Tangier Disease

Clifton‐Bligh, P.; Nestel, P. J.; Whyte, H. M.

doi:10.1056/nejm197203162861103

Cited by 42 publications

(6 citation statements)

References 29 publications

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“…The second step of this reaction is now known to be mediated via the transfer protein (4). There is, however, considerable kinetic evidence from studies in vio that only a very small pool of lipoprotein cholesterol is directly involved in ester synthesis and transfer (19,20). Furthermore, in Tangier disease, a condition where HDL is congenitally essentially absent (21), the rate of formation and transfer of cholesteryl ester is almost normal.…”

Section: Discussionmentioning

confidence: 99%

A cholesteryl ester transfer complex in human plasma.

Fielding¹,

Fielding²

1980

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

173

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Immunoadsorption affinity chromatography has been used to define the structure of lipoproteins in human plasma containing lecithin:cholesterol acyltransferase (EC 2.3.1.43) (LCAT) and transfer protein (apo D). The whole of LCAT was adsorbed by antibodies specific for apo D and for apo A-1, indicating that the enzyme is present in plasma exclusively as a complex with its cofactor (apo A-1) and product transfer protein (apo D) About 80% of apo D (but no LCAT) was removed by antibody to apo A-2, indicating the presence of most of apo D in the form of an enzyme-free complex with apo A-1 and apo A-2. After removal of LCAT with antibody to apo D, plasma was unreactive as a substrate with isolated LCAT, but substrate activity was generated by ultracentrifugal flotation with either intact or adsorbed plasma. The apparent stoichiometry of the complex with LCAT (LCAT:apo A-1:apo D) was 1.0:0.9:1.8; that of the complex containing apo A-1, apo A-2, and apo D was 3.9:2.2:1.0. Lecithin:cholesterol acyltransferase (EC 2.3.1.43) (LCAT) in human plasma catalyzes the synthesis of almost the whole of plasma cholesteryl ester content. Its activity is mediated via an apoprotein cofactor (apo A-1) (1), which is a component of lipoproteins isolated within the high density (HDL) range (2). Most plasma cholesteryl esters are associated with low density lipoprotein (LDL), which contains little or no apo A-1 and is not a substrate for LCAT (3). These esters are delivered to LDL through the activity of a cholesteryl ester transfer protein (apo D) recently identified and isolated (4). The rates of cholesteryl ester synthesis and transfer in plasma are essentially equal (4), suggesting synergism between these reactions and possible structural association of the transferase and transfer proteins. However, after centrifugal flotation, LCAT was recovered in the p > 1.21 g/cm3 density fraction whereas the greater part of transfer activity was present in the 1.063 < p < 1.21 g/cm3 density range (4, 5). A complex containing LCAT and apo D, if present in whole plasma, would play a key role in the regulation of plasma cholesterol metabolism, yet centrifugation is effective in dissociating plasma lipoprotein complexes (6). In this research, immunoadsorption chromatography has been used to determine the properties and apoprotein stoichiometry of complexes containing LCAT and apo D. Although absence of binding of one protein to immobilized antibody of another may be only ambiguous evidence for lack of association (because the complex might have dissociated during chromatography), binding of one protein to antibody of another is strong evidence that a complex exists in that form in the medium. Such evidence is here obtained for the association of LCAT and apo D. MATERIALS AND METHODSPreparation and Assay of Lipoprotein Apoproteins. Apo D was isolated as described (4) from human plasma HDL. It was a single species by polyacrylamide gel electrophoresis and was immunologically and chemically identical to the active cholesteryl ester transfer prote...

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Section: Discussionmentioning

confidence: 99%

A cholesteryl ester transfer complex in human plasma.

Fielding¹,

Fielding²

1980

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

173

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“…Therefore, cholesterol removal from the peripheral tissues is carried out only by the LCAT-dependent nonspecific mechanism in these patients. Interestingly, cholesterol esterification in the plasma of these patients is not drastically reduced in spite of their extremely low plasma HDL level (Clifton-Bligh et al, 1972;Ohtaki et al, 1983), and the accumulation of cholesterol is limited only in certain organs related to the reticuloendothelial system (Schaefer et al, 1980). Therefore, the LCAT-mediated net cellular cholesterol removal seems active and efficient through nonspecific cholesterol exchange in the tissues of many organs.…”

Section: Fig 5 Entire Time Course Of Cholesterol Flux Between Erythmentioning

confidence: 99%

Regulation of Cellular Cholesterol Efflux by Lecithin:Cholesterol Acyltransferase Reaction through Nonspecific Lipid Exchange

