Decreased APOE-containing HDL subfractions and cholesterol efflux capacity of serum in mice lacking Pcsk9
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Background: Studies in animals showed that PCSK9 is involved in HDL metabolism. We investigated the molecular mechanism by which PCSK9 regulates HDL cholesterol concentration and also whether Pcsk9 inactivation might affect cholesterol efflux capacity of serum and atherosclerotic fatty streak volume. Methods: Mass spectrometry and western blot were used to analyze the level of apolipoprotein E (APOE) and A1 (APOA1). A mouse model overexpressing human LDLR was used to test the effect of high levels of liver LDLR on the concentration of HDL cholesterol and APOE-containing HDL subfractions. Pcsk9 knockout males lacking LDLR and APOE were used to test whether LDLR and APOE are necessary for PCSK9-mediated HDL cholesterol regulation. We also investigated the effects of Pcsk9 inactivation on cholesterol efflux capacity of serum using THP-1 and J774.A1 macrophage foam cells and atherosclerotic fatty streak volume in the aortic sinus of Pcsk9 knockout males fed an atherogenic diet. Results: APOE and APOA1 were reduced in the same HDL subfractions of Pcsk9 knockout and human LDLR transgenic male mice. In Pcsk9/Ldlr double-knockout mice, HDL cholesterol concentration was lower than in Ldlr knockout mice and higher than in wild-type controls. In Pcsk9/Apoe double-knockout mice, HDL cholesterol concentration was similar to that of Apoe knockout males. In Pcsk9 knockout males, THP-1 macrophage cholesterol efflux capacity of serum was reduced and the fatty streak lesion volume was similar to wild-type controls. Conclusions: In mice, LDLR and APOE are important factors for PCSK9-mediated HDL regulation. Our data suggest that, although LDLR plays a major role in PCSK9-mediated regulation of HDL cholesterol concentration, it is not the only mechanism and that, regardless of mechanism, APOE is essential. Pcsk9 inactivation decreases the HDL cholesterol concentration and cholesterol efflux capacity in serum, but does not increase atherosclerotic fatty streak volume.
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The induced ApoE was similarly lipidated with or without the SphK2 inhibitor.
“We found that the induced ApoE was similarly lipidated (41, 42), with or without the SphK2 inhibitor (Fig. 7A).”
From Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes (2024) · cites this paper as [41]
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Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes
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- Authors
- Choi, S., Aljakna, A., Srivastava, U., Peterson, B. R., Deng, B., Prat, A., & Korstanje, R.
- Affiliations
- Jackson Laboratory (US)
- University of Kansas (US)
- University of Vermont (US)
- Montreal Clinical Research Institute (CA)
- Corresponding author
- Korstanje, Ron
- Venue
- Lipids in Health and Disease
- Published
- 2013-07-24
- Volume
- 12
- Issue
- 1
- Pages
- 112-112
- ISSN
- 1476-511X (ISSN-L)
- PMC
- PMC3751695
- OpenAlex
- W2050214825
- Cited by
- 28
- References
- 1
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 2 · 2022: 1 · 2021: 3 · 2020: 1 · 2018: 2 · 2017: 4 · 2016: 3 · 2015: 5 · 2014: 3 · 2013: 1
- FWCI
- 3.94
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Lipids in Health and Disease (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- KU ScholarWorks (University of Kansas) (submittedVersion, cc-by)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Funders
- National Institutes of Health
- Canadian Institutes of Health Research (102741, 82946)
- National Heart, Lung, and Blood Institute (HL081162, HL095668, R37HL077796, HL077796, R01HL095668, R01HL081162)
- National Cancer Institute (CA83831, R01CA083831)
- National Institute of General Medical Sciences (P20GM103449)
- National Center for Research Resources
- 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, HDL cholesterol, apolipoprotein E, apolipoprotein A-I, LDL receptor, cholesterol efflux capacity, HDL subfractions, atherosclerosis, fatty streaks, foam cells, atherogenic diet, PCSK9 knockout mice
- MeSH terms
- Proprotein Convertase 9, Animals, Apolipoproteins E, Arteriosclerosis, Cell Line, Diet, Atherogenic, Humans, Cholesterol, HDL, Macrophages, Male, Mice, Transgenic, Receptors, LDL, Serine Endopeptidases, Apolipoprotein A-I, Mice, Knockout, Proprotein Convertases, Mice
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