Apolipoprotein A-1-simulated apolipoprotein E secretion from human macrophages is independent of cholesterol efflux

M Kockx, Kerry-Anne Rye, K Gaus, Carmel Quinn, Janelle Wright, Timothy Sloan, Dimitri Sviridov, Ying Fu, David Sullivan, John Burnett, Stephan Rust, Gerd Assmann, G Anantharamaiah, Mayakonda Palgunachari, Sissel Katz, Michael Phillips, Roger Dean, Wendy Jessup, Leonard Kritharides

Research output: Contribution to journalArticle

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Abstract

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 35S-labeled cellular apoE demonstrate that macrophage apoE exists in both relatively mobile (Em) and stable (Es) 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 α-helical peptides representing amphipathic α-helical segments of apoA-I stimulate apoE secretion whereas only the C-terminal α-helix (domains 220–241) stimulates cholesterol efflux. Other α-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 α-helix-containing molecules including apoA-I and apoE.
Original languageEnglish
Pages (from-to)25966-25977
Number of pages12
JournalThe Journal of Biological Chemistry
Volume279
Issue number25
DOIs
Publication statusPublished - 2004

Fingerprint

Macrophages
Apolipoprotein A-I
Apolipoproteins E
Cholesterol
Apolipoprotein E4
Tangier Disease
Apolipoprotein E2
Apolipoprotein E3
Apolipoprotein A-II
Apolipoproteins A
Feedback
Foam Cells
Mutation
ATP-Binding Cassette Transporters
Apolipoproteins
Cell membranes

Cite this

Kockx, M ; Rye, Kerry-Anne ; Gaus, K ; Quinn, Carmel ; Wright, Janelle ; Sloan, Timothy ; Sviridov, Dimitri ; Fu, Ying ; Sullivan, David ; Burnett, John ; Rust, Stephan ; Assmann, Gerd ; Anantharamaiah, G ; Palgunachari, Mayakonda ; Katz, Sissel ; Phillips, Michael ; Dean, Roger ; Jessup, Wendy ; Kritharides, Leonard. / Apolipoprotein A-1-simulated apolipoprotein E secretion from human macrophages is independent of cholesterol efflux. In: The Journal of Biological Chemistry. 2004 ; Vol. 279, No. 25. pp. 25966-25977.
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abstract = "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 35S-labeled cellular apoE demonstrate that macrophage apoE exists in both relatively mobile (Em) and stable (Es) 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 α-helical peptides representing amphipathic α-helical segments of apoA-I stimulate apoE secretion whereas only the C-terminal α-helix (domains 220–241) stimulates cholesterol efflux. Other α-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 α-helix-containing molecules including apoA-I and apoE.",
author = "M Kockx and Kerry-Anne Rye and K Gaus and Carmel Quinn and Janelle Wright and Timothy Sloan and Dimitri Sviridov and Ying Fu and David Sullivan and John Burnett and Stephan Rust and Gerd Assmann and G Anantharamaiah and Mayakonda Palgunachari and Sissel Katz and Michael Phillips and Roger Dean and Wendy Jessup and Leonard Kritharides",
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Kockx, M, Rye, K-A, Gaus, K, Quinn, C, Wright, J, Sloan, T, Sviridov, D, Fu, Y, Sullivan, D, Burnett, J, Rust, S, Assmann, G, Anantharamaiah, G, Palgunachari, M, Katz, S, Phillips, M, Dean, R, Jessup, W & Kritharides, L 2004, 'Apolipoprotein A-1-simulated apolipoprotein E secretion from human macrophages is independent of cholesterol efflux', The Journal of Biological Chemistry, vol. 279, no. 25, pp. 25966-25977. https://doi.org/10.1074/jbc.M401177200

Apolipoprotein A-1-simulated apolipoprotein E secretion from human macrophages is independent of cholesterol efflux. / Kockx, M; Rye, Kerry-Anne; Gaus, K; Quinn, Carmel; Wright, Janelle; Sloan, Timothy; Sviridov, Dimitri; Fu, Ying; Sullivan, David; Burnett, John; Rust, Stephan; Assmann, Gerd; Anantharamaiah, G; Palgunachari, Mayakonda; Katz, Sissel; Phillips, Michael; Dean, Roger; Jessup, Wendy; Kritharides, Leonard.

In: The Journal of Biological Chemistry, Vol. 279, No. 25, 2004, p. 25966-25977.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Apolipoprotein A-1-simulated apolipoprotein E secretion from human macrophages is independent of cholesterol efflux

AU - Kockx, M

AU - Rye, Kerry-Anne

AU - Gaus, K

AU - Quinn, Carmel

AU - Wright, Janelle

AU - Sloan, Timothy

AU - Sviridov, Dimitri

AU - Fu, Ying

AU - Sullivan, David

AU - Burnett, John

AU - Rust, Stephan

AU - Assmann, Gerd

AU - Anantharamaiah, G

AU - Palgunachari, Mayakonda

AU - Katz, Sissel

AU - Phillips, Michael

AU - Dean, Roger

AU - Jessup, Wendy

AU - Kritharides, Leonard

PY - 2004

Y1 - 2004

N2 - 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 35S-labeled cellular apoE demonstrate that macrophage apoE exists in both relatively mobile (Em) and stable (Es) 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 α-helical peptides representing amphipathic α-helical segments of apoA-I stimulate apoE secretion whereas only the C-terminal α-helix (domains 220–241) stimulates cholesterol efflux. Other α-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 α-helix-containing molecules including apoA-I and apoE.

AB - 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 35S-labeled cellular apoE demonstrate that macrophage apoE exists in both relatively mobile (Em) and stable (Es) 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 α-helical peptides representing amphipathic α-helical segments of apoA-I stimulate apoE secretion whereas only the C-terminal α-helix (domains 220–241) stimulates cholesterol efflux. Other α-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 α-helix-containing molecules including apoA-I and apoE.

U2 - 10.1074/jbc.M401177200

DO - 10.1074/jbc.M401177200

M3 - Article

VL - 279

SP - 25966

EP - 25977

JO - The Journal of Biological Chemistry

JF - The Journal of Biological Chemistry

SN - 0021-9258

IS - 25

ER -