Pcsk9 Deletion Promotes Murine Nonalcoholic Steatohepatitis and Hepatic Carcinogenesis: Role of Cholesterol
Open accessAbstract
Proprotein convertase subtilisin/kexin type 9 (Pcsk9) binds to hepatic low‐density lipoprotein receptor (LDLR) and induces its internalization and degradation. Pcsk9 inhibition increases LDLR expression by hepatocytes, which causes increased uptake of circulating LDL, thereby reducing plasma LDL‐cholesterol. However, by increasing the uptake of LDL by the liver, Pcsk9 inhibition increases the exposure of the liver to cholesterol, which may result in higher risk of steatohepatitis and ever carcinogenesis. We compared Pcsk9‐/‐ knockout (KO) mice and appropriate wild‐type (WT) controls of the same strain assigned to a high‐fat (15%, wt/wt) diet for 9 months supplemented with 0.25%, 0.5%, or 0.75% dietary cholesterol. Pcsk9 KO mice on a high‐fat, high‐cholesterol diet exhibited higher levels of hepatic free cholesterol loading and hepatic cholesterol crystallization than their WT counterparts. Pcsk9 KO mice developed crown‐like structures of macrophages surrounding cholesterol crystal‐containing lipid droplets and hepatocytes, exhibited higher levels of apoptosis, and developed significantly more hepatic inflammation and fibrosis consistent with fibrosing steatohepatitis, including 5‐fold and 11‐fold more fibrosis at 0.5% and 0.75% dietary cholesterol, respectively. When injected with diethylnitrosamine, a hepatic carcinogen, early‐in‐life Pcsk9 KO mice were more likely to develop liver cancer than WT mice. Conclusion: Pcsk9 KO mice on high‐cholesterol diets developed increased hepatic free cholesterol and cholesterol crystals and fibrosing steatohepatitis with a higher predisposition to liver cancer compared with WT mice. Future studies should evaluate whether patients on long‐term treatment with anti‐PSCK9 monoclonal antibodies are at increased risk of hepatic steatosis, steatohepatitis or liver cancer, while accounting for concurrent use of statins.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
There are concerns that PCSK9 inhibition might promote intrahepatic lipid accumulation.
“there are some concerns that PCSK9 inhibition might promote intrahepatic lipid accumulation [162].”
From Targeting Intramyocellular Lipids to Improve Aging Muscle Function (2025) · cites this paper as [162]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Design and validation of a histological scoring system for nonalcoholic fatty liver disease†
Kleiner, D. E., Brunt, E. M., Van Natta, M., Behling, C., Contos, M. J., Cummings, O. W., Ferrell, L. D., Liu, Y., Torbenson, M. S., Unalp‐Arida, A., et al. (2005) · Hepatology · doi:10.1002/hep.20701 · Cited by 10,791 · see citing works
Self-citationFinak, G., McDavid, A., Yajima, M., Deng, J., Gersuk, V., Shalek, A. K., Slichter, C. K., Miller, H. W., McElrath, M. J., Prlic, M., et al. (2015) · Genome Biology · doi:10.1186/s13059-015-0844-5 · Cited by 3,159 · see citing works
Self-citationA lipidomic analysis of nonalcoholic fatty liver disease
Puri, P., Baillie, R. A., Wiest, M. M., Mirshahi, F., Choudhury, J., Cheung, O., Sargeant, C., Contos, M. J., & Sanyal, A. J. (2007) · Hepatology · doi:10.1002/hep.21763 · Cited by 1,338 · see citing works
Yamaguchi, K., Yang, L., McCall, S. J., Huang, J., Yu, X. X., Pandey, S., Bhanot, S., Monia, B. P., Li, Y.-X., & Diehl, A. M. (2007) · Hepatology · doi:10.1002/hep.21655 · Cited by 1,019 · see citing works
