December 7, 2008Open Access

Function and distribution of circulating human PCSK9 expressed extrahepatically in transgenic mice

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Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is predominantly expressed in liver and regulates cholesterol metabolism by down regulating liver LDL receptor (LDLR) proteins. Here we report transgenic overexpression of human PCSK9 in kidney increased plasma levels of PCSK9 and subsequently led to a dramatic reduction in liver LDLR proteins. The regulation of LDLR by PCSK9 displayed tissue specificity, with liver being the most responsive tissue. Even though the PCSK9 transgene was highly expressed in kidney, LDLR proteins were suppressed to a lower extent in this tissue than in liver. Adrenal LDLR proteins were not regulated by elevated plasma PCSK9. hPCSK9 transgene expression and subsequent reduction of liver LDLR led to increases in plasma total cholesterol, LDL cholesterol, and ApoB, which were further increased by a high-fat, high-cholesterol diet. We also observed that the size distribution of hPCSK9 in transgenic mouse plasma was heterogeneous. In chow-fed mice, the majority of PCSK9 proteins were in free forms; however, feeding a high-fat, high-cholesterol diet resulted in a shift of hPCSK9 distribution toward larger complexes. PCSK9 distribution in human plasma also exhibited heterogeneity and individual variability in the percentage of PCSK9 in free form and in large complexes. We provide strong evidence to support that human PCSK9 proteins secreted from extrahepatic tissue are able to promote LDLR degradation in liver and increase plasma LDL. Our data also suggest that LDLR protein regulation by PCSK9 has tissue specificity, with liver being the most responsive tissue. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is predominantly expressed in liver and regulates cholesterol metabolism by down regulating liver LDL receptor (LDLR) proteins. Here we report transgenic overexpression of human PCSK9 in kidney increased plasma levels of PCSK9 and subsequently led to a dramatic reduction in liver LDLR proteins. The regulation of LDLR by PCSK9 displayed tissue specificity, with liver being the most responsive tissue. Even though the PCSK9 transgene was highly expressed in kidney, LDLR proteins were suppressed to a lower extent in this tissue than in liver. Adrenal LDLR proteins were not regulated by elevated plasma PCSK9. hPCSK9 transgene expression and subsequent reduction of liver LDLR led to increases in plasma total cholesterol, LDL cholesterol, and ApoB, which were further increased by a high-fat, high-cholesterol diet. We also observed that the size distribution of hPCSK9 in transgenic mouse plasma was heterogeneous. In chow-fed mice, the majority of PCSK9 proteins were in free forms; however, feeding a high-fat, high-cholesterol diet resulted in a shift of hPCSK9 distribution toward larger complexes. PCSK9 distribution in human plasma also exhibited heterogeneity and individual variability in the percentage of PCSK9 in free form and in large complexes. We provide strong evidence to support that human PCSK9 proteins secreted from extrahepatic tissue are able to promote LDLR degradation in liver and increase plasma LDL. Our data also suggest that LDLR protein regulation by PCSK9 has tissue specificity, with liver being the most responsive tissue. Proprotein convertase subtilisin/kexin type 9 (PCSK9) was identified by its cosegregation with autosomal dominant hypercholesterolemia (1Abifadel 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). Gain-of-function mutations in PCSK9 cause hypercholesterolemia in humans (1Abifadel 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, 2Sun X.M. Eden E.R. Tosi I. Neuwirth C.K. Wile D. Naoumova R.P. Soutar A.K. Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia.Hum. Mol. Genet. 2005; 14: 1161-1169Crossref PubMed Scopus (133) Google Scholar, 3Leren T.P. Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia.Clin. Genet. 2004; 65: 419-422Crossref PubMed Scopus (209) Google Scholar, 4Timms K.M. Wagner S. Samuels M.E. Forbey K. Goldfine H. Jammulapati S. Skolnick M.H. Hopkins P.N. Hunt S.C. Shattuck D.M. A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree.Hum. Genet. 