PCSK9: a convertase that coordinates LDL catabolism
The identification and characterization of proprotein convertase subtilisin-like/kexin type 9 (PCSK9) have provided new insights into LDL metabolism and the causal role of LDL in coronary heart disease (CHD). PCSK9 is a secreted protease that mediates degradation of the LDL receptor by interacting with the extracellular domain and targeting the receptor for degradation. Individuals with loss-of-function mutations in PCSK9 have reduced plasma levels of LDL cholesterol and are protected from CHD; these observations have validated PCSK9 as a therapeutic target and suggested new approaches for the treatment and prevention of CHD. The identification and characterization of proprotein convertase subtilisin-like/kexin type 9 (PCSK9) have provided new insights into LDL metabolism and the causal role of LDL in coronary heart disease (CHD). PCSK9 is a secreted protease that mediates degradation of the LDL receptor by interacting with the extracellular domain and targeting the receptor for degradation. Individuals with loss-of-function mutations in PCSK9 have reduced plasma levels of LDL cholesterol and are protected from CHD; these observations have validated PCSK9 as a therapeutic target and suggested new approaches for the treatment and prevention of CHD. For the past four decades, characterization of patients with genetic disorders of lipid metabolism has revealed key components of the molecular machinery involved in biosynthetic and regulatory pathways that produce, transport, and eliminate cholesterol. These findings have led to the development of potent cholesterol-lowering drugs that reduce coronary heart disease (CHD). The identification of new forms of genetic hyperlipidemias continues to reveal novel participants, as exemplified by the discovery that mutations in proprotein convertase subtilisin-like/kexin type 9 (PCSK9) have profound effects on plasma levels of LDL cholesterol (LDL-C). Here, we focus on advances in PCSK9 biology and structure during the last 2 years. In 2003, Abifadel et al. (1Abifadel M. Varret M. Rabes J.P. Allard D. Ouguerram K. Devillers M. Cruaud C. Benjannet S. Wickham L. Erlich D. al et Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.Nat. Genet. 2003; 34: 154-156Crossref PubMed Scopus (2092) Google Scholar) identified three families with autosomal dominant hypercholesterolemia and premature CHD caused by missense mutations in the ninth member of the proprotein convertase family, PCSK9. PCSK9 encodes a 692 amino acid protein that is expressed predominantly in liver, intestine, and kidney (2Zaid A. Roubtsova A. Essalmani R. Marcinkiewicz J. Chamberland A. Hamelin J. Tremblay M. Jacques H. Jin W. Davignon J. al et Proprotein convertase subtilisin/kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration.Hepatology. 2008; 48: 646-654Crossref PubMed Scopus (302) Google Scholar). The protein contains a signal sequence, a prodomain (amino acids 31–152), a catalytic domain (amino acids 153–451), and a C-terminal domain (amino acids 452–692) that are rich in cysteines and histidines (Fig. 1A). Overexpression of PCSK9 in livers of mice markedly reduces hepatic LDL receptor (LDLR) protein (but not mRNA) levels, causing hypercholesterolemia (3Horton J.D. Cohen J.C. Hobbs H.H. Molecular biology of PCSK9: its role in LDL metabolism.Trends Biochem. Sci. 2007; 32: 71-77Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar). This finding suggested that the missense mutations identified by Abifadel et al. (1Abifadel M. Varret M. Rabes J.P. Allard D. Ouguerram K. Devillers M. Cruaud C. Benjannet S. Wickham L. Erlich D. al et Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.Nat. Genet. 