Czarnecka

Yokoyama

1996

Journal of Biological Chemistry

109

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Erythrocyte was found lacking in reactivity to lipid-free apolipoproteins to generate pre-beta-high density lipoprotein (HDL) with the cellular lipid and, therefore, was used to study cellular cholesterol efflux to plasma lipoproteins exclusively by a nonspecific exchange mechanism. Over the range of hematocrit from 1-20% (cellular cholesterol pool of 2.5 micrograms per 250 microliters), the fractional rate of cellular cholesterol efflux to lipoprotein was constant, and, therefore, absolute efflux rate was a linear function of the hematocrit of this range. In the absence of lecithin:cholesterol acyltransferase (LCAT), the cholesterol influx rate from lipoproteins was equal to the efflux rate from erythrocyte resulting in no net transfer of cholesterol, with either HDL or low density lipoprotein. In the presence of LCAT in the mixture of HDL and erythrocyte, cholesterol was esterified exclusively in HDL regardless of the origin. When the hematocrit was low and efflux of cellular cholesterol was slower than cholesterol esterification, the esterification of cell-originating cholesterol did not directly enhance the efflux. With high hematocrit that gives faster cholesterol efflux, the efflux was increased directly by the cholesterol esterification. On the other hand, the LCAT reaction significantly reduced HDL-cholesterol influx. The LCAT reaction thus induces substantial net cholesterol efflux from erythrocytes through a nonspecific cholesterol exchange mechanism.

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“…Support for the second mechanism linking ABCA1 and plasma TG rests on the observations that TD subjects exhibit decreased LPL activity (Alaupovic et al, 1991, Clifton-Bligh et al, 1972, Greten et al, 1974, Wang et al, 1987) and delayed clearance of postprandial lipid (Kolovou et al, 2003). Post-heparin LPL activity is also reduced in HSKO compared to WT mice, resulting in delayed clearance of postprandial TG (Chung et al, 2010b).…”

Section: Discussionmentioning

confidence: 99%

“…Tangier disease (TD), a rare autosomal recessive disorder, is characterized by the near absence of plasma high-density lipoprotein (HDL), elevated triglyceride (TG) levels and sterol deposition in tissue macrophages (Clifton-Bligh et al, 1972). TD is caused by mutations in the ABCA1 gene (Oram and Heinecke, 2005), which encodes the integral membrane protein ATP-binding cassette transporter A1 (ABCA1).…”

Section: Introductionmentioning

confidence: 99%

ATP-Binding Cassette Transporter A1 Deficiency in Human Induced Pluripotent Stem Cell-Derived Hepatocytes Abrogates HDL Biogenesis and Enhances Triglyceride Secretion

Pashos

Cuchel

et al. 2017

EBioMedicine

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Despite the recognized role of the ATP-binding Cassette Transporter A1 (ABCA1) in high-density lipoprotein (HDL) metabolism, our understanding of ABCA1 deficiency in human hepatocytes is limited. To define the functional effects of human hepatocyte ABCA1 deficiency, we generated induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (HLCs) from Tangier disease (TD) and matched control subjects. Control HLCs exhibited robust cholesterol efflux to apolipoprotein A-I (apoA-I) and formed nascent HDL particles. ABCA1-deficient HLCs failed to mediate lipid efflux or nascent HDL formation, but had elevated triglyceride (TG) secretion. Global transcriptome analysis revealed significantly increased ANGPTL3 expression in ABCA1-deficient HLCs. Angiopoietin-related protein 3 (ANGPTL3) was enriched in plasma of TD relative to control subjects. These results highlight the required role of ABCA1 in cholesterol efflux and nascent HDL formation by hepatocytes. Furthermore, our results suggest that hepatic ABCA1 deficiency results in increased hepatic TG and ANGPTL3 secretion, potentially underlying the elevated plasma TG levels in TD patients.

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Tangier Disease

Cited by 42 publications

References 29 publications

A cholesteryl ester transfer complex in human plasma.

A cholesteryl ester transfer complex in human plasma.

Regulation of Cellular Cholesterol Efflux by Lecithin:Cholesterol Acyltransferase Reaction through Nonspecific Lipid Exchange

ATP-Binding Cassette Transporter A1 Deficiency in Human Induced Pluripotent Stem Cell-Derived Hepatocytes Abrogates HDL Biogenesis and Enhances Triglyceride Secretion

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