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Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that regulates the expression of LDL receptor (LDLR) protein. Gain-of-function mutations in PCSK9 cause hypercholesterolemia, and loss-of-function mutations result in lower plasma LDL-cholesterol. Here, we investigate the kinetics and metabolism of circulating PCSK9 relative to tissue levels of LDLRs. The administration of recombinant human PCSK9 (32 μg) to mice by a single injection reduced hepatic LDLRs by ∼90% within 60 min, and the receptor levels returned to normal within 6 h. The half-life of the PCSK9 was estimated to be ∼5 min. Continuous infusion of PCSK9 (32 μg/h) into wild-type mice caused a ∼90% reduction in hepatic LDLRs within 2 h and no associated change in the level of LDLR in the adrenals. Parallel studies were performed using a catalytically inactive form of PCSK9, PCSK9(S386A), and similar results were obtained. Infusion of PCSK9(D374Y), a gain-of-function mutation, resulted in accelerated clearance of the mutant PCSK9 and a greater reduction in hepatic LDLRs. Combined, these data suggest that exogenously administrated PCSK9 in plasma preferentially reduces LDLR protein levels in liver at concentrations found in human plasma and that PCSK9's action on the LDLR is not dependent on catalytic activity in vivo. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that regulates the expression of LDL receptor (LDLR) protein. Gain-of-function mutations in PCSK9 cause hypercholesterolemia, and loss-of-function mutations result in lower plasma LDL-cholesterol. Here, we investigate the kinetics and metabolism of circulating PCSK9 relative to tissue levels of LDLRs. The administration of recombinant human PCSK9 (32 μg) to mice by a single injection reduced hepatic LDLRs by ∼90% within 60 min, and the receptor levels returned to normal within 6 h. The half-life of the PCSK9 was estimated to be ∼5 min. Continuous infusion of PCSK9 (32 μg/h) into wild-type mice caused a ∼90% reduction in hepatic LDLRs within 2 h and no associated change in the level of LDLR in the adrenals. Parallel studies were performed using a catalytically inactive form of PCSK9, PCSK9(S386A), and similar results were obtained. Infusion of PCSK9(D374Y), a gain-of-function mutation, resulted in accelerated clearance of the mutant PCSK9 and a greater reduction in hepatic LDLRs. Combined, these data suggest that exogenously administrated PCSK9 in plasma preferentially reduces LDLR protein levels in liver at concentrations found in human plasma and that PCSK9's action on the LDLR is not dependent on catalytic activity in vivo. LDL-cholesterol LDL receptor proprotein convertase subtilisin/kexin type 9 sterol-regulatory element binding protein transferrin receptor Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a member of the proteinase K subfamily of enzymes (1.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, 2.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.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. 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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). Similarly, humans carrying gain-of-function alleles for PCSK9 have increased plasma LDL-cholesterol (LDL-C) levels and premature coronary artery disease (6.Abifadel M. Varret M. Rabès J-P. Ouguerram K. Devillers M. Cruaud C. Benjannet S. Wickham L. Erlich D. Villéger L. et al.Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.Nat. Genet. 2003; 34: 154-156Crossref PubMed Scopus (2222) Google Scholar), whereas individuals with loss-of-function alleles have significantly reduced plasma LDL-C and are protected from atherosclerosis (7.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, 8.Cohen J.C. 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Plasma PCSK9 levels correlate with cholesterol in men but not in women.Biochem. Biophys. Res. Commun. 2007; 361: 451-456Crossref PubMed Scopus (75) Google Scholar, 12.Alborn W.E. Cao G. Careskey H.E. Qian Y-W. Subramaniam D.R. Davies J. Conner E.M. Konrad R.J. Serum proprotein convertase subtilisin kexin type 9 is correlated directly with serum LDL cholesterol.Clin. Chem. 2007; 53: 1814-1819Crossref PubMed Scopus (136) Google Scholar). The addition of recombinant human PCSK9 to the medium of HepG2 cells leads to the degradation of LDLRs in a time- and concentration-dependent manner (10.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 LDL receptors in hepatocytes and in livers of parabiotic mice.J. Clin. Invest. 