title: Serum proprotein convertase subtilisin/kexin type 9 and cell surface low-density lipoprotein receptor: evidence for a reciprocal regulation.
abstract: BACKGROUND
  Proprotein convertase subtilisin/kexin type 9 (PCSK9) modulates low-density lipoprotein (LDL) receptor (LDLR) degradation, thus influencing serum cholesterol levels. However, dysfunctional LDLR causes hypercholesterolemia without affecting PCSK9 clearance from the circulation.
  
  
  RESULTS
  To study the reciprocal effects of PCSK9 and LDLR and the resultant effects on serum cholesterol, we produced transgenic mice expressing human (h) PCSK9. Although hPCSK9 was expressed mainly in the kidney, LDLR degradation was more evident in the liver. Adrenal LDLR levels were not affected, likely because of the impaired PCSK9 retention in this tissue. In addition, hPCSK9 expression increased hepatic secretion of apolipoprotein B-containing lipoproteins in an LDLR-independent fashion. Expression of hPCSK9 raised serum murine PCSK9 levels by 4.3-fold in wild-type mice and not at all in LDLR(-/-) mice, in which murine PCSK9 levels were already 10-fold higher than in wild-type mice. In addition, LDLR(+/-) mice had a 2.7-fold elevation in murine PCSK9 levels and no elevation in cholesterol levels. Conversely, acute expression of human LDLR in transgenic mice caused a 70% decrease in serum murine PCSK9 levels. Turnover studies using physiological levels of hPCSK9 showed rapid clearance in wild-type mice (half-life, 5.2 minutes), faster clearance in human LDLR transgenics (2.9 minutes), and much slower clearance in LDLR(-/-) recipients (50.5 minutes). Supportive results were obtained with an in vitro system. Finally, up to 30% of serum hPCSK9 was associated with LDL regardless of LDLR expression.
  
  
  CONCLUSIONS
  Our results support a scenario in which LDLR represents the main route of elimination of PCSK9 and a reciprocal regulation between these 2 proteins controls serum PCSK9 levels, hepatic LDLR expression, and serum LDL levels.
authors.affiliation: Vanderbilt University, Cardiovascular Medicine, Nashville, TN 37232-6300, USA.
authors.forename: Hagai
authors.initials: H
authors.lastname: Tavori
authors.forename: Daping
authors.initials: D
authors.lastname: Fan
authors.forename: John L
authors.initials: JL
authors.lastname: Blakemore
authors.forename: Patricia G
authors.initials: PG
authors.lastname: Yancey
authors.forename: Lei
authors.initials: L
authors.lastname: Ding
authors.forename: Macrae F
authors.initials: MF
authors.lastname: Linton
authors.forename: Sergio
authors.initials: S
authors.lastname: Fazio
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood*; D004195:Disease Models, Animal; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000097:blood* / Q000235:genetics / Q000502:physiology; D011973:Receptors, LDL / Q000097:blood* / Q000172:deficiency / Q000235:genetics; D012697:Serine Endopeptidases / Q000097:blood* / Q000235:genetics / Q000502:physiology; D014162:Transfection
chemical_list: D011973:Receptors, LDL; D002784:Cholesterol; C472125:PCSK9 protein, human; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: LDL receptor; Pcsk9 protein; cholesterol; lipoproteins; mouse model