Metabolism of High-Density Lipoprotein Apolipoproteins in Tangier Disease

Ej, Schaefer; Cb, Blum; Ri, Levy; Ll, Jenkins; Alaupovic, Petar; Dm, Foster; Hb, Brewer

doi:10.1056/nejm197810262991701

Cited by 184 publications

(87 citation statements)

References 24 publications

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“…136 In addition, it was reported 129 ' 130 that a large fraction of apo A-l in Tangier plasma was found in the 1.21 g/ml infranate. Other studies confirmed this finding, but also reported 131 that 28% of apo A-l and 9 1 % of apo A-ll in the plasma of homozygotes was found in the 1.063 g/ml supemate. Radioiodinated HDL, apo A-l, and apo A-II kinetic studies performed in homozygotes studied under steady state conditions 131 ' 134 revealed apo A-l and apo A-ll residence times of 5% and 18% of normal.…”

Section: Tangier Diseasementioning

confidence: 52%

Clinical, biochemical, and genetic features in familial disorders of high density lipoprotein deficiency.

Schaefer¹

1984

Arteriosclerosis

161

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P lasma high density lipoproteins (HDL, density = 1.063 -1.21 g/ml) mostly have alpha mobility on lipoprotein electrophoresis, and are composed (weight %) of approximately 50% protein, 25% phospholipid, 20% cholesterol (mainly esterified), and triglyceride. 1 " 1 Fluctuations in HDL levels have been associated largely with alterations in HDL (d = 1.063-1.125 g/ml). 5 Cholesterol is the HDL constituent commonly measured (following precipitation of other lipoproteins), and decreased plasma HDL cholesterol concentrations have been associated with premature coronary artery disease (CAD).*" 11 The normal values for this parameter are given in Table 1.

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Section: Tangier Diseasementioning

confidence: 52%

Clinical, biochemical, and genetic features in familial disorders of high density lipoprotein deficiency.

Schaefer¹

1984

Arteriosclerosis

161

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“…The decreased apoE levels in plasma and brain that we observed are similar to those seen by others. 2 The decreased apoE levels in the CNS are not related to Apoe gene expression but likely result from increased catabolism of abnormally lipidated apoE-containing HDL lipoproteins produced in the CNS, as occurs with abnormally lipidated apoA-I and apoA-II that are secreted by the liver and are rapidly catabolized in the plasma of Tangier's disease patients (10,11).…”

Section: Discussionmentioning

confidence: 99%

“…In humans, loss-of-function mutations in ABCA1 cause Tangier's disease (6 -9), which is characterized by accumulation of cholesterol in lymphatic tissues and increased catabolism of abnormally lipidated HDL, resulting in very low levels of plasma HDL and HDL-associated apolipoproteins A-I (apoA-I) and A-II (apoA-II) (10,11). ABCA1 knock-out mice (Abca1 Ϫ/Ϫ ) have been produced, and the mice have a similar phenotype as patients with Tangier's disease (12).…”

mentioning

confidence: 99%

ABCA1 Is Required for Normal Central Nervous System ApoE Levels and for Lipidation of Astrocyte-secreted apoE

Wahrle¹,

Jiang²,

Parsadanian³

et al. 2004

Journal of Biological Chemistry

401

357

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ABCA1 is an ATP-binding cassette protein that transports cellular cholesterol and phospholipids onto high density lipoproteins (HDL) in plasma. Lack of ABCA1 in humans and mice causes abnormal lipidation and increased catabolism of HDL, resulting in very low plasma apoA-I, apoA-II, and HDL. Herein, we have used Abca1 ؊/؊ mice to ask whether ABCA1 is involved in lipidation of HDL in the central nervous system (CNS). ApoE is the most abundant CNS apolipoprotein and is present in HDL-like lipoproteins in CSF. We found that Abca1 ؊/؊ mice have greatly decreased apoE levels in both the cortex (80% reduction) and the CSF (98% reduction). CSF from Abca1 ؊/؊ mice had significantly reduced cholesterol as well as small apoE-containing lipoproteins, suggesting abnormal lipidation of apoE. Astrocytes, the primary producer of CNS apoE, were cultured from Abca1 ؉/؉ , ؉/؊ , and ؊/؊ mice, and nascent lipoprotein particles were collected. Abca1 ؊/؊ astrocytes secreted lipoprotein particles that had markedly decreased cholesterol and apoE and had smaller apoE-containing particles than particles from Abca1 ؉/؉ astrocytes. These findings demonstrate that ABCA1 plays a critical role in CNS apoE metabolism. Since apoE isoforms and levels strongly influence Alzheimer's disease pathology and risk, these data suggest that ABCA1 may be a novel therapeutic target.

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“…Increased catabolism of LpAI and LpAI:AII leading to low HDL cholesterol concentrations is characteristic of Tangier disease and LCAT deficiency. Genetic deficiency of the ABCA1 transporter (Tangier disease) is associated with decreased cholesterol efflux and poor lipidation of pre-␤ HDL, resulting in accelerated LpAI catabolism and increased CVD (124 ). In contrast, in LCAT deficiency there is effective cholesterol efflux from cholesterolloaded macrophages followed by defective maturation of pre-␤ HDL to ␣ HDL; accelerated catabolism, primarily of LpAI:AII as well as LpAI; and renal disease, but no increased risk of CVD (125,126 ).…”

Section: Apo Ai and Apo Ai:aii Particlesmentioning

confidence: 99%

HDL Measures, Particle Heterogeneity, Proposed Nomenclature, and Relation to Atherosclerotic Cardiovascular Events

et al. 2011

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BACKGROUND A growing body of evidence from epidemiological data, animal studies, and clinical trials supports HDL as the next target to reduce residual cardiovascular risk in statin-treated, high-risk patients. For more than 3 decades, HDL cholesterol has been employed as the principal clinical measure of HDL and cardiovascular risk associated with low HDL-cholesterol concentrations. The physicochemical and functional heterogeneity of HDL present important challenges to investigators in the cardiovascular field who are seeking to identify more effective laboratory and clinical methods to develop a measurement method to quantify HDL that has predictive value in assessing cardiovascular risk. CONTENT In this report, we critically evaluate the diverse physical and chemical methods that have been employed to characterize plasma HDL. To facilitate future characterization of HDL subfractions, we propose the development of a new nomenclature based on physical properties for the subfractions of HDL that includes very large HDL particles (VL-HDL), large HDL particles (L-HDL), medium HDL particles (M-HDL), small HDL particles (S-HDL), and very-small HDL particles (VS-HDL). This nomenclature also includes an entry for the pre-β-1 HDL subclass that participates in macrophage cholesterol efflux. SUMMARY We anticipate that adoption of a uniform nomenclature system for HDL subfractions that integrates terminology from several methods will enhance our ability not only to compare findings with different approaches for HDL fractionation, but also to assess the clinical effects of different agents that modulate HDL particle structure, metabolism, and function, and in turn, cardiovascular risk prediction within these HDL subfractions.

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Metabolism of High-Density Lipoprotein Apolipoproteins in Tangier Disease

Cited by 184 publications

References 24 publications

Clinical, biochemical, and genetic features in familial disorders of high density lipoprotein deficiency.

Clinical, biochemical, and genetic features in familial disorders of high density lipoprotein deficiency.

ABCA1 Is Required for Normal Central Nervous System ApoE Levels and for Lipidation of Astrocyte-secreted apoE

HDL Measures, Particle Heterogeneity, Proposed Nomenclature, and Relation to Atherosclerotic Cardiovascular Events

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