Synthetic amphipathic helical peptides promote lipid efflux from cells by an ABCA1-dependent and an ABCA1-independent pathway

Remaley, Alan T.; Fairwell, T; Stonik, John A.; Demosky, Stephen J.; Bark, Samantha E.; Neufeld, Edward B.; Bocharov, Alexander V.; Vishnyakova, Tatyana G.; Patterson, Amy P.; Eggerman, Thomas L.; Santamarina-Fojo, Silvia; Brewer, H. Bryan

doi:10.1194/jlr.m200475-jlr200

Cited by 185 publications

(202 citation statements)

References 37 publications

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“…D-Amino acids are the stereoisomers of L-amino acids that form lefthanded helical structures instead of the naturally occurring right-handed helices. Thus, these previous studies provide evidence that there is no stereoselective requirement for helical peptides to mediate cellular lipid efflux via ABCA1 (45). However, as discussed by Remaley et al (45), studies employing 37pA do not rule out the possibility that protein-protein interactions between helical apolipoproteins and ABCA1 are important for cholesterol efflux.…”

Section: Discussionmentioning

confidence: 65%

“…Therefore, the idea that protein-protein interactions between helical apolipoproteins and ABCA1 are required for cholesterol efflux and ABCA1 stabilization remains a possibility. Peptide 37pA appears to be potent mediator of cellular cholesterol efflux (45,46). This suggests that the extremely high lipid binding affinity of the helical peptide may compensate for a less than perfect topography of negatively charged residues on its polar surface by facilitating cholesterol efflux via ABCA1-dependent and -independent mechanisms (45).…”

Section: Discussionmentioning

confidence: 99%

“…Studies employing peptide 37pA suggest that helical apolipoproteins do not interact with ABCA1 via a traditional receptor/ligand-type mechanism (45,46). This is based on the findings that peptide 37pA composed of unnatural D-amino acids stimulates cholesterol efflux and stabilizes ABCA1.…”

Section: Discussionmentioning

confidence: 99%

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Identification of an Apolipoprotein A-I Structural Element That Mediates Cellular Cholesterol Efflux and Stabilizes ATP Binding Cassette Transporter A1

Natarajan

Forte

Chu

et al. 2004

Journal of Biological Chemistry

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Synthetic peptides were used in this study to identify a structural element of apolipoprotein (apo) A-I that stimulates cellular cholesterol efflux and stabilizes the ATP binding cassette transporter A1 (ABCA1). Peptides (22-mers) based on helices 1 (amino acids 44 -65) and 10 (amino acids 220 -241) of apoA-I had high lipid binding affinity but failed to mediate ABCA1-dependent cholesterol efflux, and they lacked the ability to stabilize ABCA1. The addition of helix 9 (amino acids 209 -219) to either helix 1 (creates a 1/9 chimera) or 10 (9/10 peptide) endowed cholesterol efflux capability and ABCA1 stabilization activity similar to full-length apoA-I. Adding helix 9 to helix 1 or 10 had only a small effect on lipid binding affinity compared with the 22-mer peptides, indicating that helix length and/or determinants on the polar surface of the amphipathic ␣-helices is important for cholesterol efflux. Cholesterol efflux was specific for the structure created by the 1/9 and 9/10 helical combinations, as 33-mers composed of helices 1 and 3 (1/3), 2/9, and 4/9 failed to mediate cholesterol efflux in an ABCA1-dependent manner. Transposing helices 9 and 10 (10/9 peptide) did not change the class Y structure, hydrophobicity, or amphiphilicity of the helical combination, but the topography of negatively charged amino acids on the polar surface was altered, and the 10/9 peptide neither mediated ABCA1-dependent cholesterol efflux nor stabilized ABCA1 protein. These results suggest that a specific structural element possessing a linear array of acidic residues spanning two apoA-I amphipathic ␣-helices is required to mediate cholesterol efflux and stabilize ABCA1.

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Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

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Identification of an Apolipoprotein A-I Structural Element That Mediates Cellular Cholesterol Efflux and Stabilizes ATP Binding Cassette Transporter A1

Natarajan

Forte

Chu

et al. 2004

Journal of Biological Chemistry

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“…Acetyl-18A-NH 2 (18A), an 18-aa analog of the type of amphipathic ␣-helix found in apos, mimics apoA-I in promoting cholesterol efflux by the ABCA1 pathway (40,41). 18A contains a single tyrosine residue in a KxxY motif (where K ϭ lysine, Y ϭ tyrosine, and x ϭ an amino acid unreactive with HOCl), which juxtaposes the amino acid side chains of K and Y residues in an ␣-helical peptide (27).…”

Section: Oxidation Of a Synthetic Peptide Containing Tyrosine Impairsmentioning

confidence: 99%

The myeloperoxidase product hypochlorous acid oxidizes HDL in the human artery wall and impairs ABCA1-dependent cholesterol transport