2003; 34: 154-156Crossref PubMed Scopus (2092) Google Scholar) conferred a gain-of-function to the mutant protein. Subsequent studies revealed that inactivation of PCSK9 in humans and mice resulted in hypocholesterolemia (3Horton J.D. Cohen J.C. Hobbs H.H. Molecular biology of PCSK9: its role in LDL metabolism.Trends Biochem. Sci. 2007; 32: 71-77Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar). PCSK9 is synthesized as a 73 kDa zymogen in the endoplasmic reticulum (ER) and is modified en route to the cell surface (Fig. 1B). The protein undergoes autocatalytic cleavage between residues 152 and 153 (FAQ152↓SIP). The N-terminal prodomain remains tightly associated with the 63 kDa mature protein and acts as a chaperone to transport PCSK9 through the secretory pathway (4Seidah N.G. Benjannet S. Wickham L. Marcinkiewicz J. Jasmin S.B. Stifani S. Basak A. Prat A. Chretien M. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation.Proc. Natl. Acad. Sci. USA. 2003; 100: 928-933Crossref PubMed Scopus (878) Google Scholar). A mutation in PCSK9 (C679×) that prevents folding of the C-terminal domain does not prevent autocatalytic cleavage, suggesting that cleavage is cotranslational (3Horton J.D. Cohen J.C. Hobbs H.H. Molecular biology of PCSK9: its role in LDL metabolism.Trends Biochem. Sci. 2007; 32: 71-77Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar). After cleavage, the last four amino acids of the prodomain blanket the catalytic triad, thereby restricting access to potential substrates. PCSK9 undergoes a series of posttranslational modifications, including glycosylation (4Seidah N.G. Benjannet S. Wickham L. Marcinkiewicz J. Jasmin S.B. Stifani S. Basak A. Prat A. Chretien M. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation.Proc. Natl. Acad. Sci. USA. 2003; 100: 928-933Crossref PubMed Scopus (878) Google Scholar), phosphorylation (5Dewpura T. Raymond A. Hamelin J. Seidah N.G. Mbikay M. Chretien M. Mayne J. PCSK9 is phosphorylated by a Golgi casein kinase-like kinase ex vivo and circulates as a phosphoprotein in humans.FEBS J. 2008; 275: 3480-3493Crossref PubMed Scopus (60) Google Scholar), and tyrosine sulfation (6Benjannet S. Rhainds D. Hamelin J. Nassoury N. Seidah N.G. The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural mutations and post-translational modifications.J. Biol. Chem. 2006; 281: 30561-30572Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar) (Fig. 1A). None of these modifications is required for secretion of PCSK9, and their role in PCSK9 function remains obscure. Mice in which PCSK9 has been selectively inactivated in liver have no detectable PCSK9 in the blood, suggesting that the liver is the major source of circulating PCSK9 (2Zaid A. Roubtsova A. Essalmani R. Marcinkiewicz J. Chamberland A. Hamelin J. Tremblay M. Jacques H. Jin W. Davignon J. al et Proprotein convertase subtilisin/kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration.Hepatology. 2008; 48: 646-654Crossref PubMed Scopus (302) Google Scholar). Recently, several laboratories have developed ELISAs to measure plasma PCSK9 levels in humans (3Horton J.D. Cohen J.C. Hobbs H.H. Molecular biology of PCSK9: its role in LDL metabolism.Trends Biochem. Sci. 2007; 32: 71-77Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar, 7Mayne J. Dewpura T. Raymond A. Cousins M. Chaplin A. Lahey K.A. Lahaye S.A. Mbikay M. Ooi T.C. Chretien M. Plasma PCSK9 levels are significantly modified by statins and fibrates in humans.Lipids Health Dis. 2008; 7: 22Crossref PubMed Scopus (180) Google Scholar, 8Careskey H.E. Davis R.A. Alborn W.E. Troutt J.S. Cao G. Konrad R.J. Atorvastatin increases human serum levels of proprotein convertase subtilisin/kexin type 9.J. Lipid Res. 2008; 49: 394-398Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar, 9Lambert G. Ancellin N. Charlton F. Comas D. Pilot J. Keech A. Patel S. Sullivan D.R. Cohn J.S. Rye K.A. al et