PCSK9 function and physiology (2008)

During the past few years, the proprotein convertase subtilisin kexin 9 (PCSK9) field has been red hot, fueled by the realization that PCSK9 is a key player in plasma cholesterol metabolism and by a hope, shared by scientists in academia and industry alike, that PCSK9 is a target for treating hypercholesterolemia. PCSK9 regulates the levels of the LDL receptor (1.Park S.W. Moon Y.A. Horton J.D. Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver.J. Biol. Chem. 2004; 279: 50630-50638Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar, 2.Maxwell K.N. Breslow J.L. Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype.Proc. Natl. Acad. Sci. USA. 2004; 101: 7100-7105Crossref PubMed Scopus (514) Google Scholar, 3.Benjannet S. Rhainds D. Essalmani R. Mayne J. Wickham L. Jin W. Asselin M.C. Hamelin J. Varret M. Allard D. et al.NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol.J. Biol. Chem. 2004; 279: 48865-48875Abstract Full Text Full Text PDF PubMed Scopus (516) Google Scholar), which is a plasma membrane glycoprotein that removes cholesterol-rich LDL particles from the plasma (4.Brown M.S. Goldstein J.L. Lipoprotein receptors in the liver. Control signals for plasma cholesterol traffic.J. Clin. Invest. 1983; 72: 743-747Crossref PubMed Scopus (373) Google Scholar, 5.Goldstein J.L. Brown M.S. The low-density lipoprotein pathway and its relation to atherosclerosis.Annu. Rev. Biochem. 1977; 46: 897-930Crossref PubMed Scopus (1616) Google Scholar). Gain-of-function mutations in PCSK9 reduce LDL receptor levels in the liver, resulting in high levels of LDL cholesterol in the plasma and increased susceptibility to coronary heart disease (6.Abifadel M. Varret M. Rabes J.P. Allard D. Ouguerram K. Devillers M. Cruaud C. Benjannet S. Wickham L. Erlich D. et al.Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.Nat. Genet. 2003; 34: 154-156Crossref PubMed Scopus (2222) Google Scholar). Loss-of-function mutations lead to higher levels of the LDL receptor, lower LDL cholesterol levels, and protection from coronary heart disease (7.Berge K.E. Ose L. Leren T.P. Missense mutations in the PCSK9 gene are associated with hypocholesterolemia and possibly increased response to statin therapy.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 1094-1100Crossref PubMed Scopus (208) Google Scholar, 8.Kotowski I.K. Pertsemlidis A. Luke A. Cooper R.S. Vega G.L. Cohen J.C. Hobbs H.H. A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol.Am. J. Hum. Genet. 2006; 78: 410-422Abstract Full Text Full Text PDF PubMed Scopus (445) Google Scholar, 9.Cohen J.C. Boerwinkle E. Mosley Jr., T.H. Hobbs H.H. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.N. Engl. J. Med. 2006; 354: 1264-1272Crossref PubMed Scopus (2466) Google Scholar, 10.Cohen J. Pertsemlidis A. Kotowski I.K. Graham R. Garcia C.K. Hobbs H.H. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9.Nat. Genet. 2005; 37: 161-165Crossref PubMed Scopus (1090) Google Scholar, 11.Zhao Z. Tuakli-Wosornu Y. Lagace T.A. Kinch L. Grishin N.V. Horton J.D. Cohen J.C. Hobbs H.H. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote.Am. J. Hum. Genet. 2006; 79: 514-523Abstract Full Text Full Text PDF PubMed Scopus (534) Google Scholar). The loss of PCSK9 appears to have no adverse consequences (11.Zhao Z. Tuakli-Wosornu Y. Lagace T.A. Kinch L. Grishin N.V. Horton J.D. Cohen J.C. Hobbs H.H. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote.Am. J. Hum. Genet. 