Serum proprotein convertase subtilisin/kexin type 9 and cell surface low-density lipoprotein receptor: evidence for a reciprocal regulation

Circulation. 2013 Jun 18;127(24):2403-13. doi: 10.1161/CIRCULATIONAHA.113.001592. Epub 2013 May 20.

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.

Methods and 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.

Keywords: LDL receptor; Pcsk9 protein; cholesterol; lipoproteins; mouse model.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cells, Cultured
  • Cholesterol / blood*
  • Disease Models, Animal
  • Humans
  • Hypercholesterolemia / blood
  • Hypercholesterolemia / physiopathology
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Proprotein Convertase 9
  • Proprotein Convertases / blood*
  • Proprotein Convertases / genetics
  • Proprotein Convertases / physiology
  • Receptors, LDL / blood*
  • Receptors, LDL / deficiency
  • Receptors, LDL / genetics
  • Serine Endopeptidases / blood*
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / physiology
  • Transfection

Substances

  • Receptors, LDL
  • Cholesterol
  • PCSK9 protein, human
  • Pcsk9 protein, mouse
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Serine Endopeptidases