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

Hagai Tavori, Daping Fan, John L. Blakemore, Patricia G. Yancey, Lei Ding, MacRae F. Linton, Sergio Fazio

Research output: Contribution to journalArticle

94 Citations (Scopus)

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 wildtype 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.

Original languageEnglish (US)
Pages (from-to)2403-2413
Number of pages11
JournalCirculation
Volume127
Issue number24
DOIs
StatePublished - Jun 18 2013
Externally publishedYes

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LDL Receptors
Serum
Cholesterol
Proprotein Convertase 9
LDL Lipoproteins
Transgenic Mice
Liver
Apolipoproteins B
Hypercholesterolemia
Half-Life
Blood Proteins

Keywords

  • Cholesterol
  • LDL receptor
  • Lipoproteins
  • Mouse model
  • PCSK9 protein

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Serum proprotein convertase subtilisin/kexin type 9 and cell surface low-density lipoprotein receptor evidence for a reciprocal regulation. / Tavori, Hagai; Fan, Daping; Blakemore, John L.; Yancey, Patricia G.; Ding, Lei; Linton, MacRae F.; Fazio, Sergio.

In: Circulation, Vol. 127, No. 24, 18.06.2013, p. 2403-2413.

Research output: Contribution to journalArticle

Tavori, Hagai ; Fan, Daping ; Blakemore, John L. ; Yancey, Patricia G. ; Ding, Lei ; Linton, MacRae F. ; Fazio, Sergio. / Serum proprotein convertase subtilisin/kexin type 9 and cell surface low-density lipoprotein receptor evidence for a reciprocal regulation. In: Circulation. 2013 ; Vol. 127, No. 24. pp. 2403-2413.
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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 wildtype 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.",
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T1 - Serum proprotein convertase subtilisin/kexin type 9 and cell surface low-density lipoprotein receptor evidence for a reciprocal regulation

AU - Tavori, Hagai

AU - Fan, Daping

AU - Blakemore, John L.

AU - Yancey, Patricia G.

AU - Ding, Lei

AU - Linton, MacRae F.

AU - Fazio, Sergio

PY - 2013/6/18

Y1 - 2013/6/18

N2 - 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 wildtype 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.

AB - 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 wildtype 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.

KW - Cholesterol

KW - LDL receptor

KW - Lipoproteins

KW - Mouse model

KW - PCSK9 protein

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