Homozygous Tangier disease and cardiovascular disease

Serfaty-Lacrosnière, Catherine; Civeira, Fernando; Lanzberg, A.; Isaia, P.; Berg, J.H.J. van den; Janus, Edward; Smith, Margaret; Pritchard, P H; Fröhlich, Jiří; Lees, Robert S.; Barnard, Graham F.; Ordovas, José M.; Schaefer, Ernst J.

doi:10.1016/0021-9150(94)90144-9

Cited by 227 publications

(122 citation statements)

References 63 publications

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“…1E). Collectively, these data demonstrate that hepatocyte-specific inactivation of ABCA1 induces postprandial hypertriglyceridemia, characterized by an increase in plasma VLDL and a decrease in plasma LDL, recapitulating the TD lipid phenotype (10,24).…”

Section: Targeted Deletion Of Hepatocyte Abca1 Results In Postpran-mentioning

confidence: 67%

Targeted Deletion of Hepatocyte ABCA1 Leads to Very Low Density Lipoprotein Triglyceride Overproduction and Low Density Lipoprotein Hypercatabolism

Chung

Timmins

Duong

et al. 2010

Journal of Biological Chemistry

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Loss of ABCA1 activity in Tangier disease (TD) is associated with abnormal apoB lipoprotein (Lp) metabolism in addition to the complete absence of high density lipoprotein (HDL). We used hepatocyte-specific ABCA1 knock-out (HSKO) mice to test the hypothesis that hepatic ABCA1 plays dual roles in regulating Lp metabolism and nascent HDL formation. HSKO mice recapitulated the TD lipid phenotype with postprandial hypertriglyceridemia, markedly decreased LDL, and near absence of HDL. Triglyceride (TG) secretion was 2-fold higher in HSKO compared with wild type mice, primarily due to secretion of larger TG-enriched VLDL secondary to reduced hepatic phosphatidylinositol 3-kinase signaling. HSKO mice also displayed delayed clearance of postprandial TG and reduced post-heparin plasma lipolytic activity. In addition, hepatic LDLr expression and plasma LDL catabolism were increased 2-fold in HSKO compared with wild type mice. Last, adenoviral repletion of hepatic ABCA1 in HSKO mice normalized plasma VLDL TG and hepatic phosphatidylinositol 3-kinase signaling, with a partial recovery of HDL cholesterol levels, providing evidence that hepatic ABCA1 is involved in the reciprocal regulation of apoB Lp production and HDL formation. These findings suggest that altered apoB Lp metabolism in TD subjects may result from hepatic VLDL TG overproduction and increased hepatic LDLr expression and highlight hepatic ABCA1 as an important regulatory factor for apoB-containing Lp metabolism. ABCA1 (ATP-binding cassette transporter A1) is indispensable in the initial steps of high density lipoprotein (HDL)2 formation and the process of reverse cholesterol transport from peripheral tissues to the liver. ABCA1 is expressed in many cells; however, hepatocytes make the single most important contribution to plasma HDL concentration (1-3). Mutations in ABCA1 in humans cause Tangier disease (TD), an autosomal recessive disorder characterized by severe HDL deficiency, rapid plasma clearance of HDL and apoA-I, sterol deposition in tissues, and premature coronary atherosclerosis (4 -7). In addition to HDL deficiency, TD subjects have significantly elevated plasma TG and a 50% reduction in LDL cholesterol concentrations (4,8). The TG phenotype in TD disease is complicated, with most, but not all, TD subjects displaying elevated fasting or postprandial TG elevations (9). Clee et al. (8) reported an inverse relationship between dysfunctional ABCA1 alleles and plasma TG concentrations. In addition, data from case reports of 59 Tangier patients show variable TG concentrations, with mean, median, minimum, and maximum concentrations of 210, 175, 40, and 580 mg/dl, respectively (4). The underlying mechanisms for the increased plasma TG and decreased LDL concentrations in TD subjects have not been established. In one study, apoA-II enrichment of VLDL of TD subjects was proposed to result in reduced reactivity of VLDL with lipoprotein lipase (LPL) (9, 10). Another study suggested that ABCA1-dependent cholesterol efflux decreases VLDL secretion from murine hep...