2006; 116: 2995-3005Crossref PubMed Scopus (532) Google Scholar). PCSK9 directly binds selectively to the epidermal growth factor-like repeat A domain of the LDLR (13.Zhang D-W. Lagace T.A. Garuti R. Zhao M. Horton J.D. J.C. Hobbs H.H. of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor and Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, Lagace T.A. McNutt M.C. Horton J.D. J. for LDL receptor by Natl. Acad. Sci. USA. PubMed Scopus Google Scholar), and binding and are for PCSK9 to LDLR levels (10.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 LDL receptors in hepatocytes and in livers of parabiotic mice.J. Clin. Invest. 2006; 116: 2995-3005Crossref PubMed Scopus (532) Google Scholar, D-W. Lagace T.A. Garuti R. Zhao M. Horton J.D. J.C. Hobbs H.H. of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor and Biol. 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Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9.Proc. Natl. Acad. Sci. USA. 2005; 102: 5374-5379Crossref PubMed Scopus (566) Google mice on a studies were by the and at the of Plasma human PCSK9 concentrations were by (10.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 LDL receptors in hepatocytes and in livers of parabiotic mice.J. Clin. Invest. 2006; 116: 2995-3005Crossref PubMed Scopus (532) Google Scholar). Plasma cholesterol concentrations were Horton J.D. Hammer R.E. J.L. of cholesterol and liver in mice Clin. Invest. PubMed Scopus Google Scholar). wild-type mice were with and the of PCSK9 were into the the the were by and and were for wild-type and Pcsk9−/− mice were with and a of the liver was The tissue was in and the with a A was to a infusion of PCSK9 in a for 6 h the were infusion at the the and the of human PCSK9 was by (10.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 LDL receptors in hepatocytes and in livers of parabiotic mice.J. Clin. Invest. 2006; 116: 2995-3005Crossref PubMed Scopus (532) Google Scholar). were by to the liver and the adrenals. mutant PCSK9 was with J.D. J.L. of LDL receptor gene in mice resulting from production of Clin. Invest. PubMed Scopus Google Scholar), and was into the of wild-type and The activity of the PCSK9 from protein. of were from the the injection and at the the of the the were by of tissue PCSK9 mice were the PCSK9 and were with for min. and were Hammer R.E. Horton J.D. J.L. G. of in the livers of mice inhibits and reduces Clin. Invest. 2004; 113: PubMed Scopus Google Scholar), and the protein concentrations were using the were with and for at to to (2.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). were performed with LDLR (2.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 and a from The transferrin receptor was using in mice and the were using the A of protein from hepatic and protein of wild-type and Pcsk9−/− mice was to and to (2.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). a in were with the LDLR and the by and were in serum and were in The was with a on the and was with the and of PCSK9 in we a single injection of recombinant human PCSK9 into the of wild-type mice hepatic LDLRs. wild-type mice were with with PCSK9 and h the LDLR protein levels were by LDLR levels not change in liver a single injection of 2 of human PCSK9 and the was increased to of PCSK9, hepatic LDLRs by within h of the injection of PCSK9 μg) resulted in a reduction of hepatic LDLRs and and LDLR levels low for h and the kinetics of the to PCSK9, mice were with recombinant human PCSK9 (32 μg) and at in hepatic LDLR levels were the the LDLR protein was reduced by in LDLR levels were at 60 LDLR protein levels returned to that PCSK9 was rapidly from the the half-life of PCSK9 in plasma and to LDLRs PCSK9 was into wild-type and mice, and the from plasma was in the clearance of PCSK9 in mice in The was and dependent on and the was LDLR The half-life of PCSK9 in wild-type mice was ∼5 min, and was increased to in the of LDLRs. of in the liver was ∼90% in wild-type mice, but in mice PCSK9 a half-life in and is by the The of recombinant PCSK9 the of to the effects of plasma concentrations of PCSK9 on LDLR of recombinant human PCSK9 were into wild-type mice for h and plasma was to human PCSK9 concentrations h of PCSK9 concentrations a in mice with the of PCSK9 (32 plasma concentrations of PCSK9 but were at the of the h LDLR protein levels were by from liver to infusion and from liver at the of the h infusion Infusion of of PCSK9 not LDL protein levels in infusion of hepatic LDLRs. plasma concentrations of human PCSK9 associated with reduced hepatic LDLRs were and concentrations are within the of in human plasma using (10.