Athyros, V. G., Tziomalos, K., Gossios, T. D., Griva, T., Anagnostis, P., Kargiotis, K., Pagourelias, E. D., Theocharidou, E., Karagiannis, A., & Mikhailidis, D. P. (2010) · The Lancet · doi:10.1016/s0140-6736(10)61272-x · Cited by 685 · see citing works
Decreased plasma cholesterol and hypersensitivity to statins in mice lacking <i>Pcsk9</i>
Rashid, S., Curtis, D. E., Garuti, R., Anderson, N. N., Bashmakov, Y., Ho, Y. K., Hammer, R. E., Moon, Y.-A., & Horton, J. D. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0501652102 · Cited by 679 · see citing works
Molecular biology of PCSK9: its role in LDL metabolism
HORTON, J., COHEN, J., & HOBBS, H. (2007) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2006.12.008 · Cited by 621 · see citing works
The Role of Cholesterol in the Pathogenesis of NASH
Ioannou, G. N. (2016) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2015.11.008 · Cited by 498 · see citing works
Self-citationStatin use and non-alcoholic steatohepatitis in at risk individuals
Dongiovanni, P., Petta, S., Mannisto, V., Mancina, R. M., Pipitone, R., Karja, V., Maggioni, M., Kakela, P., Wiklund, O., Mozzi, E., et al. (2015) · Journal of Hepatology · doi:10.1016/j.jhep.2015.05.006 · Cited by 390 · see citing works
Hepatic Free Cholesterol Accumulates in Obese, Diabetic Mice and Causes Nonalcoholic Steatohepatitis
Rooyen, D. M. V., Larter, C. Z., Haigh, W. G., Yeh, M. M., Ioannou, G. N., Kuver, R., Lee, S. P., Teoh, N., & Farrell, G. C. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.06.040 · Cited by 345 · see citing works
Self-citationDiethylnitrosamine (DEN)-induced carcinogenic liver injury in mice
Tolba, R., Kraus, T., Liedtke, C., Schwarz, M., & Weiskirchen, R. (2015) · Laboratory Animals · doi:10.1177/0023677215570086 · Cited by 313 · see citing works
Savard, C. E., Tartaglione, E. V., Kuver, R., Haigh, G. W., Farrell, G. C., Subramanian, S., Chait, A., Yeh, M. M., Quinn, L. S., & Ioannou, G. N. (2012) · Hepatology · doi:10.1002/hep.25789 · Cited by 297 · see citing works
Self-citationA Pilot Study Using Simvastatin in the Treatment of Nonalcoholic Steatohepatitis
Nelson, A., Torres, D. M., Morgan, A. E., Fincke, C. A., & Harrison, S. A. (2009) · Journal of Clinical Gastroenterology · doi:10.1097/mcg.0b013e31819c392e · Cited by 269 · see citing works
Foster, T., Budoff, M. J., Saab, S., Ahmadi, N., Gordon, C., & Guerci, A. D. (2010) · The American Journal of Gastroenterology · doi:10.1038/ajg.2010.299 · Cited by 260 · see citing works
Hepatic cholesterol crystals and crown-like structures distinguish NASH from simple steatosis
Ioannou, G. N., Haigh, W. G., Thorning, D., & Savard, C. E. (2013) · Journal of Lipid Research · doi:10.1194/jlr.m034876 · Cited by 256 · see citing works
Self-citationAthyros, V. G., Mikhailidis, D. P., Didangelos, T., Γιουλεμέ, Ό., Liberopoulos, E. N., Karagiannis, A. I., Kakafika, A. I., Τζιόμαλος, Κ., Burroughs, A. K., & Elisaf, M. (2006) · Current Medical Research and Opinion · doi:10.1185/030079906x104696 · Cited by 248 · see citing works
Subramanian, S., Goodspeed, L., Wang, S., Kim, J. K., Zeng, L., Ioannou, G. N., Haigh, W. G., Yeh, M. M., Kowdley, K. V., O’Brien, K. D., et al. (2011) · Journal of Lipid Research · doi:10.1194/jlr.m016246 · Cited by 240 · see citing works