2006; 79: 514-523Abstract Full Text Full Text PDF PubMed Scopus (534) Google Scholar). Thus, interest in PCSK9 as a cholesterol-lowering target has been high, and an army of investigators is now working to elucidate PCSK9 molcular interactions and physiology. In this issue of the Journal of Lipid Research (JLR), two leading research groups describe their recent efforts. Dr. Shilpa Pandit et al. (12.Pandit S. Wisniewski D. Santoro J.C. Ha S. Ramakrishnan V. Cubbon R.M. Cummings R.T. Wright S.D. Sparrow C.P. Sitlani A. Fisher T.S. Functional Analysis of Sites within PCSK9 Responsible for Hypercholesterolemia.J. Lipid Res. 2008; 49: 1333-1343Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar) from Merck Research Laboratories describe the functional basis for the hypercholesterolemia associated with gain-of-function missense mutations in PCSK9. Grefhorst et al. (13.Grefhorst A. McNutt M.C. Lagace T.A. Horton J.D. Plasma PCSK9 Preferentially Reduces Liver LDL Receptors in Mice.J. Lipid Res. 2008; 49: 1303-1311Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar) at UT-Southwestern describe the kinetics and metabolism of recombinant PCSK9 and the impact of PCSK9 on LDL receptors in the liver and adrenal gland. PCSK9 was initially identified as a new member of the proprotein convertase family and suggested to have a role in liver regeneration and the differentiation of cortical neurons (14.Seidah 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 (934) Google Scholar). Its relevance to cholesterol metabolism was suggested by a pair of unrelated observations. The first was the discovery, by Abifadel et al. (6.Abifadel M. Varret M. Rabes J.P. Allard D. Ouguerram K. Devillers M. Cruaud C. Benjannet S. Wickham L. Erlich D. et al.Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.Nat. Genet. 2003; 34: 154-156Crossref PubMed Scopus (2222) Google Scholar), that heterozygosity for specific PCSK9 missense mutations cause autosomal dominant hypercholesterolemia. For most enzymes, the loss of a single allele is inconsequential, so the authors immediately raised the possibility that PCSK9 missense mutations might increase plasma cholesterol levels via a gain-of-function mechanism (6.Abifadel M. Varret M. Rabes J.P. Allard D. Ouguerram K. Devillers M. Cruaud C. Benjannet S. Wickham L. Erlich D. et al.Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.Nat. Genet. 2003; 34: 154-156Crossref PubMed Scopus (2222) Google Scholar). The second observation was that PCSK9 mRNA levels are responsive to cellular cholesterol levels through the transcription factor SREBP-2 (15.Horton J.D. Shah N.A. Warrington J.A. Anderson N.N. Park S.W. Brown M.S. Goldstein J.L. Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes.Proc. Natl. Acad. Sci. USA. 2003; 100: 12027-12032Crossref PubMed Scopus (1097) Google Scholar, 16.Maxwell K.N. Soccio R.E. Duncan E.M. Sehayek E. Breslow J.L. Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice.J. Lipid Res. 2003; 44: 2109-2119Abstract Full Text Full Text PDF PubMed Scopus (310) Google Scholar). The human genetic and gene-expression discoveries sparked interest in defining PCSK9 function. Mouse experiments quickly established a link between PCSK9 and levels of LDL receptors in the liver. Adenoviral overexpression of PCSK9 in mice resulted in higher LDL cholesterol levels and lower levels of LDL receptors, without changing LDL receptor mRNA levels (1.Park S.W. Moon Y.A. Horton J.D. Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver.J. Biol. Chem. 2004; 279: 50630-50638Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar, 3.Benjannet S. Rhainds D. Essalmani R. Mayne J. Wickham L. Jin W. Asselin M.C. Hamelin J. Varret M. Allard D. et al.NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol.J. Biol. Chem. 2004; 279: 48865-48875Abstract Full Text Full Text PDF PubMed Scopus (516) Google Scholar, 17.Maxwell K.N. Fisher E.A. Breslow J.L. Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment.Proc. Natl. Acad. Sci. USA. 2005; 102: 2069-2074Crossref PubMed Scopus (316) Google Scholar). Similarly, PCSK9 transgenic mice exhibited increased LDL cholesterol levels, and LDL receptors in the liver were virtually eliminated (18.Lagace T.A. Curtis D.E. Garuti R. McNutt M.C. Park S.W. Prather H.B. Anderson N.N. Ho Y.K. Hammer R.E. Horton J.D. Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice.J. Clin. Invest. 2006; 116: 2995-3005Crossref PubMed Scopus (532) Google Scholar). Parabiosis studies established that the PCSK9 from a transgenic mouse reduced LDL receptor levels in the liver of a paired nontransgenic mouse (18.Lagace T.A. Curtis D.E. Garuti R. McNutt M.C. Park S.W. Prather H.B. Anderson N.N. Ho Y.K. Hammer R.E. Horton J.D. Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice.J. Clin. Invest. 2006; 116: 2995-3005Crossref PubMed Scopus (532) Google Scholar). Thus, circulating PCSK9 lowers LDL receptor levels. Conversely, knocking out PCSK9 increased hepatic LDL receptors and reduced plasma cholesterol levels (19.Rashid S. Curtis D.E. Garuti R. Anderson N.N. Bashmakov Y. Ho Y.K. Hammer R.E. Moon Y.A. Horton J.D. Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9.Proc. Natl. Acad. Sci. USA. 2005; 102: 5374-5379Crossref PubMed Scopus (566) Google Scholar). The loss-of-function findings in mice are complemented by human data. Nearly 1 in 50 African-Americans has one of two nonsense mutations in PCSK9, which lowers LDL cholesterol levels by ∼30% (9.Cohen J.C. Boerwinkle E. Mosley Jr., T.H. Hobbs H.H. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.N. Engl. J. Med. 2006; 354: 1264-1272Crossref PubMed Scopus (2466) Google Scholar, 10.Cohen J. Pertsemlidis A. Kotowski I.K. Graham R. Garcia C.K. Hobbs H.H. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9.Nat. Genet. 2005; 37: 161-165Crossref PubMed Scopus (1090) Google Scholar, 20.Hallman D.M. Srinivasan S.R. Chen W. Boerwinkle E. Berenson G.S. Relation of PCSK9 mutations to serum low-density lipoprotein cholesterol in childhood and adulthood (from The Bogalusa Heart Study).Am. J. Cardiol. 2007; 100: 69-72Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). A common missense mutation in Caucasians lowers LDL levels by ∼15% (7.Berge K.E. Ose L. Leren T.P. Missense mutations in the PCSK9 gene are associated with hypocholesterolemia and possibly increased response to statin therapy.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 1094-1100Crossref PubMed Scopus (208) Google Scholar, 8.Kotowski I.K. Pertsemlidis A. Luke A. Cooper R.S. Vega G.L. Cohen J.C. Hobbs H.H. A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol.Am. J. Hum. Genet. 2006; 78: 410-422Abstract Full Text Full Text PDF PubMed Scopus (445) Google Scholar, 9.Cohen J.C. Boerwinkle E. Mosley Jr., T.H. Hobbs H.H. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.N. Engl. J. Med. 2006; 354: 1264-1272Crossref PubMed Scopus (2466) Google Scholar, 20.Hallman D.M. Srinivasan S.R. Chen W. Boerwinkle E. Berenson G.S. Relation of PCSK9 mutations to serum low-density lipoprotein cholesterol in childhood and adulthood (from The Bogalusa Heart Study).Am. J. Cardiol. 2007; 100: 69-72Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 21.Cameron J. Holla O.L. Ranheim T. Kulseth M.A. Berge K.E. Leren T.P. Effect of mutations in the PCSK9 gene on the cell surface LDL receptors.Hum. Mol. Genet. 2006; 15: 1551-1558Crossref PubMed Scopus (226) Google Scholar). The lower cholesterol levels are accompanied by a strikingly reduced frequency of coronary heart disease (9.Cohen J.C. Boerwinkle E. Mosley Jr., T.H. Hobbs H.H. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.N. Engl. J. Med. 2006; 354: 1264-1272Crossref PubMed Scopus (2466) Google Scholar, 22.Brown M.S. Goldstein J.L. Biomedicine. Lowering LDL–not only how low, but how long?.Science. 2006; 311: 1721-1723Crossref PubMed Scopus (176) Google Scholar). loss of PCSK9 results in LDL cholesterol levels of but no (11.Zhao Z. Tuakli-Wosornu Y. Lagace T.A. Kinch L. Grishin N.V. Horton J.D. Cohen J.C. Hobbs H.H. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote.Am. J. Hum. Genet. 