Mutations in the ABC 1 gene in familial HDL deficiency with defective cholesterol efflux

Marcil, Michel; Brooks‐Wilson, Angela; Clee, Susanne M.; Roomp, Kirsten; Zhang, L.-H.; Yu, Lu; Collins, Jennifer A.; Dam, Marjel van; Molhuizen, H.O.F.; Loubster, O.; Ouellette, B. F. Francis; Sensen, Christoph Wilhelm; Fichter, Keith; Mott, Stephanie; Denis, Maxime; Boucher, Betsie; Pimstone, Simon N.; Genest, Jacques; Kastelein, J.J.P.; Hayden, Michael R.

doi:10.1016/s0140-6736(99)07026-9

Cited by 343 publications

(178 citation statements)

References 31 publications

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“…In macrophages, the LXRs regulate the expression of the adenosine triphosphate-binding cassette (ABC) proteins A1 and G1 (18 -22), which serve as free-cholesterol and phospholipid translocators enabling cholesterol efflux from the macrophage onto various acceptors, including nascent, cholesterol-poor HDL (18,21,(23)(24)(25)(26). Defective ABCA1 expression in humans is the basis for Tangier disease and is associated with cholesterol accumulation in peripheral tissues along with a near-total lack of cellular cholesterol efflux and plasma HDL (27)(28)(29)(30)(31). LXR-dependent regulation of cholesterol efflux may prove to be an important antiatherogenic process amenable to pharmacological intervention with LXR agonists.…”

Section: From Glaxosmithkline Research and Development Research Triamentioning

confidence: 99%

Liver X Receptor (LXR) Regulation of the LXRα Gene in Human Macrophages

Whitney

Watson

Goodwin

et al. 2001

Journal of Biological Chemistry

146

100

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The nuclear oxysterol receptors LXR␣ (NR1H3) and LXR␤ (NR1H2) coordinately regulate the expression of genes involved in the transport and catabolism of cholesterol. In macrophages, LXR stimulates the transcription of genes encoding transporters involved in cholesterol efflux, which may limit the transformation of these cells into foam cells in response to lipid loading. Here, we report that natural and synthetic LXR ligands induce the expression of the LXR␣ gene in primary human macrophages and differentiated THP-1 macrophages. This regulation was not observed in primary human adipocytes or hepatocytes, a human intestinal cell line, or in any mouse tissue or cell line examined. The human LXR␣ gene was isolated, and the transcription initiation site delineated. Analysis of the LXR␣ promoter revealed a functional LXR/RXR binding site ϳ2.9 kb upstream of the transcription initiation site. We conclude that LXR␣ regulates its own expression in human macrophages and that this response is likely to amplify the effects of oxysterols on reverse cholesterol transport. These findings underscore the importance of LXR as a potential therapeutic target for the treatment of atherosclerosis.

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Section: From Glaxosmithkline Research and Development Research Triamentioning

confidence: 99%

Liver X Receptor (LXR) Regulation of the LXRα Gene in Human Macrophages

Whitney

Watson

Goodwin

et al. 2001

Journal of Biological Chemistry

146

100

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“…Individuals heterozygous for ABCA1 transporter mutations have diminished UC efflux to apo A-I from their fibroblasts in cell culture, low plasma HDL-cholesterol, and premature CHD (18,24 ). These findings have established that inefficient RCT by HDLs is a causal factor in atherogenesis in such individuals.…”

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confidence: 97%

“…Efflux of UC from cells to pre-␤ 0 -HDLs in tissue fluids exceeds its esterification, leading to accumulation of UC-rich discoidal HDLs in lymph (16,17 ). For this pathway of RCT, which presumably applies to arterial smooth muscle and macrophages, ABCA1 transporter function (4,18,19 ) and pre-␤-HDL concentration (20,21 ) appear to play critical roles in regulating UC efflux.…”

mentioning

confidence: 99%

Association of Coronary Heart Disease with Pre-β-HDL Concentrations in Japanese Men

