Update on HDL Receptors and Cellular Cholesterol Transport

Kellner-Weibel, Ginny; Llera-Moya, Margarita de la

doi:10.1007/s11883-011-0169-0

Cited by 14 publications

(10 citation statements)

References 64 publications

(71 reference statements)

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“…RCT plays a critical role in atheroprotection, and has been the topic of recent comprehensive reviews [2, 3]. It is thought that, following hydrolysis from its esterified form, free cholesterol (FC) in macrophages and other cells is initially effluxed to lipid-poor/free apolipoprotein A-I (apo-AI), via the ATP Binding Cassette transporter A1 (ABCA1).…”

Section: Reverse Cholesterol Transport: Old and New Viewsmentioning

confidence: 99%

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Crosstalk between reverse cholesterol transport and innate immunity

Azzam

Fessler

2012

Trends in Endocrinology & Metabolism

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Although lipid metabolism and host defense are widely considered to be very divergent disciplines, compelling evidence suggests that host cell handling of self- and microbe-derived (e.g., lipopolysaccharide) lipids may have common evolutionary roots, and that they indeed may be inseparable processes. The innate immune response and the homeostatic network controlling cellular sterol levels are now known to reciprocally regulate one another, with important implications for several common diseases, including atherosclerosis. In the present review, we discuss recent discoveries that provide new insight into the bidirectional crosstalk between reverse cholesterol transport and innate immunity, and highlight the broader implications of these findings for therapeutic development.

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Section: Reverse Cholesterol Transport: Old and New Viewsmentioning

confidence: 99%

“…ApoA-I is the main protein of high density lipoprotein (HDL) particles. Nascent HDL formed by apoA-I lipidation then serves as an acceptor for additional cellular FC from the ABCG1 transporter [2]. ApoE, present in serum and macrophages, also facilitates cholesterol export.…”

Section: Reverse Cholesterol Transport: Old and New Viewsmentioning

confidence: 99%

Crosstalk between reverse cholesterol transport and innate immunity

Azzam

Fessler

2012

Trends in Endocrinology & Metabolism

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“…5 FC efflux occurs via ABC (ATP binding cassette) transporters, such as ABCA1, ABCG1, and ABCG4, via the scavenger receptor class B type I and via unmediated aqueous diffusion. 6,7 ABCA1 mediates FC efflux from macrophages to small, discoidal, lipid-free/ poor pre–β-HDL, and esterification of HDL-FC by lecithin-cholesterol acyltransferase leads to mature, spherical phospholipid-rich particles that promote further efflux of FC via scavenger receptor class B type I, ABCG1, and aqueous diffusion. In turn, enzymatic hydrolysis of HDL-phospholipids from mature HDL can regenerate smaller particles with release of apolipoprotein A-I.…”

mentioning

confidence: 99%

Importance of Evaluating Cell Cholesterol Influx With Efflux in Determining the Impact of Human Serum on Cholesterol Metabolism and Atherosclerosis

Weibel

Drazul-Schrader

Shivers

et al. 2014

ATVB

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Objective Cholesterol efflux relates to cardiovascular disease but cannot predict cellular cholesterol mass changes. We asked whether influx and net flux assays provide additional insights. Approach and Results Adapt a bidirectional flux assay to cells where efflux has clinical correlates and examine the association of influx, efflux, and net flux to serum triglycerides (TGs). Apolipoprotein B–depleted (high-density lipoprotein-fraction) serum from individuals with unfavorable lipids (median [interquartile range]; high-density lipoprotein-cholesterol=39 [32–42], low-density lipoprotein-cholesterol=109 [97–137], TGs=258 [184–335] mg/dL; n=13) promoted greater ATP-binding cassette transporter A1–mediated [1,2-3H] cholesterol efflux (3.8±0.3%/4 hour versus 1.2±0.4%/4 hour; P<0.0001) from cyclic 3’,5’-amp(CTP-amp)-treated J774 macrophages than from individuals with favorable lipids (high-density lipoprotein-cholesterol=72 [58–88], low-density lipoprotein-cholesterol=111 [97–131], TGs=65 [56–69] mg/dL; n=10). Thus, high TGs associated with more ATP-binding cassette transporter A1 acceptors. Efflux of cholesterol mass (µg free cholesterol/mg cell protein per 8 hour) to serum was also higher (7.06±0.33 versus 5.83±0.48; P=0.04). However, whole sera from individuals with unfavorable lipids promoted more influx (5.14±0.65 versus 2.48±0.85; P=0.02) and lower net release of cholesterol mass (1.93±0.46 versus 3.36±0.47; P=0.04). The pattern differed when mass flux was measured using apolipoprotein B–depleted serum rather than serum. Although individuals with favorable lipids tended to have greater influx than those with unfavorable lipids, efflux to apolipoprotein B–depleted serum was markedly higher (6.81±0.04 versus 2.62±0.14; P<0.0001), resulting in an efflux:influx ratio of ≈3-fold. Thus both serum and apolipoprotein B–depleted serum from individuals with favorable lipids promoted greater net cholesterol mass release despite increased ATP-binding cassette transporter A1–mediated efflux in samples of individuals with high TGs/unfavorable lipids. Conclusions When considering the efficiency of serum specimens to modulate cell cholesterol content, both influx and efflux need to be measured.