Plasma PCSK9 concentrations correlate with LDL and total cholesterol in diabetic patients and are decreased by fenofibrate treatment.Clin. Chem. 2008; 54: 1038-1045Crossref PubMed Scopus (141) Google Scholar). The mean concentration of PCSK9 varies widely between these assays (ranging from 500 ng/ml to 4 μg/ml) likely due to differences in antibody specificities and the standards used in the assays. PCSK9 levels correlate with LDL-C (r = 0.3–0.6) but not HDL-C (8Careskey H.E. Davis R.A. Alborn W.E. Troutt J.S. Cao G. Konrad R.J. Atorvastatin increases human serum levels of proprotein convertase subtilisin/kexin type 9.J. Lipid Res. 2008; 49: 394-398Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar, 9Lambert G. Ancellin N. Charlton F. Comas D. Pilot J. Keech A. Patel S. Sullivan D.R. Cohn J.S. Rye K.A. al et Plasma PCSK9 concentrations correlate with LDL and total cholesterol in diabetic patients and are decreased by fenofibrate treatment.Clin. Chem. 2008; 54: 1038-1045Crossref PubMed Scopus (141) Google Scholar). Plasma levels of LDL-C and PCSK9 may be directly related because expression of PCSK9 promotes the degradation of hepatic LDLRs. The levels of these two proteins are not invariably coupled; treatment with high-dose statins reduces plasma levels of LDL-C but increases levels of circulating PCSK9 (8Careskey H.E. Davis R.A. Alborn W.E. Troutt J.S. Cao G. Konrad R.J. Atorvastatin increases human serum levels of proprotein convertase subtilisin/kexin type 9.J. Lipid Res. 2008; 49: 394-398Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar). Recombinant PCSK9 has a half-life of ∼5 min in the blood of wild-type mice (10Grefhorst A. McNutt M.C. J.D. Plasma PCSK9 reduces liver LDL in Lipid Res. 2008; 49: Full Text Full Text PDF PubMed Scopus Google Scholar). the increases the half-life of PCSK9 to as a major for PCSK9 (10Grefhorst A. McNutt M.C. J.D. Plasma PCSK9 reduces liver LDL in Lipid Res. 2008; 49: Full Text Full Text PDF PubMed Scopus Google Scholar). The of PCSK9 from in that the of PCSK9 be the plasma concentrations of PCSK9. The of PCSK9 on LDL-C levels to be through inactivation of does not reduce plasma cholesterol levels in mice (2Zaid A. Roubtsova A. Essalmani R. Marcinkiewicz J. Chamberland A. Hamelin J. Tremblay M. Jacques H. Jin W. Davignon J. al et Proprotein convertase subtilisin/kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration.Hepatology. 2008; 48: 646-654Crossref PubMed Scopus (302) Google Scholar). in wild-type and PCSK9 mice that circulating PCSK9 degradation of in the liver (3Horton J.D. Cohen J.C. Hobbs H.H. Molecular biology of PCSK9: its role in LDL metabolism.Trends Biochem. Sci. 2007; 32: 71-77Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar). of human PCSK9 into mice to levels with in human plasma caused a of hepatic (10Grefhorst A. McNutt M.C. J.D. Plasma PCSK9 reduces liver LDL in Lipid Res. 2008; 49: Full Text Full Text PDF PubMed Scopus Google Scholar). These PCSK9 the cell remains that the protein with the of the in the secretory pathway (Fig. Overexpression of PCSK9 the degradation of the in a reticulum Natl. Acad. Sci. USA. PubMed Scopus Google Scholar). is not to PCSK9 in the of PCSK9 into mice levels as as for hepatic expression but to reduce in (10Grefhorst A. McNutt M.C. J.D. Plasma PCSK9 reduces liver LDL in Lipid Res. 2008; 49: Full Text Full Text PDF PubMed Scopus Google Scholar). not in of mice (3Horton J.D. Cohen J.C. Hobbs H.H. Molecular biology of PCSK9: its role in LDL metabolism.Trends Biochem. Sci. 2007; 32: 71-77Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar). in reduced in several in the of of PCSK9 R.J. A. M. Alborn W.E. Konrad R.J. Cao G. proprotein convertase subtilisin/kexin type 9 reduces hepatic and low-density lipoprotein in Res. 2008; PubMed Scopus Google