PCSK9 binds to multiple receptors and can be functionally inhibited by an EGF-A peptide.
ABSTRACT Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low density lipoprotein receptor (LDLR) and induces its internalization and degradation. PCSK9 binding to LDLR is mediated through the LDLR epidermal growth factor-like repeat A (EGF-A) domain. We show for the first time that an EGF-A peptide inhibits PCSK9-mediated degradation of LDLR in HepG2 cells. In addition to LDLR, we show that PCSK9 also binds directly to ApoER2 and mouse VLDLR. Importantly, binding of PCSK9 to either LDLR or mouse VLDLR was effectively inhibited by EGF-A while binding to ApoER2 was less affected. In contrast, LDL receptor-associated protein (RAP), which interacts with LDL receptor repeat type A (LA) domains, inhibited PCSK9 binding to ApoER2 with greater efficacy than either LDLR or mVLDLR. These data demonstrate that while PCSK9 binds several receptors via its EGF-A binding domain, additional contacts with other receptor domains are also involved.
- SourceAvailable from: Maciej Banach[Show abstract] [Hide abstract]
ABSTRACT: Proprotein convertase subtilisin/kexin 9 (PCSK9) is part of the proteinase K subfamily of subtilases and plays a key role in lipid metabolism. It increases degradation of the low-density lipoprotein receptor (LDL-R), modulates cholesterol metabolism and transport, and contributes to the production of apolipoprotein B (apoB) in intestinal cells. Exogenous PCSK9 modifies the activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and acyl coenzyme A:cholesterol acyltransferase and enhances secretion of chylomicrons by modulating production of lipids and apoB-48. Statins increase PCSK9 messenger RNA expression and attenuate the capacity to increase LDL-R levels. Therefore, the inhibition of PCSK9 in combination with statins provides a promising approach for lowering low-density lipoprotein cholesterol (LDL-C) concentrations. This review will address new therapeutic strategies targeting PCSK9, including monoclonal antibodies, antisense oligonucleotides, small interfering RNAs, and other small molecule inhibitors. Further studies are still needed to determine the efficacy and safety of the PCSK9 inhibitors not only to decrease LDL-C but also to investigate the potential underlying mechanisms involved and to test whether these compounds actually reduce cardiovascular end points and mortality.Journal of Cardiovascular Pharmacology and Therapeutics 06/2014; · 3.07 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising treatment target to lower serum cholesterol, a major risk factor of cardiovascular diseases. Gain-of-function mutations of PCSK9 are associated with hypercholesterolemia and increased risk of cardiovascular events. Conversely, loss-of-function mutations cause low-plasma LDL-C levels and a reduction of cardiovascular risk without known unwanted effects on individual health. Experimental studies have revealed that PCSK9 reduces the hepatic uptake of LDL-C by increasing the endosomal and lysosomal degradation of LDL receptors (LDLR). A number of clinical studies have demonstrated that inhibition of PCSK9 alone and in addition to statins potently reduces serum LDL-C concentrations. This review summarizes the current data on the regulation of PCSK9, its molecular function in lipid homeostasis and the emerging evidence on the extra-hepatic effects of PCSK9.Basic research in cardiology. 03/2015; 110(2):463.
- [Show abstract] [Hide abstract]
ABSTRACT: Proprotein convertase subtilisin kexin type 9 (PCSK9) is a circulatory ligand that terminates the lifecycle of the low-density lipoprotein (LDL) receptor (LDLR) thus affecting plasma LDL-cholesterol (LDL-C) levels. Recent evidence shows that in addition to the straightforward mechanism of action, there are more complex interactions between PCSK9, LDLR and plasma lipoprotein levels, including: (a) the presence of both parallel and reciprocal regulation of surface LDLR and plasma PCSK9; (b) a correlation between PCSK9 and LDL-C levels dependent not only on the fact that PCSK9 removes hepatic LDLR, but also due to the fact that up to 40% of plasma PCSK9 is physically associated with LDL; and (c) an association between plasma PCSK9 production and the assembly and secretion of triglyceride-rich lipoproteins.Atherosclerosis 12/2014; · 3.71 Impact Factor