Regulation and mechanisms of macrophage cholesterol efflux

Tall, Alan R.; Costet, Philippe; Wang, Nan

doi:10.1172/jci0216391

Cited by 189 publications

(77 citation statements)

References 50 publications

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“…ABCA1 is highly expressed in the liver and tissue macrophages (32, 33). When mutated, it can cause Tangier disease, which involves abnormally low levels of HDL and premature atherosclerosis (6, 17, 18, 34–37). Moreover, myeloid-specific deletion of ABCA1 markedly increased atherosclerosis in mice without affecting plasma lipoprotein levels (6).…”

Section: One Key Cardioprotective Property Of Hdl Involves Reversementioning

confidence: 99%

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Site-specific oxidation of apolipoprotein A-I impairs cholesterol export by ABCA1, a key cardioprotective function of HDL

Shao

2012

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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The mechanisms that deprive HDL of its cardioprotective properties are poorly understood. One potential pathway involves oxidative damage of HDL proteins by myeloperoxidase (MPO) a heme enzyme secreted by human artery wall macrophages. Mass spectrometric analysis demonstrated that levels of 3-chlorotyrosine and 3-nitrotyrosine—two characteristic products of MPO—are elevated in HDL isolated from patients with established cardiovascular disease. When apolipoprotein A-I (apoA-I), the major HDL protein, is oxidized by MPO, its ability to promote cellular cholesterol efflux by the membrane-associated ATP-binding cassette transporter A1 (ABCA1) pathway is diminished. Biochemical studies revealed that oxidation of specific tyrosine and methionine residues in apoA-I contributes to this loss of ABCA1 activity. Another potential mechanism for generating dysfunctional HDL involves covalent modification of apoA-I by reactive carbonyls, which have been implicated in atherogenesis and diabetic vascular disease. Indeed, modification of apoA-I by malondialdehyde (MDA) or acrolein also markedly impaired the lipoprotein’s ability to promote cellular cholesterol efflux by the ABCA1 pathway. Tandem mass spectrometric analyses revealed that these reactive carbonyls target specific Lys residues in the C-terminus of apoA-I. Importantly, immunochemical analyses showed that levels of MDA-protein adducts are elevated in HDL isolated from human atherosclerotic lesions. Also, apoA-I co-localized with acrolein adducts in such lesions. Thus, lipid peroxidation products might specifically modify HDL in vivo. Our observations support the hypotheses that MPO and reactive carbonyls might generate dysfunctional HDL in humans.

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Section: One Key Cardioprotective Property Of Hdl Involves Reversementioning

confidence: 99%

“…In the artery wall, membrane-associated ABCA1 interacts with lipid-free or poorly-lipidated apoA-I to remove excess cholesterol from resident macrophages (17, 18, 77, 78). ApoA-I contains amphipathic α-helices, a structural motif that promotes lipid association (22, 24, 79, 80).…”

Section: Myeloperoxidase (Mpo) a Heme Enzyme That Produces Reactimentioning

confidence: 99%

Site-specific oxidation of apolipoprotein A-I impairs cholesterol export by ABCA1, a key cardioprotective function of HDL

Shao

2012

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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“…In addition, the nuclear receptor LXR α (liver X receptor α ), which enhances expression of ABCA1 (ATP-binding cassette transporter A1), a protein which mediates cellular cholesterol efflux [102], has also been shown to be a PPAR γ target gene in human and mouse macrophages [103, 104]. Taken together, these data suggest a broader spectrum of PPAR γ effects within the macrophage with the overall balance favouring cholesterol efflux and an antiatherogenic effect.…”

Section: Pparγ-a Key Therapeutic Target In the Human Metabolic Synmentioning

confidence: 99%

‘Striking the Right Balance’ in Targeting PPARγ in the Metabolic Syndrome: Novel Insights from Human Genetic Studies