Scholar). PCSK9 in is A protein required for in but not in cell (3Horton J.D. Cohen J.C. Hobbs H.H. Molecular biology of PCSK9: its role in LDL metabolism.Trends Biochem. Sci. 2007; 32: 71-77Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar). A be that PCSK9 selectively in the liver to prevent the of thereby their to PCSK9 is the of by regulatory proteins (3Horton J.D. Cohen J.C. Hobbs H.H. Molecular biology of PCSK9: its role in LDL metabolism.Trends Biochem. Sci. 2007; 32: 71-77Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar), which involved in acid and cholesterol metabolism from to Lipid Res. 2008; Google Scholar). in the of PCSK9 has been D. of proprotein convertase subtilisin/kexin type 9 expression by Lipid Res. 2008; 49: Full Text Full Text PDF PubMed Scopus Google Scholar). has been in the of PCSK9 G. F. A. M. PCSK9 expression is by and regulatory protein Biol. Chem. 2006; 281: Full Text Full Text PDF PubMed Scopus Google Scholar), to a role (3Horton J.D. Cohen J.C. Hobbs H.H. Molecular biology of PCSK9: its role in LDL metabolism.Trends Biochem. Sci. 2007; 32: 71-77Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar). that as cholesterol are associated with PCSK9 levels in livers of mice D. of proprotein convertase subtilisin/kexin type 9 expression by Lipid Res. 2008; 49: Full Text Full Text PDF PubMed Scopus Google Scholar). Mice that hepatic have reduced PCSK9 levels, mice that not of the receptor receptor reduce PCSK9 in human C. S. S. M. of the receptor PCSK9 expression in human 2008; PubMed Scopus Google Scholar, S. C. Ouguerram K. M. for the of proprotein convertase subtilisin/kexin type 9.J. Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). The of these and studies have provided new insights into PCSK9 and promotes degradation. The extracellular domain of the of N-terminal domain that mediates to by domain that contains a of and from a by a domain G. L. K. K. J. of the LDL receptor extracellular domain PubMed Scopus Google Scholar). After LDL to the the undergoes and is to the (Fig. from to Lipid Res. 2008; Google Scholar). The are in the of the and the to the cell PCSK9 to the domain of the in a R. M. J.D. Cohen J.C. Hobbs H.H. of proprotein convertase subtilisin/kexin 9 to A of lipoprotein receptor receptor and increases Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). of the that not PCSK9 are required for including the domain and three R. Cohen J.C. Hobbs H.H. for degradation of the low-density lipoprotein Natl. Acad. Sci. USA. 2008; PubMed Scopus Google Scholar). The for these is not The C-terminal domain of PCSK9 does not to the but is required for degradation R. Cohen J.C. Hobbs H.H. for degradation of the low-density lipoprotein Natl. Acad. Sci. USA. 2008; PubMed Scopus Google Scholar). the may protein that to the domain may prevent the of a protein required for of the from to the cell In the structure of the the 4 and with the domain G. L. K. K. J. of the LDL receptor extracellular domain PubMed Scopus Google Scholar). These findings suggested that the from to a acid thereby the of LDL G. L. K. K. J. of the LDL receptor extracellular domain PubMed Scopus Google Scholar). The in is not required for degradation by PCSK9 R. Cohen J.C. Hobbs H.H. for degradation of the low-density lipoprotein Natl. Acad. Sci. USA. 2008; PubMed Scopus Google Scholar), but the of PCSK9 to the is suggesting that PCSK9 to in the R. M. J.D. Cohen J.C. Hobbs H.H. of proprotein convertase subtilisin/kexin 9 to A of lipoprotein receptor receptor and increases Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, D. M.C. J.S. al et and studies of PCSK9 and its to hypercholesterolemia.Nat. Biol. 2007; PubMed Scopus Google Scholar, S. M. J.C. D. A. al et of and lipoprotein on LDL receptor Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). is