Bergt

Pennathur

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

400

375

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Although oxidatively damaged lipoproteins are implicated in vascular injury, there is little information regarding the role of highdensity lipoprotein (HDL) oxidation in atherogenesis. One potential pathway involves hypochlorous acid (HOCl) produced by myeloperoxidase (MPO), a heme protein secreted by phagocytes. We previously showed that 3-chlorotyrosine is a specific product of HOCl. Therefore, to explore the role of oxidized HDL in the pathogenesis of vascular disease, we used MS to quantify 3-chlorotyrosine in HDL isolated from plasma and atherosclerotic tissue. HDL from human aortic atherosclerotic intima had an 8-fold higher level of 3-chlorotyrosine than plasma HDL. Tandem MS analysis identified MPO as a component of lesion HDL, suggesting that the two interact in the artery wall. Moreover, immunohistochemical studies found that specific epitopes derived from HOCl colocalized with apolipoprotein A-I, the major protein of HDL. These observations strongly support the hypothesis that MPO promotes HDL oxidation in the human artery wall. Levels of 3-chlorotyrosine were elevated in HDL isolated from the blood of humans with established coronary artery disease, suggesting that circulating levels of oxidized HDL represent a unique marker for clinically significant atherosclerosis. HDL or lipid-free apolipoprotein A-I exposed to HOCl was less able to remove cholesterol from cultured cells by a pathway requiring the cell membrane transporter ATP-binding cassette transporter A1. The detection of 3-chlorotyrosine in HDL isolated from vascular lesions raises the possibility that MPO, by virtue of its ability to form HOCl, may promote atherogenesis by counteracting the established antiatherogenic effects of HDL and the ATP-binding cassette transporter A1 pathway.

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“…In the case of apoA-I, binding to the cell surface is involved, but whether the interaction is directly with ABCA1 or with adjacent membrane PL is a matter of debate (11,16). The presence of an amphipathic ␣-helix is required in the acceptor protein for efficient PL and FC efflux (17)(18)(19), and it is well established that the strongly lipid-binding C-terminal ␣-helix in apoA-I plays a key role in efflux to this protein (20 -24). This domain of apoA-I could mediate the initial interaction with the plasma membrane and/or be required for retention of released PL molecules and stabilization of the nascent HDL particles.…”

mentioning

confidence: 99%

Effects of Apolipoprotein A-I on ATP-binding Cassette Transporter A1-mediated Efflux of Macrophage Phospholipid and Cholesterol

Liu

Bortnick

Nickel

et al. 2003

Journal of Biological Chemistry

117

143

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The mechanism of formation of high density lipoprotein (HDL) particles by the action of ATP-binding cassette transporter A1 (ABCA1) is not defined completely. To address this issue, we monitored efflux to apoA-I of phosphatidylcholine (PC), sphingomyelin (SM), and unesterified (free) cholesterol (FC) from J774 macrophages, in which ABCA1 is up-regulated, and investigated the nature of the particles formed. The various apoA-I/lipid particles appearing in the extracellular medium were separated by gel filtration chromatography. The presence of apoA-I in the extracellular medium led to the simultaneous formation of more than one type of poorly lipidated apoA-I-containing particle: there were 9-and 12-nm diameter particles containing ϳ3:1 and 1:1 phospholipid/FC (mol/mol), respectively, which were present together with 6-nm monomeric apoA-I. Removal of the C-terminal ␣-helix (residues 223-243) of apoA-I reduced phospholipid and FC efflux and prevented formation of the 9-and 12-nm HDL particles; the apoA-I variant formed larger particles that eluted in the void volume. FC loading of the J774 cells also led to the formation of larger apoA-I-containing particles that were highly enriched in FC. Besides creating HDL particles, ABCA1 mediated release of larger (20 -450-nm diameter) FC-rich particles that were not involved in HDL formation and that are probably membrane vesicles. These particles contained 1:1 PC/SM in contrast to the HDL particles, which contained 2:1 PC/SM. This is consistent with lipid raft and non-raft plasma membrane domains being involved primarily in ABCA1-mediated vesicle release and nascent HDL formation, respectively.

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Synthetic amphipathic helical peptides promote lipid efflux from cells by an ABCA1-dependent and an ABCA1-independent pathway

Cited by 185 publications

References 37 publications

Identification of an Apolipoprotein A-I Structural Element That Mediates Cellular Cholesterol Efflux and Stabilizes ATP Binding Cassette Transporter A1

Identification of an Apolipoprotein A-I Structural Element That Mediates Cellular Cholesterol Efflux and Stabilizes ATP Binding Cassette Transporter A1

The myeloperoxidase product hypochlorous acid oxidizes HDL in the human artery wall and impairs ABCA1-dependent cholesterol transport

Effects of Apolipoprotein A-I on ATP-binding Cassette Transporter A1-mediated Efflux of Macrophage Phospholipid and Cholesterol

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