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Section: Targeted Deletion Of Hepatocyte Abca1 Results In Postpran-mentioning

confidence: 67%

Targeted Deletion of Hepatocyte ABCA1 Leads to Very Low Density Lipoprotein Triglyceride Overproduction and Low Density Lipoprotein Hypercatabolism

Chung

Timmins

Duong

et al. 2010

Journal of Biological Chemistry

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“…3,4 In contrast to other conditions associated with apoA-I/HDL abnormalities, eg, fish-eye disease 19 or Tangier disease, 20 there does not appear to be any clear association between the apolipoprotein abnormality and any pathological condition. 3 In the present investigation, quantitative data on the cardiovascular condition are provided to investigate in detail comparable series of apoA-I M carriers and control subjects from the same kindred.…”

Section: Discussionmentioning

confidence: 97%

Cardiovascular Status of Carriers of the Apolipoprotein A-I _Milano Mutant

et al. 2001

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Background-Carriers of the apolipoprotein A-I Milano (apoA-I M ) mutant present with very low plasma HDL cholesterol and moderate hypertriglyceridemia, apparently not leading to premature coronary heart disease. The objective of this study was to establish whether this high-risk lipid/lipoprotein profile is associated with structural changes in the carotid arteries and heart, indicative of preclinical atherosclerosis. Methods and Results-Twenty-one A-I M carriers were compared with age-and sex-matched control subjects from the same kindred and with 2 series of matched subjects with primary hypoalphalipoproteinemia (HA). Structural changes in the carotid arteries were defined as the intima-media thickness (IMT) measured by B-mode ultrasound. HA subjects, both recruited among patients attending our Lipid Clinic and blood donors, showed significant thickening of the carotids (average IMT, 0.86Ϯ0.25 and 0.88Ϯ0.29 mm, respectively) compared with control subjects (average IMT, 0.64Ϯ0.12 mm); the apoA-I M carriers instead showed normal arterial thickness (average IMT, 0.63Ϯ0.10 mm). Moreover, a significantly higher prevalence of atherosclerotic plaques was found in patients and blood donors with HA (both 57%) compared with apoA-I M carriers (33%) and control subjects (21%). Echocardiographic findings and maximal treadmill ECG did not differ significantly between apoA-I M carriers and control subjects, apart from a slight increase in left ventricular end-diastolic dimension in the carriers. Conclusions-Despite severe HA, carriers of the apoA-I M mutant do not show structural changes in the arteries and heart, in contrast to HA subjects, who are characterized by a marked increase in carotid IMT and increased prevalence of atherosclerotic plaques.

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“…ABCA1 is a member of a large family of ABC transporters and contains two ATP-binding domains and two sixhelix transmembrane domains (3). Mutations in ABCA1 cause Tangier disease (4 -7), which is characterized by a severe HDL deficiency, rapid clearance of apoA-I from the plasma, deposition of sterols in tissue macrophages, and prevalent atherosclerosis (8,9). Lipidation of apoA-I by ABCA1 is the key rate-limiting step in generating plasma HDL (10 -12).…”

mentioning

confidence: 99%

Unsaturated Fatty Acids Phosphorylate and Destabilize ABCA1 through a Phospholipase D2 Pathway