Self-citationLiang, Q., Teoh, N., Xu, L., Pok, S., Li, X., Chu, E. S., Chiu, J., Dong, L., Arfianti, A., Haigh, W. G., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-06931-6 · Cited by 223 · see citing works
Self-citationRole of Cholesterol‐Associated Steatohepatitis in the Development of NASH
Horn, C. L., Morales, A. L., Savard, C. E., Farrell, G. C., & Ioannou, G. N. (2021) · Hepatology Communications · doi:10.1002/hep4.1801 · Cited by 215 · see citing works
Self-citationGuedeney, P., Giustino, G., Sorrentino, S., Claessen, B. E., Camaj, A., Kalkman, D. N., Vogel, B., Sartori, S., De Rosa, S., Baber, U., et al. (2022) · European Heart Journal · doi:10.1093/eurheartj/ehz430 · Cited by 208 · see citing works
Cholesterol crystallization within hepatocyte lipid droplets and its role in murine NASH
Ioannou, G. N., Subramanian, S., Chait, A., Haigh, W. G., Yeh, M. M., Farrell, G. C., Lee, S. P., & Savard, C. E. (2017) · Journal of Lipid Research · doi:10.1194/jlr.m072454 · Cited by 173 · see citing works
Self-citationIoannou, G. N., Morrow, O., Connole, M. L., & Lee, S. P. (2009) · Hepatology · doi:10.1002/hep.22941 · Cited by 168 · see citing works
Self-citationLiver fat accumulation is associated with circulating PCSK9
Ruscica, M., Ferri, N., Macchi, C., Meroni, M., Lanti, C., Ricci, C., Maggioni, M., Fracanzani, A. L., Badiali, S., Fargion, S. R., et al. (2016) · Annals of Medicine · doi:10.1080/07853890.2016.1188328 · Cited by 154 · see citing works
Kargiotis, K. (2015) · World Journal of Gastroenterology · doi:10.3748/wjg.v21.i25.7860 · Cited by 146 · see citing works
Cariou, B., Ouguerram, K., Zaïr, Y., Guérois, R., Langhi, C., Kourimate, S., Benoit, I., May, C. L., Gayet, C., Belabbas, K., et al. (2009) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.109.194191 · Cited by 139 · see citing works
Liver carcinogenesis by FOS-dependent inflammation and cholesterol dysregulation
Bakiri, L., Hamacher, R., Graña‐Castro, O., Guío-Carrión, A., Campos‐Olivas, R., Martínez, L., Dienes, H. P., Thomsen, M. K., Hasenfuss, S. C., & Wagner, E. F. (2017) · The Journal of Experimental Medicine · doi:10.1084/jem.20160935 · Cited by 133 · see citing works
Fasano, T., Cefalu, A. B., Leo, E. D., Noto, D., Pollaccia, D., Bocchi, L., Valenti, V., Bonardi, R., Guardamagna, O., Averna, M. R., et al. (2006) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000255311.26383.2f · Cited by 128 · see citing works
Ioannou, G. N., Rooyen, D. M. V., Savard, C. E., Haigh, W. G., Yeh, M. M., Teoh, N., & Farrell, G. C. (2014) · Journal of Lipid Research · doi:10.1194/jlr.m053785 · Cited by 93 · see citing works
Self-citationRudolf, M., & Curcio, C. A. (2009) · Journal of Histochemistry & Cytochemistry · doi:10.1369/jhc.2009.953448 · Cited by 93 · see citing works
Ioannou, G. N., Landis, C. S., Jin, G., Haigh, W. G., Farrell, G. C., Kuver, R., Lee, S. P., & Savard, C. E. (2019) · Hepatology Communications · doi:10.1002/hep4.1348 · Cited by 84 · see citing works
Self-citationLebeau, P. F., Byun, J. H., Platko, K., Al‐Hashimi, A., Lhoták, Š., MacDonald, M. E., Mejía‐Benítez, A., Prat, A., Igdoura, S. A., Trigatti, B. L., et al. (2019) · JHEP Reports · doi:10.1016/j.jhepr.2019.10.009 · Cited by 83 · see citing works
PCSK9 deficiency results in increased ectopic fat accumulation in experimental models and in humans