2004; 114: 349-353Crossref PubMed Scopus (271) Google Scholar), whereas loss-of-function mutations in humans lead to a reduction in LDL cholesterol and a marked decrease in the risk of coronary heart disease (5Cohen 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, 6Cohen 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, 7Kotowski 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). PCSK9 is a member of the subtilisin serine protease family and the proteinase K subfamily. The protein is synthesized as a proprotein that autocatalytically cleaves to generate mature protein (8Seidah 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). PCSK9 protein is secreted as a complex containing cleaved N-terminal prodomain, which remains associated with the catalytic domain (8Seidah 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 catalytic activity is required for PCSK9 maturation and secretion (9Benjannet 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) but appears not to be essential for the reduction of LDLR (LDL receptor) by secreted PCSK9 (10McNutt M.C. Lagace T.A. Horton J.D. Catalytic activity is not required for secreted PCSK9 to reduce low density lipoprotein receptors in HepG2 cells.J. Biol. Chem. 2007; 282: 20799-20803Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar). PCSK9 is predominantly expressed in liver, intestine, and to a lesser extent, in kidney (8Seidah 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). PCSK9 gene expression is regulated by cholesterol via sterol regulatory element-binding protein (SREBP) pathways (11Park 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, 12Maxwell 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). In mice, PCSK9 gene expression is downregulated by dietary cholesterol and dramatically upregulated by hepatic overexpression of the transactivation domain of SREBP-1a and SREBP-2 (12Maxwell 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). Deletion of PCSK9 in mice leads to elevated liver LDLR protein (but not mRNA) and to reduced plasma total cholesterol, mainly HDL cholesterol (13Rashid 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). Furthermore, PCSK9 deficiency increases LDL clearance and enhances the response to statin (13Rashid 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). Knockdown of PCSK9 by antisense approach also decreases total cholesterol in high-fat–fed mice in an LDLR dependent manner (14Graham M.J. Lemonidis K.M. Whipple C.P. Subramaniam A. Monia B.P. Crooke S.T. Crooke R.M. Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice.J. Lipid Res. 2007; 48: 763-767Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar). Hepatic overexpression of murine or human PCSK9 by adenovirus (9Benjannet 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, 15Maxwell 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, 16Lalanne F. Lambert G. Amar M.J. Chetiveaux M. Zair Y. Jarnoux A.L. Ouguerram K. Friburg J. Seidah N.G. Brewer Jr., H.B. et al.Wild-type PCSK9 inhibits LDL clearance but does not affect apoB-containing lipoprotein production in mouse and cultured cells.J. Lipid Res. 2005; 46: 1312-1319Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar) or transgene (17Zaid A. Roubtsova A. Essalmani R. Marcinkiewicz J. Chamberland A. Hamelin J. Tremblay M. Jacques H. Jin W. Davignon J. et al.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 (326) Google Scholar) results in the reduction of liver LDLR protein and elevation of LDL cholesterol. Transgenic mice overexpressing PCSK9 in liver accumulated PCSK9 to a level of 100–400 μg/ml in plasma and reduced liver LDLR protein in wild-type mice that are parabiotically joined with transgenic mice (18Lagace 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). Grefhorst et al. demonstrated that infusion of recombinant hPCSK9 at 32 μg/hour gave rise to about 1 μg/ml of plasma PCSK9 and preferentially promoted LDLR degradation over a six h period (19Grefhorst 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). Mounting evidence suggests that PCSK9 functions extracellularly to promote the degradation of LDLR by directly interacting with LDLR on the cell surface, resulting in reduced receptor recycling by unknown mechanisms (18Lagace 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, 20Fisher T.S. Lo Surdo P. Pandit S. Mattu M. Santoro J.C. Wisniewski D. Cummings R.T. A. R.M. et of and low density lipoprotein (LDL) on LDL receptor Biol. Chem. 2007; 282: Full Text Full Text PDF PubMed Scopus Google Scholar, Lagace T.A. Garuti R. 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 recycling and increases Biol. Chem. 2007; 282: Full Text Full Text PDF PubMed Scopus Google Scholar, J. T.P. of mutations in the PCSK9 gene on the cell LDL Mol. Genet. 2006; PubMed Scopus Google Scholar). In the we transgenic mice which PCSK9 in kidney to the of PCSK9 in the regulation of plasma We provide evidence to support that plasma PCSK9 expressed in extrahepatic tissue is able to promote LDLR degradation in liver and plasma LDL. The data also suggest that LDLR protein regulation by PCSK9 has tissue specificity, with liver being the most responsive tissue. we the plasma distribution of PCSK9 protein in transgenic mice and in human PCSK9 with a was expressed the of a human containing a and a A was the and PCSK9 to the The expression is by a from the gene at the and of the transgene M. G. A of the domain as an in human and against effect in Full Text PDF PubMed Scopus Google Scholar). The human PCSK9 expression containing was the of from the as A. M. K. R. the A Scholar). Transgenic and transgenic were identified by a from the hPCSK9 transgenic mice and wild-type were in