Wang

Oram

2005

Journal of Biological Chemistry

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Abnormal high density lipoprotein (HDL) metabolism among patients with diabetes and insulin resistance may contribute to their increased risk of atherosclerosis. ATP-binding cassette transporter ABCA1 mediates the transport of cholesterol and phospholipids from cells to HDL apolipoproteins and thus modulates HDL levels and atherogenesis. Unsaturated fatty acids, which are elevated in diabetes, impair the ABCA1 pathway in cultured cells by destabilizing ABCA1 protein. Here we examined the cellular pathway that mediates the ABCA1 destabilizing effects of fatty acids. The longchain acyl-CoA synthetase inhibitor triacsin C completely reversed fatty acid-induced ABCA1 destabilization, indicating that fatty acids need to be activated to their CoA derivatives to enhance ABCA1 degradation. Unsaturated but not saturated fatty acids stimulated phospholipase D (PLD) activity, the PLD inhibitor 1-butanol prevented the unsaturated fatty acid-induced reduction in ABCA1 levels, and the PLD2 activator mastoparan markedly reduced ABCA1 protein levels, implicating a role for PLD2 in the ABCA1 destabilizing effects of fatty acids. Unsaturated fatty acids and mastoparan increased phosphorylation of ABCA1 serines. PLD2 small interfering RNA abolished the ability of unsaturated fatty acids to inhibit lipid transport activity, to reduce protein levels, and to increase serine phosphorylation of ABCA1. The diacylglycerol analog oleoylacetylglycerol also reduced ABCA1 protein levels and increased its serine phosphorylation, suggesting that PLD2-generated diacylglycerols promote the destabilizing phosphorylation of ABCA1. These data provide evidence that intracellular unsaturated acyl-CoA derivatives destabilize ABCA1 by activating a PLD2 signaling pathway.Population studies have revealed an inverse relationship between plasma high density lipoprotein (HDL) 2 levels and risk for cardiovascular disease, implying that factors associated with HDL metabolism are atheroprotective. One of these factors is ATP-binding cassette transporter A1 (ABCA1), an integral membrane protein that mediates the transport of cellular cholesterol and phospholipids to lipid-deficient HDL apolipoproteins (1, 2). ABCA1 is a member of a large family of ABC transporters and contains two ATP-binding domains and two sixhelix transmembrane domains (3). Mutations in ABCA1 cause Tangier disease (4 -7), which is characterized by a severe HDL deficiency, rapid clearance of apoA-I from the plasma, deposition of sterols in tissue macrophages, and prevalent atherosclerosis (8, 9). Lipidation of apoA-I by ABCA1 is the key rate-limiting step in generating plasma HDL (10 -12).ABCA1 expression is tightly regulated. In macrophages, cholesterol loading markedly increases ABCA1 mRNA and protein levels (7, 13), consistent with a transporter that functions to export excess cholesterol. The transcription of this gene is regulated by nuclear liver X receptors (LXR␣ and LXR␤) and retinoid X receptor (RXR) (14 -17), which form heterodimers that are activated by oxysterols and retinoic acid...

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Homozygous Tangier disease and cardiovascular disease

Cited by 227 publications

References 63 publications

Targeted Deletion of Hepatocyte ABCA1 Leads to Very Low Density Lipoprotein Triglyceride Overproduction and Low Density Lipoprotein Hypercatabolism

Targeted Deletion of Hepatocyte ABCA1 Leads to Very Low Density Lipoprotein Triglyceride Overproduction and Low Density Lipoprotein Hypercatabolism

Cardiovascular Status of Carriers of the Apolipoprotein A-I _Milano Mutant

Unsaturated Fatty Acids Phosphorylate and Destabilize ABCA1 through a Phospholipase D2 Pathway

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Homozygous Tangier disease and cardiovascular disease

Cited by 227 publications

References 63 publications

Targeted Deletion of Hepatocyte ABCA1 Leads to Very Low Density Lipoprotein Triglyceride Overproduction and Low Density Lipoprotein Hypercatabolism

Targeted Deletion of Hepatocyte ABCA1 Leads to Very Low Density Lipoprotein Triglyceride Overproduction and Low Density Lipoprotein Hypercatabolism

Cardiovascular Status of Carriers of the Apolipoprotein A-I Milano Mutant

Unsaturated Fatty Acids Phosphorylate and Destabilize ABCA1 through a Phospholipase D2 Pathway

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Product

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About

Cardiovascular Status of Carriers of the Apolipoprotein A-I _Milano Mutant