The unique role of proprotein convertase subtilisin/kexin 9 in cholesterol homeostasis

Abstract

Abstract. Mousavi SA, Berge KE, Leren TP (Rikshospitalet University Hospital, Norway). The unique role of PCSK9 in cholesterol homeostasis (Review). J Intern Med 2009; 266: 507-519.The LDL receptor (LDLR) plays an essential role in the regulation of plasma (LDL) cholesterol concentrations by virtue of its ability to clear plasma LDL. Down-regulation of the LDLR by proprotein convertase subtilisin ⁄ kexin 9 (PCSK9) has recently emerged as a regulatory mechanism that controls plasma LDL cholesterol concentrations. Studies in which PCSK9 is over-expressed in mice, have demonstrated that PCSK9, by enhancing hepatic LDLR degradation, decreases the availability of the LDLR for LDL uptake, resulting in increased plasma LDL cholesterol levels. However, PCSK9 has also recently been shown to mediate down-regulation of surface receptors other than the LDLR, suggesting that it may have much broader roles than initially thought.

Role of the C-terminal domain of PCSK9 in degradation of the LDL receptors

“…The cells were cultured in 1,720 cm 2 Corning Hyperfl asks (Sigma-Aldrich Corp., St. Louis, MO) in the presence of tetracycline (1 µg/µl) to induce expression of the transgenes. EC-LDLR or ⌬ 1-7-EC-LDLR in the media was purifi ed by the use of nickel-NTA agarose resin according to manufacturer's instructions (Qiagen GmbH, Hilden, Germany).…”

Common and Low-Frequency Genetic Variants in the PCSK9 Locus Influence Circulating PCSK9 Levels

“…2,3 Proprotein convertase subtilisin/kexin type 9 (PCSK9) shortens the half-life of the LDL-receptor (LDLR), 4 a process independent of its catalytic activity. 5 Human studies demonstrated that dominant gain-of-function mutations of PCSK9 cause familial hypercholesterolemia and CHD, 6 whereas loss-of-function mutations are associated with hypocholesterolemia and protection from CHD.…”

Chemical Modification of Oligonucleotides: A Novel Approach Towards Gene Targeting

“…Suppression of PCSK9 by reducing expression level of PCSK9 mRNA may cause an increase in the amount of the LDL receptor, resulting in the reduction of serum LDL cholesterol level. Thus, the PCSK9 mRNA has the potential to be an antisense target for the treatment of hypercholesterolemia [15][16][17]. We present the excellent antisense effect of 2',4'-BNA NC modified antisense oligonucleotides to reduce the expression level of the PCSK9 mRNA.…”

“…We also show the biological application of 2',4'-BNA NC -modified oligonucleotides to reduce expression level of target mRNA in mammalian cells [14]. PCSK9 is a serine protease involved in the degradation of LDL receptor [15][16][17]. Suppression of PCSK9 by reducing expression level of PCSK9 mRNA may cause an increase in the amount of the LDL receptor, resulting in the reduction of serum LDL cholesterol level.…”