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 LDL receptors in hepatocytes and in livers of parabiotic mice.J. Clin. Invest. 2006; 116: 2995-3005Crossref PubMed Scopus (532) Google Scholar). with to of PCSK9 for h not affect plasma cholesterol levels not and these we the infusion in Pcsk9−/− mice to the of mouse PCSK9 to the effects on hepatic LDLRs Pcsk9−/− mice hepatic LDLRs wild-type mice (1.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). Infusion of of PCSK9 into the Pcsk9−/− mice not levels of PCSK9 protein the of the h infusion of PCSK9 at and the plasma concentrations of human PCSK9 were and to infusion and at the of the h infusion were by to the effects of PCSK9 on the levels of LDLRs Infusion of PCSK9 at of and resulted in in hepatic LDLR protein in a results that the of plasma PCSK9 at concentrations in human plasma degradation of hepatic LDLRs. The the levels of LDLRs tissue J.L. of low density lipoprotein receptors by in the of mice and in Biol. Chem. Full Text PDF PubMed Google of in the PCSK9 in plasma LDLRs in the in a manner similar to that found in wild-type mice were with the of recombinant human PCSK9 protein (32 μg/h) for h and 6 and LDLRs were by with the data in infusion of the of PCSK9 for and 6 h LDLRs in liver change in the levels of LDLR was in the of these we the of LDLR protein in livers and from wild-type and Pcsk9−/− the LDLR protein the was In the LDLR protein level in Pcsk9−/− livers was increased whereas the level in the of the Pcsk9−/− mice was in the wild-type data the that PCSK9 a reduced activity on LDLRs in the adrenals. the plasma kinetics and of a PCSK9 protein with a gain-of-function associated with hypercholesterolemia in humans (6.Abifadel M. Varret M. Rabès J-P. Ouguerram K. Devillers M. Cruaud C. Benjannet S. Wickham L. Erlich D. Villéger L. et al.Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.Nat. Genet. 2003; 34: 154-156Crossref PubMed Scopus (2222) Google Scholar). was that to the medium of HepG2 cells was wild-type PCSK9 in LDLRs (10.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 LDL receptors in hepatocytes and in livers of parabiotic mice.J. Clin. Invest. 2006; 116: 2995-3005Crossref PubMed Scopus (532) Google Scholar). A for the increased activity of the mutant protein is that binds the LDLR with to greater the wild-type PCSK9 S. M. J.C. D. A. et of and low density lipoprotein (LDL) on LDL receptor Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, D. D.E. M.C. J.L. T.A. A.H. et and studies of PCSK9 and its to hypercholesterolemia.Nat. Biol. 2007; PubMed Scopus Google Scholar). the gain-of-function protein plasma was with and into wild-type mice, and clearance from the plasma was of from the was that of wild-type protein of and for and PCSK9(D374Y), result is with the of the mutant protein for the the gain-of-function mutant increased activity in was for h into Pcsk9−/− mice at and μg/h) and effects on hepatic LDLR protein levels were in infusion of of not result in PCSK9 concentrations in a result found infusion of wild-type PCSK9 protein Infusion of resulted in plasma concentrations of at is significantly lower was with the wild-type protein in the Pcsk9−/− mice the lower plasma of PCSK9(D374Y), hepatic LDLR levels were reduced significantly results are with a on LDLR expression in (10.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 LDL receptors in hepatocytes and in livers of parabiotic mice.J. Clin. Invest. 2006; 116: 2995-3005Crossref PubMed Scopus (532) Google Scholar). we catalytic was for degradation of hepatic LDLRs in vivo. we that catalytically inactive PCSK9 reduced LDLRs wild-type PCSK9 to the medium of HepG2 cells M.C. Lagace T.A. Horton J.D. activity is not for secreted PCSK9 to low density lipoprotein receptors in HepG2 cells.J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). was in the catalytically inactive PCSK9 protein was from the medium of cells by of the and a catalytically inactive domain in of a at M.C. Lagace T.A. Horton J.D. activity is not for secreted PCSK9 to low density lipoprotein receptors in HepG2 cells.J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). PCSK9 was into Pcsk9−/− mice at a of and the effects on hepatic LDLRs were by in hepatic LDLRs were with the catalytically inactive and wild-type that catalytic activity is not for PCSK9 to the degradation of hepatic LDLRs in vivo. PCSK9 a of plasma LDL-C and cardiovascular the and of action on LDLR are In the we the kinetics and of plasma PCSK9 and a gain-of-function PCSK9(D374Y), was to PCSK9 in mouse plasma LDLR at concentrations found in human The to of recombinant human PCSK9 from cells the injection of the protein into mice to the levels of circulating human PCSK9 that in LDLR in the liver and the found that plasma PCSK9 levels within the of the concentrations found in humans (10.