Circulating proprotein convertase subtilisin kexin type 9 has a diurnal rhythm synchronous with cholesterol synthesis and is reduced by fasting in humans
Abstract
Objective— To gain insight into the function of proprotein convertase subtilisin kexin type 9 (PCSK9) in humans by establishing whether circulating levels are influenced by diurnal, dietary, and hormonal changes. Methods and Results— We monitored circulating PCSK9 in a set of dynamic human experiments and could show that serum PCSK9 levels display a diurnal rhythm that closely parallels that of cholesterol synthesis, measured as serum lathosterol. In contrast to these marked diurnal changes in cholesterol metabolism, serum low-density lipoprotein (LDL) cholesterol levels remained stable during the diurnal cycle. Depletion of liver cholesterol by treatment with the bile acid–binding resin, cholestyramine, abolished the diurnal rhythms of both PCSK9 and lathosterol. Fasting (>18 hours) strongly reduced circulating PCSK9 and lathosterol levels, whereas serum LDL levels remained unchanged. Growth hormone, known to be increased during fasting in humans, reduced circulating PCSK9 in parallel to LDL cholesterol levels. Conclusion— Throughout the day, and in response to fasting and cholesterol depletion, circulating PCSK9 displays marked variation, presumably related to oscillations in hepatic cholesterol that modify its activity in parallel with cholesterol synthesis. In addition to this sterol-mediated regulation, additional effects on LDL receptors may be mediated by hormones directly influencing PCSK9.
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PCSK9 expression is also observed in adult mouse and human cerebellum and can be measured in human cerebrospinal fluid.
“however, PCSK9 expression is also observed in adult mouse and human cerebellum (Seidah et al., 2003; gtexportal.org) and can be measured in human cerebrospinal fluid (CSF) (Persson et al., 2010; Chen et al., 2014).”
From PCSK9 deficiency alters brain lipid composition without affecting brain development and function (2023) · cites this paper as Persson et al., 2010
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Determination of serum levels of unesterified lathosterol by isotope dilution-mass spectrometry
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Bjermo, H., Iggman, D., Kullberg, J., Dahlman, I., Johansson, L., Persson, L., Berglund, J., Pulkki, K., Basu, S., Uusitupa, M., et al. (2012) · The American Journal of Clinical Nutrition · doi:10.3945/ajcn.111.030114 · Cited by 490 · see citing works
Self-citationKosenko, T., Golder, M., Leblond, G., Weng, W., & Lagace, T. A. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.421370 · Cited by 181 · see citing works
Lipid lowering therapy and circulating PCSK9 concentration
Nozue, T. (2017) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.rv17012 · Cited by 127 · see citing works
Targeting PCSK9 for hypercholesterolemia
Norata, G. D., Tibolla, G., & Catapano, A. L. (2014) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-011613-140025 · Cited by 127 · see citing works
Troutt, J. S., Rudling, M., Persson, L., Ståhle, L., Angelin, B., Butterfield, A. M., Schade, A. E., Cao, G., & Konrad, R. J. (2012) · Clinical Chemistry · doi:10.1373/clinchem.2012.186866 · Cited by 100 · see citing works
Self-citationPCSK9: A Multi-Faceted Protein That Is Involved in Cardiovascular Biology
Sundararaman, S. S., Döring, Y., & van der Vorst, E. P. C. (2021) · Biomedicines · doi:10.3390/biomedicines9070793 · Cited by 67 · see citing works
Chen, H. J., Chuang, S. Y., Chang, H. Y., & Pan, W. H. (2019) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2019.01.003 · Cited by 39 · see citing works
Brouwers, M. C. G. J., Konrad, R. J., van Himbergen, T. M., Isaacs, A., Otokozawa, S., Troutt, J. S., Schaefer, E. J., van Greevenbroek, M. M. J., Stalenhoef, A. F. H., & de Graaf, J. (2013) · Nutrition, Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2012.11.008 · Cited by 24 · see citing works
Self-citationRodríguez‐Pérez, C., Ramprasath, V. R., Pu, S., Sabra, A., Quirantes‐Piné, R., Segura‐Carretero, A., & Jones, P. J. (2016) · Lipids · doi:10.1007/s11745-015-4099-4 · Cited by 16 · see citing works
PCSK9 deficiency alters brain lipid composition without affecting brain development and function
Pärn, A., Olsen, D., Tuvikene, J., Kaas, M., Borisova, E., Bilgin, M., Elhauge, M., Vilstrup, J., Madsen, P., Ambrozkiewicz, M. C., et al. (2023) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.1084633 · Cited by 16 · see citing works
Zheng, X., Yuan, W., Li, L., Ma, H., Zhu, M., Li, X., & Feng, X. (2025) · European Journal of Medical Research · doi:10.1186/s40001-025-02937-1 · Cited by 9 · see citing works
- Authors
- Persson, L., Cao, G., Ståhle, L., Sjöberg, B. G., Troutt, J. S., Konrad, R. J., Gälman, C., Wallén, H., Eriksson, M., Hafström, I., Lind, S., Dahlin, M., Åmark, P., Angelin, B., & Rudling, M.
- Affiliations
- Karolinska University Hospital (SE)
- From the Department of Endocrinology, Metabolism and Diabetes and the Center for Biosciences and Nutrition, Department of Medicine (L.P., B.G.S., C.G., M.E., B.A., and M.R.), Karolinska Institutet at Karolinska University Hospital at Huddinge, Stockholm, Sweden; Lilly Research Laboratories (G.C., J.S.T., and R.J.K.), Division of Eli Lilly and Company, Indianapolis, Ind. USA; the Division of Clinical Pharmacology (L.S.), Karolinska Institutet at Karolinska University Hospital at Huddinge, Stockholm,...
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2010-12
- Volume
- 30
- Issue
- 12
- Pages
- 2666-2672
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- OpenAlex
- W2146010644
- Cited by
- 165
- References
- 1
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 4 · 2023: 6 · 2022: 14 · 2021: 9 · 2020: 12 · 2019: 12 · 2018: 11 · 2017: 11 · 2016: 16 · 2015: 13 · 2014: 13 · 2013: 15 · 2012: 7
- FWCI
- 10.61
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- PCSK9, diurnal cycle, cholesterol biosynthesis, lathosterol, fasting, LDL cholesterol, cholestyramine, bile acid sequestrants, growth hormone, liver cholesterol, LDL receptor, circadian rhythm, serum PCSK9 levels
- MeSH terms
- Atorvastatin, Proprotein Convertase 9, Anticholesteremic Agents, Energy Intake, Cholesterol, Cholestyramine Resin, Circadian Rhythm, Fasting, Female, Heptanoic Acids, Humans, Cholesterol, LDL, Liver, Male, Pyrroles, Receptors, LDL, Serine Endopeptidases, Sweden, Down-Regulation, Cross-Over Studies, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Human Growth Hormone, Proprotein Convertases, Diet, Ketogenic
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