PCSK9 and LDL for to the The structure of PCSK9 by three in D. M.C. J.S. al et and studies of PCSK9 and its to hypercholesterolemia.Nat. Biol. 2007; PubMed Scopus Google Scholar, J. S.A. G. The structure of PCSK9 A with the C-terminal Natl. Acad. Sci. USA. 2007; PubMed Scopus Google Scholar, S. S. The structure of PCSK9: a of plasma 2007; Full Text Full Text PDF PubMed Scopus Google Scholar), of a of The catalytic domain that of for the with the prodomain that the from substrates. The C-terminal domain is a structure that contains three with The structure of PCSK9 in with the from the revealed that PCSK9 the N-terminal of the McNutt M.C. J.D. J. Molecular for LDL receptor by Natl. Acad. Sci. USA. 2008; PubMed Scopus Google Scholar). The prodomain and the C-terminal domain of PCSK9 not the domain (Fig. The between PCSK9 and is from the catalytic and is by residues by several levels of PCSK9 and expression in promotes of PCSK9 with of the of which may that PCSK9 and S. G. Benjannet S. Marcinkiewicz J. Nassoury N. H. J. Prat A. Seidah N.G. The proprotein convertase PCSK9 the degradation of lipoprotein receptor (LDLR) and its and Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). Mutations in PCSK9 are for a of genetic R.A. S. R. M. al et of in patients in the to plasma lipid levels and coronary heart disease Genet. 2006; PubMed Scopus Google Scholar). In with hypercholesterolemia which is caused by mutations in the a of missense mutations in PCSK9 cause studies of PCSK9 into the by which two gain-of-function mutations in PCSK9, and may function to degradation. is wild-type PCSK9 in degradation of to to for the receptor (3Horton J.D. Cohen J.C. Hobbs H.H. Molecular biology of PCSK9: its role in LDL metabolism.Trends Biochem. Sci. 2007; 32: 71-77Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar, D. M.C. J.S. al et and studies of PCSK9 and its to hypercholesterolemia.Nat. Biol. 2007; PubMed Scopus Google Scholar, S. M. J.C. D. A. al et of and lipoprotein on LDL receptor Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). In the structure of the forms a with to the of tyrosine to the of to of a new A. L. L. J.C. A. al et and characterization of the type and natural hypercholesterolemia Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). with amino including and increases the between PCSK9 and the S. D. J.C. S. A. al et of PCSK9 for Lipid Res. 2008; 49: Full Text Full Text PDF PubMed Scopus Google Scholar). the may that PCSK9 with to the of on the and with proteins that of for the is associated with hypercholesterolemia M. S. in 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). acid are associated with plasma LDL-C levels and CHD is in R.A. S. R. M. al et of in patients in the to plasma lipid levels and coronary heart disease Genet. 2006; PubMed Scopus Google Scholar, Patel D. C. hypercholesterolemia in four families with the mutation in the PCSK9 and treatment Biol. PubMed Scopus Google Scholar), likely because the mutant PCSK9 a in as to the patients with these mutations have to R.A. S. R. M. al et of in patients in the to plasma lipid levels and coronary heart disease Genet. 2006; PubMed Scopus Google Scholar, Patel D. C. hypercholesterolemia in four families with the mutation in the PCSK9 and treatment Biol. PubMed Scopus Google Scholar). The gain-of-function mutation does not the of PCSK9 for the D. M.C. J.S. al et and studies of PCSK9 and its to hypercholesterolemia.Nat. Biol. 2007; PubMed Scopus Google Scholar, McNutt M.C. J.D. J. Molecular for LDL receptor by Natl. Acad. Sci. USA. 2008; PubMed Scopus Google Scholar). The and a mutation in J. T. T. of novel mutations in the catalytic domain of the PCSK9 2008; PubMed Scopus (60) Google Scholar), may a potential cleavage in PCSK9 (6Benjannet S. Rhainds D. Hamelin