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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. 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.
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Pcsk9-/- mice are a model of increased hepatic LDL receptors.
“We overexpressed RNF130 in Pcsk9–/– mice, a model of increased hepatic LDL receptors27,28.”
From RNF130 Regulates LDLR Availability and Plasma LDL Cholesterol Levels (2023) · cites this paper as [27]
The Results section on PCSK9 and LDLR expression reports that expressing human PCSK9 reduced hepatic LDLR levels by 41%, supporting the underlying relationship. But the paper studies PCSK9-overexpressing mice, not Pcsk9−/− mice, and does not establish that the knockout mice are a model of increased hepatic LDLR. (LLM, conf=0.81)
Experimental — accuracy not yet measuredPCSK9 is known to have a complex reciprocal regulatory relationship with LDLR.
“PCSK9 is known to have a complex reciprocal regulatory relationship with LDLR27,42.”
From RNF130 Regulates LDLR Availability and Plasma LDL Cholesterol Levels (2023) · cites this paper as [27]
Ldlr is the main route of Pcsk9 clearance.
“Ldlr was reported to be the main route of Pcsk9 clearance.22”
From The Sirt1 activator SRT3025 provides atheroprotection in Apoe−/− mice by reducing hepatic Pcsk9 secretion and enhancing Ldlr expression (2015) · cites this paper as [22]
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Variation in PCSK9 and HMGCR and Risk of Cardiovascular Disease and Diabetes
Ference, B. A., Robinson, J. G., Brook, R. D., Catapano, A. L., Chapman, M. J., Neff, D. R., Voros, S., Giugliano, R. P., Davey Smith, G., Fazio, S., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1604304 · Cited by 743
Self-citationThe Evolving Future of PCSK9 Inhibitors
Rosenson, R. S., Hegele, R. A., Fazio, S., & Cannon, C. P. (2018) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2018.04.054 · Cited by 264
Self-citationThe hypercholesterolemia-risk gene SORT1 facilitates PCSK9 secretion
Gustafsen, C., Kjolby, M., Nyegaard, M., Mattheisen, M., Lundhede, J., Buttenschøn, H., Mors, O., Bentzon, J. F., Madsen, P., Nykjaer, A., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2013.12.006 · Cited by 170
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PCSK9 inhibition to reduce cardiovascular disease risk: recent findings from the biology of PCSK9
Tavori, H., Giunzioni, I., & Fazio, S. (2015) · Current Opinion in Endocrinology, Diabetes & Obesity · doi:10.1097/med.0000000000000137 · Cited by 30
Self-citationPCSK9 inhibition and cholesterol homeostasis in insulin producing β-cells
Päth, G., Perakakis, N., Mantzoros, C. S., & Seufert, J. (2022) · Lipids in Health and Disease · doi:10.1186/s12944-022-01751-6 · Cited by 24
Alirocumab: PCSK9 inhibitor for LDL cholesterol reduction
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Self-citationRNF130 Regulates LDLR Availability and Plasma LDL Cholesterol Levels
Clifford, B. L., Jarrett, K. E., Cheng, J., Cheng, A., Seldin, M., Morand, P., Lee, R., Chen, M., Baldan, A., de Aguiar Vallim, T. Q., et al. (2023) · Circulation Research · doi:10.1161/circresaha.122.321938 · Cited by 20
Testa, G., Giannelli, S., Staurenghi, E., Cecci, R., Floro, L., Gamba, P., Sottero, B., & Leonarduzzi, G. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252413637 · Cited by 14
“In turn, the LDLR regulates PCSK9 trafficking, since the binding of pro-PCSK9 to the precursor form of the LDLR promotes PCSK9 auto-catalytic cleavage [58,68].”
Tavori, H., Fan, D., Giunzioni, I., Zhu, L., Linton, M. F., Fogo, A. B., & Fazio, S. (2014) · Journal of Lipid Research · doi:10.1194/jlr.m049874 · Cited by 10
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Metadata
- Authors
- Tavori, H., Fan, D., Blakemore, J. L., Yancey, P. G., Ding, L., Linton, M. F., & Fazio, S.
- Affiliations
- From the Atherosclerosis Research Unit, Division of Cardiovascular Medicine, Departments of Medicine (H.T., J.L.B., P.G.Y., L.D., M.F.L., S.F.), Pharmacology (M.F.L.), and Pathology, Microbiology, and Immunology (S.F.), Vanderbilt University Medical Center, Nashville, TN; and Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia (D.F.).
- Venue
- Circulation
- Published
- 2013-06-18
- Volume
- 127
- Issue
- 24
- Pages
- 2403-2413
- ISSN
- 0009-7322
- 1524-4539
- PMC
- PMC3806304
- Cited by
- 178
- References
- 4
- Language
- en
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