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“…The ability of HDL to remove excess cholesterol from peripheral cells and deliver it to the liver for excretion by the reverse cholesterol transport pathway is believed to be one of the main anti-atherogenic functions of HDL (Kellner-Weibel and de la Llera-Moya, 2011). This process begins when apoA-I, by acting like a protein detergent, removes phospholipid and cholesterol from a lipid microdomain in the plasma membrane created by the ABCA1 transporter (Nofer and Remaley, 2005).…”

Section: The Therapeutic Potential Of Apolipoprotein A-i Mimetic Peptmentioning

confidence: 99%

“…The ABCA1 transporter is believed to be a phospholipid flippase and is the defective gene in Tangier disease, which is a disorder associated with very low HDL-C levels due to the hypercatabolism of apoA-I. Normally when apoA-I acquires phospholipid by the ABCA1 transporter, it becomes too large to be catabolized by the kidney and also becomes competent for effluxing cholesterol from cells by additional mechanisms, such as by the ABCG1 transporter and by SR-BI, as well as by a passive aqueous diffusion process (Kellner-Weibel and de la Llera-Moya, 2011). …”

Section: The Therapeutic Potential Of Apolipoprotein A-i Mimetic Peptmentioning

confidence: 99%

Apolipoprotein Mimetic Peptides: A New Approach for the Treatment of Asthma

Yao¹,

Vitek²,

Remaley³

et al. 2012

Front. Pharmacol.

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New treatments are needed for severe asthmatics to improve disease control and avoid severe toxicities associated with oral corticosteroids. We have used a murine model of house dust mite (HDM)-induced asthma to identify steroid-unresponsive genes that might represent targets for new therapeutic approaches for severe asthma. This strategy identified apolipoprotein E as a steroid-unresponsive gene with increased mRNA expression in the lungs of HDM-challenged mice. Furthermore, apolipoprotein E functioned as an endogenous negative regulator of airway hyperreactivity and goblet cell hyperplasia in experimental HDM-induced asthma. The ability of apolipoprotein E, which is expressed by lung macrophages, to attenuate AHR, and goblet cell hyperplasia is mediated by low density lipoprotein (LDL) receptors expressed by airway epithelial cells. Consistent with this, administration of an apolipoprotein E mimetic peptide, corresponding to amino acids 130–149 of the LDL receptor-binding domain of the holo-apoE protein, significantly reduced AHR and goblet cell hyperplasia in HDM-challenged apoE−/− mice. These findings identified the apolipoprotein E – LDL receptor pathway as a new druggable target for asthma that can be activated by administration of apoE-mimetic peptides. Similarly, apolipoprotein A-I may have therapeutic potential in asthma based upon its anti-inflammatory, anti-oxidative, and anti-fibrotic properties. Furthermore, administration of apolipoprotein A-I mimetic peptides has attenuated airway inflammation, airway remodeling, and airway hyperreactivity in murine models of experimental asthma. Thus, site-directed delivery of inhaled apolipoprotein E or apolipoprotein A-I mimetic peptides may represent novel treatment approaches that can be developed for asthma, including severe disease.

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Update on HDL Receptors and Cellular Cholesterol Transport

Cited by 14 publications

References 64 publications

Crosstalk between reverse cholesterol transport and innate immunity

Crosstalk between reverse cholesterol transport and innate immunity

Importance of Evaluating Cell Cholesterol Influx With Efflux in Determining the Impact of Human Serum on Cholesterol Metabolism and Atherosclerosis

Apolipoprotein Mimetic Peptides: A New Approach for the Treatment of Asthma

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