J. Nassoury N. Seidah N.G. The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural mutations and post-translational modifications.J. Biol. Chem. 2006; 281: 30561-30572Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar). is these mutations be to the half-life of PCSK9, causing these to have circulating levels of the protein. The gain-of-function mutation in PCSK9 is which in the prodomain (Fig. 1A). The mutation reduces autocatalytic cleavage of PCSK9, in decreased PCSK9 The mutant protein has a in for the D. M.C. J.S. al et and studies of PCSK9 and its to hypercholesterolemia.Nat. Biol. 2007; PubMed Scopus Google Scholar, S. M. J.C. D. A. al et of and lipoprotein on LDL receptor Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). In functional studies of a mutant PCSK9 that contains the and is on the of the protein to reduce LDL in suggesting that the two mutations through S. D. J.C. S. A. al et of PCSK9 for Lipid Res. 2008; 49: Full Text Full Text PDF PubMed Scopus Google Scholar). The mutation may with of the to the cell as has been suggested Overexpression of PCSK9 the degradation of the in a reticulum Natl. Acad. Sci. USA. PubMed Scopus Google Scholar, Charlton F. N. R. F. Sullivan D.R. Rye K.A. al et and characterization of two PCSK9 associated with hypercholesterolemia in from and 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). loss-of-function in PCSK9 have been identified in with hypocholesterolemia (3Horton J.D. Cohen J.C. Hobbs H.H. Molecular biology of PCSK9: its role in LDL metabolism.Trends Biochem. Sci. 2007; 32: 71-77Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar). of these mutations are but three to the between LDL-C levels and CHD. In the in a missense mutation in the prodomain in of associated with a in LDL-C and a in CHD (3Horton J.D. Cohen J.C. Hobbs H.H. Molecular biology of PCSK9: its role in LDL metabolism.Trends Biochem. Sci. 2007; 32: 71-77Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar). In the two mutations and in of caused a in LDL-C and in CHD (3Horton J.D. Cohen J.C. Hobbs H.H. Molecular biology of PCSK9: its role in LDL metabolism.Trends Biochem. Sci. 2007; 32: 71-77Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar). The in CHD associated with the mutation has been in two studies R. N. for prevention of coronary 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, S. A PCSK9 missense associated with a reduced of J. 2008; PubMed Scopus Google Scholar). the in CHD in with PCSK9 be due to of PCSK9 on CHD that is of the on LDL-C Recently, in and have been to LDL-C levels and CHD S. A. R. al et identified that lipid concentrations and of coronary Genet. 2008; PubMed Scopus Google Scholar). These findings are with the loss-of-function in PCSK9 CHD through plasma levels of the between hypocholesterolemia and and in proprotein convertase subtilisin/kexin type 9 protease LDL and 2007; PubMed Scopus Google Scholar) the of PCSK9 loss-of-function in with and and differences in between the two studies are these that plasma levels of cholesterol are a not a causal to with total PCSK9 have been identified The mutation in PCSK9 is and blood cholesterol in a 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). plasma levels of LDL-C and the of the of PCSK9 in LDL in the consequences of PCSK9 of the from human studies that PCSK9 be target for the treatment of for the development of of the protease has been by the finding that the catalytic of PCSK9 is not required for degradation M.C. J.D. is not required for secreted PCSK9 to reduce lipoprotein in Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). of PCSK9 catalytic may be autocatalytic of PCSK9 is required for secretion of the protein from the to PCSK9 is to the PCSK9 with to mice reduced PCSK9 expression by and plasma cholesterol levels