Gurnell

2007

PPAR Research

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At a time when the twin epidemics of obesity and type 2 diabetes threaten to engulf even the most well-resourced Western healthcare systems, the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) has emerged as a bona fide therapeutic target for treating human metabolic disease. The novel insulin-sensitizing antidiabetic thiazolidinediones (TZDs, e.g., rosiglitazone, pioglitazone), which are licensed for use in the treatment of type 2 diabetes, are high-affinity PPARγ ligands, whose beneficial effects extend beyond improvement in glycaemic control to include amelioration of dyslipidaemia, lowering of blood pressure, and favourable modulation of macrophage lipid handling and inflammatory responses. However, a major drawback to the clinical use of exisiting TZDs is weight gain, reflecting both enhanced adipogenesis and fluid retention, neither of which is desirable in a population that is already overweight and prone to cardiovascular disease. Accordingly, the “search is on” to identify the next generation of PPARγ modulators that will promote maximal clinical benefit by targeting specific facets of the metabolic syndrome (glucose intolerance/diabetes, dyslipidaemia, and hypertension), while simultaneously avoiding undesirable side effects of PPARγ activation (e.g., weight gain). This paper outlines the important clinical and laboratory observations made in human subjects harboring genetic variations in PPARγ that support such a therapeutic strategy.

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“…ABCA1 is a 12-transmembrane protein with ATP binding sites (Walker motifs) located in a large cytoplasmic central region (amino acids 899 – 1120 marked here as D1) and C-terminal cytoplasmic domain (amino acids 1908 – 2261, marked here as D2) [8]. Our studies demonstrated that Nef binds to ABCA1 [1], and identified an DDDHLK motif in the C-terminal cytoplasmic domain of ABCA1 as essential for the Nef interaction with ABCA1 [9].…”

Section: Introductionmentioning

confidence: 99%

The ABCA1 domain responsible for interaction with HIV-1 Nef is conformational and not linear

Jacob¹,

Hunegnaw²,

Sabyrzyanova³

et al. 2014

Biochemical and Biophysical Research Communications

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HIV-1 Nef is an accessory protein responsible for inactivation of a number of host cell proteins essential for anti-viral immune responses. In most cases, Nef binds to the target protein and directs it to a degradation pathway. Our previous studies demonstrated that Nef impairs activity of the cellular cholesterol transporter, ABCA1, and that Nef interacts with ABCA1. Mutation of the 2226DDDHLK motif in the C-terminal cytoplasmic tail of ABCA1 disrupted interaction with Nef. Here, we tested Nef interaction with the ABCA1 C-terminal cytoplasmic fragment using yeast 2-hybrid system assay and co-immunoprecipitation analysis in human cells. Surprisingly, analysis in a yeast 2-hybrid system did not reveal any interaction between Nef and the C-terminal cytoplasmic fragment of ABCA1. Using coimmunoprecipitation from HEK 293T cells expressing these polypeptides, only a very weak interaction could be detected. The 2226DDDHLK motif in the C-terminal cytoplasmic tail of ABCA1 found previously to be essential for interaction between ABCA1 and Nef is insufficient to bestow strong binding to Nef. Molecular modeling suggested that interaction with Nef may be mediated by a conformational epitope composed of the sequences within the cytoplasmic loop of ABCA1 and the C-terminal cytoplasmic domain. Studies are now underway to characterize this epitope.

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Regulation and mechanisms of macrophage cholesterol efflux

Cited by 189 publications

References 50 publications

Site-specific oxidation of apolipoprotein A-I impairs cholesterol export by ABCA1, a key cardioprotective function of HDL

Site-specific oxidation of apolipoprotein A-I impairs cholesterol export by ABCA1, a key cardioprotective function of HDL

‘Striking the Right Balance’ in Targeting PPARγ in the Metabolic Syndrome: Novel Insights from Human Genetic Studies

The ABCA1 domain responsible for interaction with HIV-1 Nef is conformational and not linear

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