Apolipoprotein A-I Activates Protein Kinase Cα Signaling to Phosphorylate and Stabilize ATP Binding Cassette Transporter A1 for the High Density Lipoprotein Assembly
Open accessAbstract
ATP-binding cassette transporter A1 (ABCA1) plays an essential role in the helical apolipoprotein-mediated assembly of high density lipoprotein, and the apolipoporteins stabilize ABCA1 against calpain-mediated degradation during the reaction ((2002) J. Biol. Chem. 277, 22426-22429). Protein kinase C (PKC) inhibitors suppressed both ABCA1 stabilization and cellular lipid release mediated by apolipoprotein A-I (apoA-I) but not ABCA1 increase by calpain inhibitors. The increase of ABCA1 and the cellular lipid release by apoA-I were both suppressed by a phosphatidylcholine phospholipase C (PC-PLC) inhibitor but not by the inhibitors of phosphatidylinositol-PLC and phosphatidylinositol 3-kinase. A protein phosphatase inhibitor further enhanced the ABCA1 increase by apoA-I. Biochemical and microscopic evidence indicated that apoA-I activated PKC alpha, and phosphorylation of ABCA1 was directly demonstrated by apoA-I via PKC. Finally, digestion of sphingomyelin increased ABCA1, and a PC-PLC inhibitor suppressed it. We conclude that apoA-I activates PKC alpha by PC-PLC-mediated generation of diacylglycerol initiated by the removal of cellular sphingomyelin ((2002) J. Biol. Chem. 277, 44709-44714), and subsequently phosphorylates and stabilizes ABCA1.
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Protein kinase C activation promotes apoA-I-induced stabilization of ABCA1 protein, which is downregulated in KO astrocytes.
“Protein kinase C activation promotes apoA-I-induced stabilization of ABCA1 protein57, downregulated in the KO astrocytes.”
From An iPSC-derived astrocyte model of fragile X syndrome exhibits dysregulated cholesterol homeostasis (2023) · cites this paper as [57]
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- McNeish, J., Aiello, R. J., Guyot, D., Turi, T., Gabel, C., Aldinger, C., Hoppe, K. L., Roach, M. L., Royer, L. J., de Wet, J., Broccardo, C., Chimini, G., and Francone, O. L. (2000) Proc. Natl. Acad. Sci. U. S. A. 97, 4245-4250
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Glycosphingolipid Accumulation Inhibits Cholesterol Efflux via the ABCA1/Apolipoprotein A-I Pathway
Glaros, E. N., Kim, W. S., Quinn, C. M., Wong, J., Gelissen, I., Jessup, W., & Garner, B. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m413862200 · Cited by 75 · see citing works
An iPSC-derived astrocyte model of fragile X syndrome exhibits dysregulated cholesterol homeostasis
Talvio, K., Wagner, V. A., Minkeviciene, R., Kirkwood, J. S., Kulinich, A. O., Umemori, J., Bhatia, A., Hur, M., Käkelä, R., Ethell, I. M., et al. (2023) · Communications Biology · doi:10.1038/s42003-023-05147-9 · Cited by 8 · see citing works
- Authors
- Yamauchi, Y., Hayashi, M., Abe-Dohmae, S., & Yokoyama, S.
- Affiliations
- Nagoya City University (JP)
- Corresponding author
- Yokoyama, Shinji
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-11
- Volume
- 278
- Issue
- 48
- Pages
- 47890-47897
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2025716299
- Cited by
- 134
- References
- 0
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 5 · 2022: 3 · 2021: 4 · 2020: 1 · 2019: 7 · 2018: 4 · 2017: 3 · 2016: 1 · 2015: 5 · 2014: 8 · 2013: 9 · 2012: 8
- FWCI
- 12.84
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- apolipoprotein A-I, ABCA1, protein kinase C alpha, diacylglycerol, sphingomyelin, protein phosphatase
- MeSH terms
- Apolipoproteins, Calpain, Cell Line, Diglycerides, Dose-Response Relationship, Drug, Enzyme Activation, Enzyme Inhibitors, Fibroblasts, Humans, Lipoproteins, HDL, Luminescent Proteins, Models, Biological, Type C Phospholipases, Phosphorylation, Protein Kinase C, Recombinant Fusion Proteins, RNA, Messenger, Sphingomyelins, Time Factors, Blotting, Western, Signal Transduction, Apolipoprotein A-I, ATP-Binding Cassette Transporters, Reverse Transcriptase Polymerase Chain Reaction, Green Fluorescent Proteins, Lipid Metabolism, Protein Kinase C-alpha, ATP Binding Cassette Transporter 1
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