Low Density Lipoprotein Binds to Proprotein Convertase Subtilisin/Kexin Type-9 (PCSK9) in Human Plasma and Inhibits PCSK9-mediated Low Density Lipoprotein Receptor Degradation

Kosenko, Tanja; Golder, Mia; Leblond, Geoffrey; Weng, Willy; Lagace, Thomas A.

doi:10.1074/jbc.m112.421370

Cited by 162 publications

(220 citation statements)

References 51 publications

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“…Association of PCSK9 with LDL particles in plasma lowers the ability of PCSK9 to bind to cell surface LDL receptors, blunting PCSK9-mediated LDL receptor degradation. An N-terminal region of the PCSK9 prodomain (amino acid residues 31-52) was required for binding to LDL in vitro [148]. An endogenous inhibitor annexin A2 interacts with the C-terminal of PCSK9 preventing PCSK9 from interacting with LDL receptor [149].…”

Section: Ldl Receptor and Apolipoproteinsmentioning

confidence: 99%

Recent advances in physiological lipoprotein metabolism

Ramasamy

2014

Clinical Chemistry and Laboratory Medicine (CCLM)

178

159

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Abstract:Research into lipoprotein metabolism has developed because understanding lipoprotein metabolism has important clinical indications. Lipoproteins are risk factors for cardiovascular disease. Recent advances include the identification of factors in the synthesis and secretion of triglyceride rich lipoproteins, chylomicrons (CM) and very low density lipoproteins (VLDL). These included the identification of microsomal transfer protein, the cotranslational targeting of apoproteinB (apoB) for degradation regulated by the availability of lipids, and the characterization of transport vesicles transporting primordial apoB containing particles to the Golgi. The lipase maturation factor 1, glycosylphosphatidylinositol-anchored high density lipoprotein binding protein 1 and an angiopoietin-like protein play a role in lipoprotein lipase (LPL)-mediated hydrolysis of secreted CMs and VLDL so that the right amount of fatty acid is delivered to the right tissue at the right time. Expression of the low density lipoprotein (LDL) receptor is regulated at both transcriptional and posttranscriptional level. Proprotein convertase subtilisin/ kexin type 9 (PCSK9) has a pivotal role in the degradation of LDL receptor. Plasma remnant lipoproteins bind to specific receptors in the liver, the LDL receptor, VLDL receptor and LDL receptor-like proteins prior to removal from the plasma. Reverse cholesterol transport occurs when lipid free apoAI recruits cholesterol and phospholipid to assemble high density lipoprotein (HDL) particles. The discovery of ABC transporters (ABCA1 and ABCG1) and scavenger receptor class B type I (SR-BI) provided further information on the biogenesis of HDL. In humans HDLcholesterol can be returned to the liver either by direct uptake by SR-BI or through cholesteryl ester transfer protein exchange of cholesteryl ester for triglycerides in apoB lipoproteins, followed by hepatic uptake of apoB containing particles. Cholesterol content in cells is regulated by several transcription factors, including the liver X receptor and sterol regulatory element binding protein. This review summarizes recent advances in knowledge of the molecular mechanisms regulating lipoprotein metabolism.Keywords: ABCA1; angiopoietin-like proteins; apoC; apoAI; apolipoprotein E (apoE); cholesterol ester transfer protein; chylomicron; LDL receptor; lecithin cholesterol acyl transferase; lipoprotein(a); lipoprotein lipase; microsomal transfer protein; propertin convertase subtilisin/ kexin type 9; SR-BI; phospholipid transfer protein; very low density lipoproteins (VLDL). Abstract 1695

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Section: Ldl Receptor and Apolipoproteinsmentioning

confidence: 99%

Recent advances in physiological lipoprotein metabolism

Ramasamy

2014

Clinical Chemistry and Laboratory Medicine (CCLM)

178

159

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“…Finally, it was reported that the N-terminal negatively charged sequence of the prosegment of PCSK9 is critical for the binding of the [prosegment≡PCSK9] to LDL-C (likely to a positively charged sequence within ApoB). 60 Because liver expresses mostly ApoB-100 and the small intestine ApoB-48, and the latter does not bind the LDLR, it is possible that the difference between liver and small intestine in relation to responsiveness to circulating PCSK9 may be affected by these 2 isoforms of ApoB.…”

Section: Small Intestine and Pancreasmentioning

confidence: 99%

“…Recent evidence suggested that the association of PCSK9 with LDL particles in plasma lowers the ability of PCSK9 to bind to cell surface LDLR, thereby blunting PCSK9-mediated LDLR degradation. 60 Because ApoB is the major protein in LDL, this suggests that it is the active component that binds PCSK9 in plasma and blunts its function on the LDLR. Whether such binding implicates the interaction of the acidic aa 31 to 58 at the N terminus of the prosegment of PCSK9 with a positively charged domain in ApoB has yet to be demonstrated.…”

mentioning

confidence: 99%

Pcsk9

Seidah

Awan

Chrétien³

et al. 2014

Circulation Research

495

197

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“…In plasma, it is estimated that approximately 40% of circulating PCSK9 is carried on the LDL cholesterol (LDL-C) particle and is postulated to bind apo B100 (15 ).…”

Section: Circulating Isoforms Mature and Furin Cleaved (Potential Role)mentioning

confidence: 99%

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9): Lessons Learned from Patients with Hypercholesterolemia

2014

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BACKGROUND:Identification of the proprotein convertase subtilisin/kexin type 9 (PCSK9) as the third gene causing familial hypercholesterolemia (FH) and understanding its complex biology has led to the discovery of a novel class of therapeutic agents.CONTENT: PCSK9 undergoes autocatalytic cleavage in the endoplasmic reticulum and enters the secretory pathway. The PCSK9 gene is under the regulatory control of sterol receptor binding proteins 1 and 2. Statins increase PCSK9 and this may modulate the response to this class of medications. In plasma, PCSK9 binds to the epidermal growth factor-like domain of the LDL receptor (LDL-R) on the cell and, once incorporated in the late endosomal pathway, directs the LDL-R toward lysosomal degradation rather than recycling to the plasma membrane. Thus, gain-of-function PCSK9 mutations lead to an FH phenotype, whereas loss-of-function mutations are associated with increased LDL-R-mediated endocytosis of LDL particles and lower LDL cholesterol in plasma. Inhibition of PCSK9 is thus an attractive therapeutic target. Presently, this is achieved by using monoclonal antibodies for allosteric inhibition of the PCSK9 -LDL-R interaction. Phase 2 and 3 clinical trials in patients with moderate and severe hypercholesterolemia (including FH) show that this approach is safe and highly efficacious to lower LDL-C and lipoprotein(a).

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Low Density Lipoprotein Binds to Proprotein Convertase Subtilisin/Kexin Type-9 (PCSK9) in Human Plasma and Inhibits PCSK9-mediated Low Density Lipoprotein Receptor Degradation

Cited by 162 publications

References 51 publications

Recent advances in physiological lipoprotein metabolism

Recent advances in physiological lipoprotein metabolism

Pcsk9

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9): Lessons Learned from Patients with Hypercholesterolemia

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