this were on a and or high-fat, high-cholesterol diet cholesterol and The were diet for at of The was by and to the by the of was from mice for cholesterol levels in plasma or were by were by protein mouse plasma from six mice was and with lipoprotein 1 and as M. L. J. of human in transgenic effects on cholesterol and Lipid Res. Full Text PDF PubMed Google Scholar). human plasma from were with the and were for and were by an was as Y. L. E. J. Cooper P.N. E.M. plasma levels and clearance of density lipoprotein and cholesterol in receptor B type transgenic mice.J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). PCSK9 was with of and the mice were to with and were was from as by the and to to individual liver or kidney and from were for analysis was and an Sequence was to a against a PCSK9 and against human PCSK9 protein were as and human PCSK9 protein was as protein for the D. D.E. M.C. J.L. T.A. M.J. et and of PCSK9 and its to hypercholesterolemia.Nat. Mol. Biol. 2007; 14: PubMed Scopus Google Scholar). were with of in at by with of in of mouse plasma with a or of human PCSK9 protein from 1 to were with at for 1 PCSK9 protein was with of 1 μg/ml for 1 h by with and for and of for about with of the were on the at Plasma PCSK9 levels were a with human PCSK9 protein by of plasma PCSK9 was expressed as mice were to with and were Hepatic and kidney total proteins were from individual tissue Adrenal were for protein were in 1 1 with a The from a at were liver or kidney protein were at of protein for proteins were by and to LDLR protein was with a LDLR and and human PCSK9 protein in transgenic mice was against distribution of human PCSK9 and mouse PCSK9 was by PCSK9 was predominantly expressed in the liver of wild-type and transgenic mice hPCSK9 transgene expression was to be by an the hPCSK9 transgene was expressed in the mechanisms kidney expression in this are be by the of the and the human the expression in kidney is observed in than is that results from the The expression levels of hPCSK9 in liver were low and to be to the levels of in wild-type We that hepatic gene expression was reduced in hPCSK9 transgenic mice total liver PCSK9 expression in transgenic mice to that in wild-type low levels of hPCSK9 transgene expression were in PCSK9 protein levels were in kidney and in liver, with expression results A form of PCSK9 was also and the by Benjannet et S. Rhainds D. Hamelin J. Seidah N.G. The proprotein convertase PCSK9 is by of natural mutations and Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). PCSK9 protein in transgenic mice was secreted and resulted in elevation of plasma PCSK9 levels to about which is the levels in human plasma has that hepatic expression or of recombinant PCSK9 reduced liver LDLR protein 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, 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, 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, K.N. Breslow J.L. of PCSK9 the degradation of the LDLR in a Natl. Acad. Sci. USA. 2005; 102: PubMed Scopus Google Scholar, Y. S. A. H. T.P. W. et PCSK9 low density lipoprotein receptor Lipid Res. 2007; 48: Full Text Full Text PDF PubMed Scopus Google Scholar). We liver LDLR protein expression to elevated plasma PCSK9 from an extrahepatic affect liver expression of hPCSK9 LDLR protein in liver elevated plasma PCSK9 levels not affect LDLR protein levels kidney has the expression levels of hPCSK9 LDLR protein was reduced by about LDLR was not in the transgenic mice not the decrease in the LDLR protein is most to the regulation of plasma and lipoprotein metabolism by PCSK9 in the of hPCSK9 transgenic and wild-type mice were a diet for to of hepatic overexpression of PCSK9 (9Benjannet 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, 15Maxwell 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, A. Roubtsova A. Essalmani R. Marcinkiewicz J. Chamberland A. Hamelin J. Tremblay M. Jacques H. Jin W. Davignon J. et al.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 (326) Google Scholar), extrahepatic overexpression of hPCSK9 elevated plasma total cholesterol in mice by diet feeding increased total cholesterol in wild-type mice by about and hPCSK9 expression led to a further increase in plasma cholesterol to about by were increased in hPCSK9 transgenic mice with wild-type mice, of the diet that increased cholesterol was to the increase in containing LDL. to plasma lipoprotein distribution in chow-fed transgenic mice, we that PCSK9 overexpression elevated LDL cholesterol but not HDL cholesterol diet increased LDL and HDL in wild-type PCSK9 transgene expression further increased LDL but effect on HDL of plasma PCSK9 not liver total cholesterol and levels We plasma distribution of hPCSK9 protein in transgenic mice by PCSK9 protein levels in were by as in and In mice with the majority of PCSK9 the and with the distribution of hPCSK9 the majority of hPCSK9 proteins as free with complexes. a of PCSK9 to was in larger and with LDL diet feeding