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 LDL receptors in hepatocytes and in livers of parabiotic mice.J. Clin. Invest. 2006; 116: 2995-3005Crossref PubMed Scopus (532) Google were associated with in hepatic LDLR protein. A plasma of human PCSK9 of in mice no PCSK9 was to hepatic LDLRs by are with circulating PCSK9 a on LDLR in studies the that PCSK9 to LDLR infusion of PCSK9 not affect LDLR in adrenals. The for PCSK9 is not in the of mice and effects in tissue result from the action of plasma the infusion of PCSK9 was (32 μg/h) for to 6 resulting in plasma PCSK9 concentrations of not no reduction in LDLR protein was in the the of LDLRs in liver In Pcsk9−/− mice, LDLRs in the were increased with wild-type mice was significantly that in liver and the that PCSK9 is but not inactive in the adrenals. The for the reduced of the to the effects of PCSK9 are not PCSK9 effects on LDLR levels in in cultured cells (2.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, 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 LDL receptors in hepatocytes and in livers of parabiotic mice.J. Clin. 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Hobbs H.H. of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor and Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). was not the of LDLRs PCSK9 clearance from The clearance studies in suggest that LDLRs in PCSK9 The of clearance of the of the is in is not The of the LDLR for PCSK9 to affect the half-life of the protein. clearance studies using PCSK9(D374Y), a to greater for the LDLR S. M. J.C. D. A. et of and low density lipoprotein (LDL) on LDL receptor Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, D. D.E. M.C. J.L. T.A. A.H. et and studies of PCSK9 and its to hypercholesterolemia.Nat. 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Benjannet S. Wickham L. J. S. A. A. Chretien M. The proprotein convertase convertase liver and Natl. Acad. Sci. USA. 2003; PubMed Scopus Google Scholar), the catalytic activity of PCSK9 is not for the degradation of LDLRs to the medium of cultured cells M.C. Lagace T.A. Horton J.D. activity is not for secreted PCSK9 to low density lipoprotein receptors in HepG2 cells.J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, J. C. R. G. et PCSK9 LDL receptor degradation of J. 2007; PubMed Scopus Google Scholar). The data in 6 that infusion of catalytically inactive protein to the of hepatic LDLRs in a manner that was to that of the catalytically protein. in data that the LDLR degradation activity of PCSK9 is of the A is PCSK9 and in the the of the LDLR expression that is in The studies the that the of PCSK9 action is the liver and that the secreted form of PCSK9 preferentially LDLR expression in tissue to and from the liver to The LDLR and to cholesterol are by a single sterol-regulatory element binding J.D. J.L. of the of cholesterol and in the liver.J. Clin. Invest. PubMed Scopus Google Scholar). regulates PCSK9, LDLRs J.D. J.A. Anderson N.N. Park S.W. J.L. of data from and knockout mice Natl. Acad. Sci. USA. 2003; PubMed Scopus Google Scholar, D. Park S.W. regulation of proprotein convertase subtilisin/kexin type 9 expression by sterol-regulatory element binding Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). In the lipid and from PCSK9, preferentially reduces hepatic the of the secreted lipoprotein and the and secreted to the levels of PCSK9 plasma LDL-C levels and the risk of cardiovascular Combined, the data of the suggest that exogenously administrated PCSK9 in plasma preferentially reduces LDLR protein levels in liver at concentrations found in human was not dependent on PCSK9 catalytic that of PCSK9 catalytic activity that in plasma not be in PCSK9's action on hepatic LDLRs. the results of these studies suggest that that to the of PCSK9 and the LDLR at the be a to PCSK9 and for The to L. and W. for of the and S. for Y. K. and
Grefhorst et al. (Thu,) studied this question.
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