2006; 79: 514-523Abstract Full Text Full Text PDF PubMed Scopus (534) Google Scholar, D.M. The mutation in PCSK9 is and lowers cholesterol in a African 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). is PCSK9 and lower hepatic LDL receptor PCSK9 is a in liver, with an a and a of function. studies between the and J. J.L. The of PCSK9 at A with within the Natl. Acad. Sci. USA. 2007; PubMed Scopus Google Scholar), an associated with but the of this is its PCSK9 an cleavage that the but the to the and S. Rhainds D. Essalmani R. Mayne J. Wickham L. Jin W. Asselin M.C. Hamelin J. Varret M. Allard D. et al.NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol.J. Biol. Chem. 2004; 279: 48865-48875Abstract Full Text Full Text PDF PubMed Scopus (516) Google Scholar, 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 (934) Google Scholar). The is for the of PCSK9 (14.Seidah 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 (934) Google Scholar), the as a and The of the the of PCSK9 J. J.L. The of PCSK9 at A with within the Natl. Acad. Sci. USA. 2007; PubMed Scopus Google Scholar, D.E. S. S. The of a of plasma 2007; 15: Full Text Full Text PDF PubMed Scopus Google Scholar, Lagace T.A. McNutt M.C. Horton J.D. J. Molecular basis for LDL receptor by Natl. Acad. Sci. USA. 2008; PubMed Scopus Google Scholar). The observation that PCSK9 hepatic LDL receptors suggested the that the LDL receptor is and by PCSK9. was by the of Dr. Horton M.C. Lagace T.A. Horton J.D. is for PCSK9 to reduce low density lipoprotein receptors in Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). a for a of PCSK9 and that the protein the to lower LDL receptor levels M.C. Lagace T.A. Horton J.D. is for PCSK9 to reduce low density lipoprotein receptors in Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). PCSK9 lowers LDL receptor levels was for years, but recent studies are to the PCSK9 to the LDL receptor on the surface of but the of LDL receptors of the receptor (18.Lagace T.A. Curtis D.E. Garuti R. McNutt M.C. Park S.W. Prather H.B. Anderson N.N. Ho Y.K. Hammer R.E. Horton J.D. Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice.J. Clin. Invest. 2006; 116: 2995-3005Crossref PubMed Scopus (532) Google Scholar). the of the the of PCSK9 for the LDL receptor by Lagace T.A. Garuti R. Z. M. Horton J.D. Cohen J.C. Hobbs H.H. of proprotein convertase subtilisin/kexin type 9 to A of low density lipoprotein receptor decreases receptor and Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, T.S. Pandit S. M. Santoro J.C. Wisniewski D. Cummings R.T. A. Cubbon R.M. et of and low density lipoprotein (LDL) on LDL receptor Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). PCSK9 to the factor A of the LDL receptor Lagace T.A. Garuti R. Z. M. Horton J.D. Cohen J.C. Hobbs H.H. of proprotein convertase subtilisin/kexin type 9 to A of low density lipoprotein receptor decreases receptor and Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar), a to for of the LDL receptor from to the cell surface Goldstein J.L. Anderson Brown M.S. and of LDL receptor by factor PubMed Scopus Google Scholar, L. K. K. Brown M.S. Goldstein J.L. J. of the LDL receptor at PubMed Scopus Google Scholar, of two from the receptor accelerates its J. PubMed Scopus Google Scholar). A of PCSK9 to the A that the on PCSK9 for the LDL receptor is from its Lagace T.A. McNutt M.C. Horton J.D. J. Molecular basis for LDL receptor by Natl. Acad. Sci. USA. 2008; PubMed Scopus Google Scholar). the of PCSK9 to the LDL receptor results in the of LDL receptors from the cell surface to K.N. Fisher E.A. Breslow J.L. Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment.Proc. Natl. Acad. Sci. USA. 2005; 102: 2069-2074Crossref PubMed Scopus (316) Google Scholar, T.A. Curtis D.E. Garuti R. McNutt M.C. Park S.W. Prather H.B. Anderson N.N. Ho Y.K. Hammer R.E. Horton J.D. Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice.J. Clin. Invest. 2006; 116: 2995-3005Crossref PubMed Scopus (532) Google Scholar). Thus, PCSK9 appears to the of the LDL receptor, LDL receptors to degradation in and from to the cell surface K.N. Fisher E.A. Breslow J.L. Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment.Proc. Natl. Acad. Sci. USA. 2005; 102: 2069-2074Crossref PubMed Scopus (316) Google Scholar, T.A. Curtis D.E. Garuti R. McNutt M.C. Park S.W. Prather H.B. Anderson N.N. Ho Y.K. Hammer R.E. Horton J.D. Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice.J. Clin. Invest. 