Apolipoprotein A-I-stimulated Apolipoprotein E Secretion from Human Macrophages Is Independent of Cholesterol Efflux
| Autor: | Carmel M. Quinn, Gerd Assmann, Mayakonda N. Palgunachari, Dimitri Sviridov, Janelle Wright, John R. Burnett, Gattadahalli M. Anantharamaiah, Kerry-Anne Rye, Ying Fu, Maaike Kockx, Sissel Lund Katz, Katharina Gaus, Michael C. Phillips, Leonard Kritharides, Roger T. Dean, Stephan Rust, Timothy Sloane, David R. Sullivan, Wendy Jessup |
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| Rok vydání: | 2004 |
| Předmět: |
Apolipoprotein E
Sucrose Time Factors Apolipoprotein B Biochemistry Monocytes chemistry.chemical_compound Tangier disease polycyclic compounds RNA Processing Post-Transcriptional Phospholipids Tangier Disease Reverse Transcriptase Polymerase Chain Reaction Exons Recombinant Proteins Cholesterol Electrophoresis Polyacrylamide Gel lipids (amino acids peptides and proteins) Efflux Lipoproteins HDL ATP Binding Cassette Transporter 1 medicine.medical_specialty Blotting Western Enzyme-Linked Immunosorbent Assay Biology Apolipoproteins E Internal medicine Centrifugation Density Gradient medicine Humans Biotinylation Secretion Autocrine signalling Molecular Biology Apolipoprotein A-I Macrophages nutritional and metabolic diseases Cell Biology Lipid Metabolism medicine.disease Protein Structure Tertiary Endocrinology chemistry ABCA1 Mutation Leukocytes Mononuclear biology.protein ATP-Binding Cassette Transporters Peptides Ultracentrifugation |
| Zdroj: | Journal of Biological Chemistry. 279:25966-25977 |
| ISSN: | 0021-9258 |
| Popis: | Apolipoprotein A-I (apoA-I)-mediated cholesterol efflux involves the binding of apoA-I to the plasma membrane via its C terminus and requires cellular ATP-binding cassette transporter (ABCA1) activity. ApoA-I also stimulates secretion of apolipoprotein E (apoE) from macrophage foam cells, although the mechanism of this process is not understood. In this study, we demonstrate that apoA-I stimulates secretion of apoE independently of both ABCA1-mediated cholesterol efflux and of lipid binding by its C terminus. Pulse-chase experiments using (35)S-labeled cellular apoE demonstrate that macrophage apoE exists in both relatively mobile (E(m)) and stable (E(s)) pools, that apoA-I diverts apoE from degradation to secretion, and that only a small proportion of apoA-I-mobilized apoE is derived from the cell surface. The structural requirements for induction of apoE secretion and cholesterol efflux are clearly dissociated, as C-terminal deletions in recombinant apoA-I reduce cholesterol efflux but increase apoE secretion, and deletion of central helices 5 and 6 decreases apoE secretion without perturbing cholesterol efflux. Moreover, a range of 11- and 22-mer alpha-helical peptides representing amphipathic alpha-helical segments of apoA-I stimulate apoE secretion whereas only the C-terminal alpha-helix (domains 220-241) stimulates cholesterol efflux. Other alpha-helix-containing apolipoproteins (apoA-II, apoA-IV, apoE2, apoE3, apoE4) also stimulate apoE secretion, implying a positive feedback autocrine loop for apoE secretion, although apoE4 is less effective. Finally, apoA-I stimulates apoE secretion normally from macrophages of two unrelated subjects with genetically confirmed Tangier Disease (mutations C733R and c.5220-5222delTCT; and mutations A1046D and c.4629-4630insA), despite severely inhibited cholesterol efflux. We conclude that apoA-I stimulates secretion of apoE independently of cholesterol efflux, and that this represents a novel, ABCA-1-independent, positive feedback pathway for stimulation of potentially anti-atherogenic apoE secretion by alpha-helix-containing molecules including apoA-I and apoE. |
| Databáze: | OpenAIRE |
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