Baragetti, A., Balzarotti, G., Grigore, L., Pellegatta, F., Guerrini, U., Pisano, G., Fracanzani, A. L., Fargion, S. R., Norata, G. D., & Catapano, A. L. (2017) · European Journal of Preventive Cardiology · doi:10.1177/2047487317724342 · Cited by 80 · see citing works
Lebeau, P. F., Byun, J. H., Platko, K., MacDonald, M. E., Poon, S. V., Faiyaz, M., Seidah, N. G., & Austin, R. C. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.008094 · Cited by 61 · see citing works
Theocharidou, E., Papademetriou, M., Reklou, A., et al. (2018) · Current Pharmaceutical Design · doi:10.2174/1381612824666181010123127 · Cited by 56 · see citing works
Gomez, M. V., Dutta, M., Suvorov, A., Shi, X., Gu, H., Mani, S., & Cui, J. Y. (2020) · Toxicological Sciences · doi:10.1093/toxsci/kfaa161 · Cited by 42 · see citing works
Self-citationCirculating PCSK9 is associated with liver biomarkers and hepatic steatosis
Paquette, M., Gauthier, D., Chamberland, A., Prat, A., Rolfe, E. D. L., Rasmussen, J., Kaduka, L. U., Seidah, N. G., Bernard, S., Christensen, D. L., et al. (2020) · Clinical Biochemistry · doi:10.1016/j.clinbiochem.2020.01.003 · Cited by 40 · see citing works
Lebeau, P. F., Wassef, H., Byun, J. H., Platko, K., Ason, B. L., Jackson, S. M., Dobroff, J., Shetterly, S., Richards, W. G., Al‐Hashimi, A., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci128650 · Cited by 40 · see citing works
Genetic Inhibition ofPCSK9and Liver Function
Rimbert, A., Smati, S., Dijk, W., May, C. L., & Cariou, B. (2020) · JAMA Cardiology · doi:10.1001/jamacardio.2020.5341 · Cited by 36 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
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
Targeting Intramyocellular Lipids to Improve Aging Muscle Function
Russ, D. W., Manickam, R., & Tipparaju, S. M. (2025) · Lipids in Health and Disease · doi:10.1186/s12944-025-02622-6 · Cited by 15 · see citing works
“However, there are some concerns that PCSK9 inhibition might promote intrahepatic lipid accumulation [162].”
- Authors
- Ioannou, G. N., Lee, S. P., Linsley, P. S., Gersuk, V., Yeh, M. M., Chen, Y., Peng, Y., Dutta, M., Mascarinas, G., Molla, B., Cui, J. Y., & Savard, C.
- Affiliations
- University of Washington (US)
- Benaroya Research Institute (US)
- Tri-Service General Hospital (TW)
- Corresponding author
- Ioannou, George N.
- ORCID
- Venue
- Hepatology Communications
- Published
- 2021-11-24
- Volume
- 6
- Issue
- 4
- Pages
- 780-794
- ISSN
- 2471-254X (ISSN-L)
- PMC
- PMC8948564
- OpenAlex
- W3217789692
- Cited by
- 52
- References
- 38
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 12 · 2023: 17 · 2022: 8
- FWCI
- 6.66
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Hepatology Communications (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX002910, BX002910)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK017047, P30DK017047)
- National Institute of Environmental Health Sciences (P30ES007033)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- PCSK9, nonalcoholic steatohepatitis, hepatocarcinogenesis, liver cholesterol, free cholesterol, cholesterol crystals, liver fibrosis, liver inflammation, LDL receptor, high-fat high-cholesterol diet, diethylnitrosamine, liver cancer, anti-PCSK9 monoclonal antibodies, statins, hepatocyte apoptosis
- MeSH terms
- Proprotein Convertase 9, Animals, Cholesterol, Mice, Inbred C57BL, Serine Endopeptidases, Proprotein Convertases, Mice, Carcinogenesis, Non-alcoholic Fatty Liver Disease
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