hPCSK9 distribution toward larger lower The size distribution is and not the of and the were large in size with LDL and that by size free and large complexes. and of hPCSK9 in large and and hPCSK9 proteins as free lower the size distribution of plasma PCSK9 in we PCSK9 plasma from We that human size distribution than mouse HDL PCSK9 in human plasma displayed a size distribution and individual The individual was the percentage of PCSK9 in free and in large complexes. of PCSK9 from levels of plasma PCSK9, total cholesterol, and lipoprotein are in The PCSK9 of was to that in transgenic mice with diet. was and of PCSK9 in free and in large with the PCSK9 in large and free lower The of were in the In this we transgenic mice that human PCSK9 in kidney and increased PCSK9 We strong evidence to support that human PCSK9 proteins secreted from extrahepatic tissue are able to promote LDLR degradation in liver and increase plasma LDL. that hepatic overexpression of murine or human PCSK9 results in increased LDL cholesterol by LDL clearance via reduction of liver LDLR proteins (9Benjannet 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, 15Maxwell 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, 16Lalanne F. Lambert G. Amar M.J. Chetiveaux M. Zair Y. Jarnoux A.L. Ouguerram K. Friburg J. Seidah N.G. Brewer Jr., H.B. et al.Wild-type PCSK9 inhibits LDL clearance but does not affect apoB-containing lipoprotein production in mouse and cultured cells.J. Lipid Res. 2005; 46: 1312-1319Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, A. Roubtsova A. Essalmani R. Marcinkiewicz J. Chamberland A. Hamelin J. Tremblay M. Jacques H. Jin W. Davignon J. et al.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 (326) Google Scholar). The of PCSK9 was by a by in which plasma PCSK9 and LDL levels were increased in the (18Lagace 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). further the of PCSK9 by that infusion of recombinant hPCSK9 preferentially promoted liver LDLR degradation (19Grefhorst 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). LDL elevation was observed in this demonstrated LDLR and LDL elevation of of recombinant PCSK9 in mice Y. S. A. H. T.P. W. et PCSK9 low density lipoprotein receptor Lipid Res. 2007; 48: Full Text Full Text PDF PubMed Scopus Google Scholar, T.P. A. M. G. Secreted proprotein convertase subtilisin/kexin type 9 reduces hepatic and extrahepatic low-density lipoprotein receptors in Res. 2008; PubMed Scopus Google Scholar). The from that recombinant PCSK9 proteins are from The clearance of PCSK9 the effects on LDLR and plasma LDL. of a mouse that hPCSK9 in kidney a for to the regulation of lipoprotein metabolism by elevated PCSK9. In transgenic mice, expression of hPCSK9 in liver reduced appears to be in liver PCSK9 and hPCSK9 were able to in human not that hPCSK9 and not in of LDLR data support that degradation of liver LDLR in transgenic mice is mainly to elevated PCSK9. kidney expressed levels of hPCSK9 the extent of LDLR reduction was lower than that in liver, that PCSK9 preferentially reduces liver LDLR (19Grefhorst 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). LDLR in was not regulated by PCSK9, with the results by (19Grefhorst 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). Our suggest that LDLR regulation by PCSK9 has tissue are to the response in the levels of expression in kidney an of LDLR be a response of to PCSK9, with liver being the most responsive or secreted hPCSK9 in kidney an increased The mechanisms that the response to PCSK9 further We the plasma distribution of PCSK9 protein by In transgenic mice with the majority of hPCSK9 was in that with free PCSK9, and a percentage of plasma hPCSK9 proteins were in large in size with LDL feeding the of PCSK9 in larger than the size of PCSK9 though plasma total PCSK9 levels by diet feeding hPCSK9 expression is by a The PCSK9 containing that with LDL not with LDL We were to the of PCSK9 and LDL. The large containing hPCSK9 or associated with plasma proteins. A report that PCSK9 protein to form or and to this D. S. L. S. of human PCSK9 with its 2008; PubMed Scopus Google Scholar). The mechanisms hPCSK9 complex and the of the PCSK9 containing are unknown and are further et al. that the majority of PCSK9 was associated with LDL in human transgenic mice on diet D. S. L. S. of human PCSK9 with its 2008; PubMed Scopus Google Scholar), which is from The expression levels and the distribution of transgene or of the mice to the PCSK9 in human plasma exhibited a size distribution and individual variability in the percentage of PCSK9 in free and in large complexes. The mechanisms to the distribution to be we were to PCSK9 distribution and plasma or PCSK9 with a of cholesterol and PCSK9 levels to on the The for to generate transgenic apolipoprotein B and cholesterol low density lipoprotein receptor convertase subtilisin/kexin type 9 sterol regulatory element-binding protein

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