Hashimoto¹,

Kujiraoka²,

Egashira³

et al. 2004

Clinical Chemistry

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Background:In individuals heterozygous for ABCA1 transporter mutations, defective reverse cholesterol transport (RCT) causes low HDL-cholesterol and premature coronary heart disease (CHD). However, the extent to which impaired RCT underlies premature CHD in others with low HDL-cholesterol is not known. The primary acceptors of cell cholesterol are a minor subclass of lipid-poor pre-␤-HDLs. These are generated during remodeling of ␣-HDLs, which account for almost all HDL-cholesterol. We studied the strength of the association of CHD with pre-␤-HDL concentrations in Japanese men. Methods: Blood was collected from 42 men with clinical CHD and 44 healthy controls 40 -70 years of age. Pre-␤-HDL was assayed by crossed immunoelectrophoresis. Results: Cases had lower HDL-cholesterol (؊23%), total apolipoprotein A-I (؊26%), and pre-␤-HDL (؊55%; all P <0.001) concentrations; lower pre-␤-HDL:␣-HDL ratios (؊45%; P <0.001); and higher plasma triglycerides (20%; P <0.03) than the controls. On stepwise logistic regression, CHD was associated most strongly with pre-␤-HDL concentrations. On ROC analysis, pre-␤-

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“…ABCA1 has been shown to regulate the apolipoprotein-(apo) mediated lipid removal pathway from cells, 6 and both TD patients and mice with a disrupted Abca1 gene have defective transport of lipids from the Golgi to the plasma membrane. 7 Furthermore, mutations in ABCA1 have been found in some patients with familial hypoalphalipoproteinemia (FHA), 8 a relatively more common disorder than TD. Cellular cholesterol efflux appears to be abnormal in some patients with FHA due to mutant ABCA1, but there is no obvious tissue deposition of cholesterol esters, and the low plasma HDL cholesterol concentrations demonstrate an apparent autosomal codominant pattern of expression in ABCA1 mutation carriers.…”

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confidence: 99%

Common and Rare ABCA1 Variants Affecting Plasma HDL Cholesterol

Wang

Burnett

Near

et al. 2000

ATVB

115

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Abstract-Mutations in ABCA1, a member of the ATP-binding cassette family, have been shown to underlie Tangier disease (TD) and familial hypoalphalipoproteinemia (FHA), which are genetic disorders that are characterized by depressed concentrations of plasma high density lipoprotein (HDL) cholesterol. An important question is whether common variants within the coding sequence of ABCA1 can affect plasma HDL cholesterol in the general population.To address this issue, we developed a screening strategy to find common ABCA1 variants. This strategy involved long-range amplification of genomic DNA by using coding sequences only, followed by deep sequencing into the introns. This method helped us to characterize a new set of amplification primers, which permitted amplification of virtually all of the coding sequence of ABCA1 and its intron-exon boundaries with a single DNA amplification program. With these new sequencing primers, we found 3 novel ABCA1 mutations: a frameshift mutation (4570insA, A1484S3 X1492), a missense mutation (A986D) in a TD family, and a missense mutation (R170C) in aboriginal subjects with FHA. We also used these sequencing primers to characterize 4 novel common amino acid variants in ABCA1, in addition to 5 novel common silent variants. We tested for association of the ABCA1 I/M823 variant with plasma HDL cholesterol in Canadian Inuit and found that M823/M823 homozygotes had significantly higher plasma HDL cholesterol compared with subjects with the other genotypes. The results provide proof of principle of the effectiveness of this approach to identify both rare and common ABCA1 genomic variants and also suggest that common amino acid variation in ABCA1 is a determinant of plasma HDL cholesterol in the general population. (Arterioscler

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Mutations in the ABC 1 gene in familial HDL deficiency with defective cholesterol efflux

Cited by 343 publications

References 31 publications

Liver X Receptor (LXR) Regulation of the LXRα Gene in Human Macrophages

Liver X Receptor (LXR) Regulation of the LXRα Gene in Human Macrophages

Association of Coronary Heart Disease with Pre-β-HDL Concentrations in Japanese Men

Common and Rare ABCA1 Variants Affecting Plasma HDL Cholesterol

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