatalytic cleavage in the endoplasmic reticulum and secreted as a heterodimer protein [43]. PCSK9 causes a reduction in the number of LDL cholesterol receptor by enhancing the degradation of hepatic LDL receptor and this reduces LDL cholesterol uptake leading to a subsequent increase in circulating LDL cholesterol levels [43, 44]. In addition, recent studies showed that very low-density lipoprotein receptor and apolipoprotein E2 receptor are also partly regulated by PCSK9 [45].…”