2006; 116: 2995-3005Crossref PubMed Scopus (532) Google Scholar, M.C. Lagace T.A. Horton J.D. is for PCSK9 to reduce low density lipoprotein receptors in Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, Lagace T.A. Garuti R. Z. M. Horton J.D. Cohen J.C. Hobbs H.H. of proprotein convertase subtilisin/kexin type 9 to A of low density lipoprotein receptor decreases receptor and Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, T.S. Pandit S. M. Santoro J.C. Wisniewski D. Cummings R.T. A. Cubbon R.M. et of and low density lipoprotein (LDL) on LDL receptor Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). The but that the of PCSK9 in the LDL receptor that of to the receptor and The in the and cellular of PCSK9 have on the by which PCSK9 gain-of-function mutations cause autosomal dominant hypercholesterolemia. In the issue of the Dr. Shilpa Pandit et al. (12.Pandit S. Wisniewski D. Santoro J.C. Ha S. Ramakrishnan V. Cubbon R.M. Cummings R.T. Wright S.D. Sparrow C.P. Sitlani A. Fisher T.S. Functional Analysis of Sites within PCSK9 Responsible for Hypercholesterolemia.J. Lipid Res. 2008; 49: 1333-1343Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar) by which missense mutations at and and reduce LDL In the of the results of from at increased the of PCSK9 for the LDL receptor, and this with in LDL The PCSK9 Lagace T.A. McNutt M.C. Horton J.D. J. Molecular basis for LDL receptor by Natl. Acad. Sci. USA. 2008; PubMed Scopus Google Scholar) has findings in is in the between PCSK9 and the LDL receptor, and changing that LDL receptor by and interactions by the of a is that the at exhibited the for the LDL receptor (12.Pandit S. Wisniewski D. Santoro J.C. Ha S. Ramakrishnan V. Cubbon R.M. Cummings R.T. Wright S.D. Sparrow C.P. Sitlani A. Fisher T.S. Functional Analysis of Sites within PCSK9 Responsible for Hypercholesterolemia.J. Lipid Res. 2008; 49: 1333-1343Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar), that has against higher The mutation is in the is from the LDL J. J.L. The of PCSK9 at A with within the Natl. Acad. Sci. USA. 2007; PubMed Scopus Google Scholar, D.E. S. S. The of a of plasma 2007; 15: Full Text Full Text PDF PubMed Scopus Google Scholar, Lagace T.A. McNutt M.C. Horton J.D. J. Molecular basis for LDL receptor by Natl. Acad. Sci. USA. 2008; PubMed Scopus Google Scholar), and studies that this mutation has no impact on for the LDL receptor (12.Pandit S. Wisniewski D. Santoro J.C. Ha S. Ramakrishnan V. Cubbon R.M. Cummings R.T. Wright S.D. Sparrow C.P. Sitlani A. Fisher T.S. Functional Analysis of Sites within PCSK9 Responsible for Hypercholesterolemia.J. Lipid Res. 2008; 49: 1333-1343Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar). the the reduced LDL receptor (12.Pandit S. Wisniewski D. Santoro J.C. Ha S. Ramakrishnan V. Cubbon R.M. Cummings R.T. Wright S.D. Sparrow C.P. Sitlani A. Fisher T.S. Functional Analysis of Sites within PCSK9 Responsible for Hypercholesterolemia.J. Lipid Res. 2008; 49: 1333-1343Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 21.Cameron J. Holla O.L. Ranheim T. Kulseth M.A. Berge K.E. Leren T.P. Effect of mutations in the PCSK9 gene on the cell surface LDL receptors.Hum. Mol. Genet. 2006; 15: 1551-1558Crossref PubMed Scopus (226) Google Scholar). The mutation the of the but is at that this its to reduce LDL that the interactions with the cellular that LDL receptors to In is that the the and mutations are the impact of the two on LDL receptors is a PCSK9 protein is PCSK9 in LDL receptors (12.Pandit S. Wisniewski D. Santoro J.C. Ha S. Ramakrishnan V. Cubbon R.M. Cummings R.T. Wright S.D. Sparrow C.P. Sitlani A. Fisher T.S. Functional Analysis of Sites within PCSK9 Responsible for Hypercholesterolemia.J. Lipid Res. 2008; 49: 1333-1343Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar). PCSK9 in has been by a of for plasma PCSK9 levels (18.Lagace T.A. Curtis D.E. Garuti R. McNutt M.C. Park S.W. Prather H.B. Anderson N.N. Ho Y.K. Hammer R.E. Horton J.D. Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice.J. Clin. Invest. 