Circulating proprotein convertase subtilisin/kexin 9 (PCSK9) regulates VLDLR protein and triglyceride accumulation in visceral adipose tissue
Abstract
Objective—: Proprotein convertase subtilisin/kexin 9 (PCSK9) promotes the degradation of the low-density lipoprotein receptor (LDLR), and its gene is the third locus implicated in familial hypercholesterolemia. Herein, we investigated the role of PCSK9 in adipose tissue metabolism. Methods and Results—: At 6 months of age, Pcsk9 −/− mice accumulated ≈80% more visceral adipose tissue than wild-type mice. This was associated with adipocyte hypertrophy and increased in vivo fatty acid uptake and ex vivo triglyceride synthesis. Moreover, adipocyte hypertrophy was also observed in Pcsk9 −/− Ldlr −/− mice, indicating that the LDLR is not implicated. Rather, we show here by immunohistochemistry that Pcsk9 −/− males and females exhibit 4- and ≈40-fold higher cell surface levels of very-low-density lipoprotein receptor (VLDLR) in perigonadal depots, respectively. Expression of PCSK9 in the liver of Pcsk9 −/− females reestablished both circulating PCSK9 and normal VLDLR levels. In contrast, specific inactivation of PCSK9 in the liver of wild-type females led to ≈50-fold higher levels of perigonadal VLDLR. Conclusion—: In vivo, endogenous PCSK9 regulates VLDLR protein levels in adipose tissue. This regulation is achieved by circulating PCSK9 that originates entirely in the liver. PCSK9 is thus pivotal in fat metabolism: it maintains high circulating cholesterol levels via hepatic LDLR degradation, but it also limits visceral adipogenesis likely via adipose VLDLR regulation.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
VLDLR and ApoER2 are key signaling receptors in the Reelin pathway and critical for proper cortical and cerebellar development as well as neuronal plasticity.
“These proteins are key signaling receptors in the Reelin pathway (Poirier et al., 2008; Roubtsova et al., 2011; Sekine et al., 2014) and hence critical for proper cortical and cerebellar development as well as neuronal plasticity (Trommsdorff et al., 1999; Armstrong et al., 2019).”
From PCSK9 deficiency alters brain lipid composition without affecting brain development and function (2023) · cites this paper as Roubtsova et al., 2011
Cites
Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity
Fabbrini, E., Magkos, F., Mohammed, B. S., Pietka, T., Abumrad, N. A., Patterson, B. W., Okunade, A., & Klein, S. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0904944106 · Cited by 972 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Da Dalt, L., Ruscica, M., Bonacina, F., Balzarotti, G., Dhyani, A., Di Cairano, E., Baragetti, A., Arnaboldi, L., De Metrio, S., Pellegatta, F., et al. (2019) · European Heart Journal · doi:10.1093/eurheartj/ehy357 · Cited by 209 · see citing works
Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): From bench to bedside
Bao, X., Liang, Y., Chang, H., Cai, T., Feng, B., Gordon, K., Zhu, Y., Shi, H., He, Y., & Xie, L. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01690-3 · Cited by 187 · see citing works
PCSK9 regulates neuronal apoptosis by adjusting ApoER2 levels and signaling
Kysenius, K., Muggalla, P., Mätlik, K., Arumäe, U., & Huttunen, H. J. (2012) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-012-0977-6 · Cited by 137 · 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
Thedrez, A., Blom, D. J., Ramin-Mangata, S., Blanchard, V., Croyal, M., Chemello, K., Nativel, B., Pichelin, M., Cariou, B., Bourane, S., et al. (2018) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.117.310217 · Cited by 105 · see citing works
Rousselet, E., Marcinkiewicz, J., Kriz, J., Zhou, A., Hatten, M. E., Prat, A., & Seidah, N. G. (2011) · Journal of Lipid Research · doi:10.1194/jlr.m014118 · Cited by 107 · see citing works
Self-citationExpanding biology of PCSK9: roles in atherosclerosis and beyond
Seidah, N. G., & Garçon, D. (2022) · Current Atherosclerosis Reports · doi:10.1007/s11883-022-01057-z · Cited by 76 · 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
PCSK9 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 · 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
- Authors
- Roubtsova, A., Munkonda, M. N., Awan, Z., Marcinkiewicz, J., Chamberland, A., Lazure, C., Cianflone, K., Seidah, N. G., & Prat, A.
- Affiliations
- Institut universitaire de cardiologie et de pneumologie de Québec (CA)
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2011-04
- Volume
- 31
- Issue
- 4
- Pages
- 785-791
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- OpenAlex
- W2108493094
- Cited by
- 244
- References
- 1
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 8 · 2023: 9 · 2022: 16 · 2021: 17 · 2020: 15 · 2019: 14 · 2018: 19 · 2017: 24 · 2016: 17 · 2015: 32 · 2014: 17 · 2013: 25 · 2012: 12
- FWCI
- 12.75
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research (102741, 82946, 64446)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- PCSK9, VLDLR, visceral adipose tissue, triglyceride accumulation, adipocyte hypertrophy, adipogenesis, LDL receptor degradation, fatty acid uptake, triglyceride synthesis, fat metabolism, PCSK9 knockout mice, sex differences
- MeSH terms
- Proprotein Convertase 9, Age Factors, Animals, Cholesterol, Female, Homeostasis, Hydrolysis, Hypertrophy, Immunohistochemistry, Liver, Male, Mice, Inbred C57BL, Receptors, LDL, Serine Endopeptidases, Sex Factors, Triglycerides, Adipocytes, Mice, Knockout, Oleic Acid, Proprotein Convertases, Intra-Abdominal Fat, Adiposity, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