by A. of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in Lipid Res. 2007; 48: Full Text Full Text PDF PubMed Scopus Google Scholar). A of in to reduced plasma PCSK9 levels by and plasma LDL-C levels by M. A. A. D. K. R. al et targeting PCSK9 plasma cholesterol in and LDL cholesterol in Natl. Acad. Sci. USA. 2008; PubMed Scopus Google Scholar). Plasma LDL-C levels significantly A to PCSK9 is to prevent of PCSK9 to the cell surface with PCSK9. R.J. S. A. H. W. al et PCSK9 lipoprotein receptor through Lipid Res. 2007; 48: Full Text Full Text PDF PubMed Scopus Google Scholar) to L. L. R. H. PCSK9 to and be by Res. 2008; PubMed Scopus Google Scholar) the of PCSK9 to degradation. The of on PCSK9 the cell to hypercholesterolemia with of that of PCSK9 the effects of these LDL is and plasma cholesterol levels are reduced in mice with mice (3Horton J.D. Cohen J.C. Hobbs H.H. Molecular biology of PCSK9: its role in LDL metabolism.Trends Biochem. Sci. 2007; 32: 71-77Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar). PCSK9 in plasma PCSK9 levels J. Dewpura T. Raymond A. Cousins M. Chaplin A. Lahey K.A. Lahaye S.A. Mbikay M. Ooi T.C. Chretien M. Plasma PCSK9 levels are significantly modified by statins and fibrates in humans.Lipids Health Dis. 2008; 7: 22Crossref PubMed Scopus (180) Google Scholar, 8Careskey H.E. Davis R.A. Alborn W.E. Troutt J.S. Cao G. Konrad R.J. Atorvastatin increases human serum levels of proprotein convertase subtilisin/kexin type 9.J. Lipid Res. 2008; 49: 394-398Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar). The in PCSK9 the in hepatic which may LDL-C with the of and of the reduce plasma LDL levels by H.E. of the and of and J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). is that PCSK9 has degradation. proteins that contains are to with PCSK9, on the structure of the The of PCSK9 in humans is plasma cholesterol levels, but remains that to as may reveal associated with of PCSK9. For mice no PCSK9 in liver have liver regeneration a (2Zaid A. Roubtsova A. Essalmani R. Marcinkiewicz J. Chamberland A. Hamelin J. Tremblay M. Jacques H. Jin W. Davignon J. al et Proprotein convertase subtilisin/kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration.Hepatology. 2008; 48: 646-654Crossref PubMed Scopus (302) Google Scholar). The reduced CHD in with loss-of-function mutations in PCSK9 that LDL is for the development of CHD and that a in LDL-C levels in the of and (3Horton J.D. Cohen J.C. Hobbs H.H. Molecular biology of PCSK9: its role in LDL metabolism.Trends Biochem. Sci. 2007; 32: 71-77Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar). The in CHD associated with PCSK9 is be from This the of of to LDL-C as as the of mutations in PCSK9 are associated with reduced plasma levels of in W. of PCSK9 mutations to serum low-density lipoprotein cholesterol in and The J. 2007; 100: Full Text Full Text PDF PubMed Scopus Google Scholar). In with a as a plasma of measure of cholesterol the LDL as of cholesterol a in patients Hobbs H.H. In The and Molecular of C. A. W. and D. Scholar) and of the on the and treatment of blood cholesterol in Scholar). CHD a of LDL is by a This is in in and in in and is significantly in are for PCSK9 loss-of-function These findings new in plasma levels of LDL-C the of cholesterol-lowering new to the of blood to LDL of CHD The discovery of PCSK9, the of the by which plasma LDL and the of PCSK9 as a therapeutic target for the treatment of hypercholesterolemia in years. The in a is a to the of characterization and genetic studies of patients (1Abifadel M. Varret M. Rabes J.P. Allard D. Ouguerram K. Devillers M. Cruaud C. Benjannet S. Wickham L. Erlich D. al et Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.Nat. Genet. 2003; 34: 154-156Crossref PubMed Scopus (2092) Google Scholar), in the