2006; 116: 2995-3005Crossref PubMed Scopus (532) Google Scholar, J. E.M. proprotein convertase subtilisin kexin type 9 is with serum LDL Chem. 2007; PubMed Scopus Google Scholar), expression to of and PCSK9 and a for PCSK9 M.C. Lagace T.A. Horton J.D. is for PCSK9 to reduce low density lipoprotein receptors in Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). have to key the of PCSK9 in the plasma levels of PCSK9 in to for the regulation of LDL is the of PCSK9 in the and is its by LDL a gain-of-function PCSK9 in LDL receptors in and is the of a gain-of-function a PCSK9 reduce LDL receptors in The by Dr. (13.Grefhorst A. McNutt M.C. Lagace T.A. Horton J.D. Plasma PCSK9 Preferentially Reduces Liver LDL Receptors in Mice.J. Lipid Res. 2008; 49: 1303-1311Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar) in this issue of the of recombinant human PCSK9 established that the levels of PCSK9 in human plasma are to reduce hepatic LDL A gain-of-function PCSK9 was a PCSK9 in LDL receptors, that an of PCSK9 in the plasma from LDL The of PCSK9 from the plasma was in LDL that the LDL receptor is a key factor in PCSK9 levels in the The of the PCSK9 was with its higher for the LDL Dr. that of PCSK9 at high levels, on LDL receptors in the adrenal an with high levels of LDL receptors (13.Grefhorst A. McNutt M.C. Lagace T.A. Horton J.D. Plasma PCSK9 Preferentially Reduces Liver LDL Receptors in Mice.J. Lipid Res. 2008; 49: 1303-1311Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar). observation suggested that the cellular for of LDL receptors in the liver and Dr. an the regulation of PCSK9 in the liver, via the expression of the LDL receptor and PCSK9, a that in lowers LDL is the for this SREBP-2 is accompanied by increased and Dr. that of LDL receptors in the liver, via PCSK9, might from the liver, for hepatic to their in of the PCSK9 from its as a cholesterol-lowering is that of PCSK9 lower plasma cholesterol levels, and is no to that the loss of PCSK9 of PCSK9 the effects of PCSK9 (19.Rashid S. Curtis D.E. Garuti R. Anderson N.N. Bashmakov Y. Ho Y.K. Hammer R.E. Moon Y.A. Horton J.D. Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9.Proc. Natl. Acad. Sci. USA. 2005; 102: 5374-5379Crossref PubMed Scopus (566) Google Scholar, human serum levels of proprotein convertase subtilisin/kexin type Lipid Res. 2008; 49: Full Text Full Text PDF PubMed Scopus Google Scholar, A. J. N.G. L. Prat A. PCSK9, the gene the proprotein convertase neural apoptosis-regulated in Thromb. Vasc. Biol. 2004; PubMed Scopus Google Scholar), which the on their of which is to increase LDL receptors in the liver. for PCSK9 are cleavage is for the of PCSK9, a of might S. Rhainds D. Essalmani R. Mayne J. Wickham L. Jin W. Asselin M.C. Hamelin J. Varret M. Allard D. et al.NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol.J. Biol. Chem. 2004; 279: 48865-48875Abstract Full Text Full Text PDF PubMed Scopus (516) Google Scholar), that was specific for PCSK9 and lead to a of PCSK9. that the receptor interactions of interactions is a by are for liver R.M. Graham C.P. S. oligonucleotide lowers LDL cholesterol in mice without hepatic Lipid Res. 2005; 46: Full Text Full Text PDF PubMed Scopus Google Scholar, J. J.D. E. Graham R.M. of and low-density lipoprotein cholesterol by of an of 2006; PubMed Scopus Google Scholar), and studies in mice that this is for PCSK9 C.P. A. R.M. of proprotein convertase subtilisin/kexin type 9 serum LDL in mice.J. Lipid Res. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). is interest in to receptor interactions (18.Lagace T.A. Curtis D.E. Garuti R. McNutt M.C. Park S.W. Prather H.B. Anderson N.N. Ho Y.K. Hammer R.E. Horton J.D. Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice.J. Clin. Invest. 2006; 116: 2995-3005Crossref PubMed Scopus (532) Google Scholar). the few years, the of the and studies on of PCSK9 function. the for and industry scientists have their in PCSK9 is PCSK9 in LDL receptors in the liver in the adrenal are the for the of LDL receptors to the mutation reduce LDL receptor lead to the of new LDL receptors new the and PCSK9 PCSK9 is has been in are PCSK9 nonsense mutations common in for but no one their at and their are to the of the the few and for