PCSK9 targets important for lipid metabolism

Abstract

Ischemic heart disease is the main cause of death worldwide and it is accelerated by increased low-density lipoprotein (LDL) cholesterol (LDL-C) and/or lipoprotein (a) (Lp(a)) concentrations. Proprotein convertase subtilisin/kexin type 9 (PCSK9) alters both LDL-C and in part Lp(a) concentrations through its ability to induce degradation of the LDL receptor (LDLR). PCSK9, however, has additional targets which are potentially involved in lipid metabolism regulation such as the very low density lipoprotein receptor (VLDL), CD36 (cluster of differentiation 36) and the epithelial cholesterol transporter (NPC1L1) and it affects expression of apolipoprotein B48. The PCSK9 activity is tightly regulated at several levels by factors influencing its transcription, secretion, or by extracellular inactivation and clearance. Many comorbidities (kidney insufficiency, hypothyreoidism, hyperinsulinemia, inflammation) modify PCSK9 expression and release. Two humanized antibodies directed against extracellular PCSK9 received approval by the European and US authorities and additional PCSK9 directed therapeutics (such as silencing RNA) are already in clinical trials. Their results demonstrate a significant reduction in both LDL-C and Lp(a) concentrations – independent of the concomitant medication – and one of them reduced plaque size in high risk cardiovascular patients; results of two ongoing large clinical endpoints studies are awaited. In this review, we summarize and discuss the recent biological data on PCSK9, the regulation of PCSK9, and finally briefly summarize the data of recent clinical studies in the context of lipid metabolism.

What’s new on therapies for elevated lipoprotein(a)

“…While the mechanisms are unknown, it has been postulated to be via several receptors, including the LDL receptor, the apoE receptor or scavenger receptor class B type 1, which may also catabolize Lp(a). Other mechanisms include targeting docking, sorting and endocytic receptors or reductions in apoB or assembly of Lp(a) on hepatocyte surface [42,43].…”

Lipoprotein(a) and proprotein convertase subtilisin/kexin type 9 inhibitors

“…Evidently, the PCSK9 protein also exerts effects on other receptors like VLDL receptor, LDL receptor-related protein 1 or the apolipoprotein E receptor [3].…”

“…The clearance of Lp(a) from the bloodstream is still not fully understood. Hepatic (LDL receptor (LDLR), VLDL receptor, scavenger receptor B1, LDL receptor-related protein 1, cluster of differentiation 36 receptor (CD36), plasminogen receptor) and nonhepatic receptors are probably involved [1][2][3][4]. Renal mechanisms may also play a role.…”

Can modulators of apolipoproteinB biogenesis serve as an alternate target for cholesterol-lowering drugs?

“…The most promising antibody was developed against proprotein convertase subtilisin/kexin type 9 (PCSK9), a serine protease whose levels appear to positively correlate with CAD lesions [134, 135]. In humans, PCSK9 targets the LDL receptor for degradation by the lysosome through a mechanism that has not been fully elucidated [134, 136]. By inhibiting PCSK9, more LDL receptors are present on the cell surface to bind apoB, thereby reducing circulating LDLs by up to 60%.…”