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

Schaefer, Ernst J.

doi:10.1161/01.atv.4.4.303

Cited by 162 publications

(50 citation statements)

References 131 publications

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“…A number of previous observations suggest metabolic processes that might contribute to the correlations involving HDL 2 subspecies reported here. It has been reported that the fractional catabollc rate of HDL 2 (especially HDI-a) is Inversely related to levels of triglyceride or VLDL 17 possibly accounting for the reciprocal relations of HDLj and VLDL changes. Furthermore, levels of HDLj, 16 and more recently larger LDL, 19 have been positively correlated with levels of adipose tissue lipoprotein lipase.…”

Section: Discussionmentioning

confidence: 99%

Coordinate changes in levels of human serum low and high density lipoprotein subclasses in healthy men.

et al. 1988

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Measurement of serum lipoproteins by analytic ultracentrifugation revealed significant correlations involving subfractions of low density (LDL) and high density (HDL) lipoproteins in 81 men studied cross-sectionally at baseline and longitudinally during a 1-year exercise trial. One-year changes in lipoprotein levels in 38 exercising men and in 30 sedentary controls showed correlations that paralleled those observed at baseline. Positive correlations observed between plasma levels of larger, more buoyant LDL of flotation rate (Sof) 7 to 10 (LDL-I) and HDL2 may be due to processes that also coregulate changes in levels of these lipoprotein subclasses. Similarly, positive correlations among smaller, more dense LDL of Sof 2 to 6 (LDL-III), IDL, and HDL3 suggest that levels of these lipoprotein species are also coordinately regulated. An inverse correlation of change in LDL-I with change in LDL-III raises the possibility of precursor-product relationships between LDL in these categories. Thus, changes in lipoproteins which are related to coronary disease risk are not independent of one another, and the development of coronary disease may be influenced by processes linking the metabolism of individual IDL, LDL, and HDL components.

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Section: Discussionmentioning

confidence: 99%

Coordinate changes in levels of human serum low and high density lipoprotein subclasses in healthy men.

et al. 1988

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“…The biochemical mechanism(s) behind this observed relationship is still unknown but is believed to be related to the role of HDL in promoting the transport of cholesterol from peripheral tissues to the liver for catabolism (reverse cholesterol transport) (3), thus preventing the accumulation of excess cellular cholesterol and the development of foam cells. Although this putative role of HDL in reverse cholesterol transport has not been proven conclusively, this concept is supported by many of the clinical features found in patients with HDL deficiency (4). Furthermore, in vitro studies have shown that HDL can promote cellular cholesterol efflux (5,6).…”

Section: Introductionmentioning

confidence: 99%

Characterization of apolipoprotein A-I- and A-II-containing lipoproteins in a new case of high density lipoprotein deficiency resembling Tangier disease and their effects on intracellular cholesterol efflux.

et al. 1993

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A 48-yr-old Caucasian female of central European origin (subject IM) with low plasma cholesterol and normal plasma triglyceride (TG) had extremely low apo A-I (6 mg/dl), A-II (5 mg/dl), and HDL cholesterol (2 mg/dl) levels. She had most of the clinical symptoms typically associated with Tangier disease, including early corneal opacities, yellow-streaked tonsils, hepatomegaly, and variable degrees of peripheral neuropathy, but had no splenomegaly. She had a myocardial infarction at age 46. Since HDL are postulated to be involved in the transport of excess cholesterol from peripheral tissues to the liver for degradation, and the ability of an HDL particle to promote cellular cholesterol efflux appears to be related to its density, size, and apo A-I and A-II contents, we isolated and characterized the HDL particles of this patient and all her first degree relatives (mother, a brother, and two children). The plasma A-I, A-II, and HDL cholesterol levels of all five relatives were either normal or high. Using anti-A-I and anti-A-II immunosorbents, we found three populations of particles in IM: one contained both apo A-I and A-II, Lp(AI w All); one contained apo A-I but no A-II, Lp(AI w/o All); and the third (an unusual one) contained apo A-Il but no A-I, Lp(AII). Two-thirds of her plasma A-I and A-II existed in separate HDL particles, i.e., in Lp(AI w/o AII) and Lp(AII), respectively. Only Lp(AI w All) and Lp(AI w/o All) were present in the plasma of the relatives. All three populations of the patient's HDL particles had a normal core/ surface lipid ratio, but the cores were enriched with TG. The apo A-I-containing particles, however, were considerably smaller and contained much less lipid than Lp(AII). Despite these unusual physicochemical characteristics, the apo A-I-containing particles and Lp(AII) were effective suppressors of intracellular cholesterol esterification in cholesterol-loaded human skin fibroblast. The patient's plasma apo D and lecithin cholesterol acyltransferase levels were reduced, with an increased proportion located in non-HDL plasma fractions. These findings are discussed in light of

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“…Marked HDL deficiency states (HDL cholesterol , 5 mg/dl) and undetectable plasma apolipoprotein A-I (apoA-I) levels have been reported in humans as a result of mutations at the APOA1/C3/A4 gene locus (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Such patients lack apoA-I-containing HDL in plasma, with normal or decreased triglyceride levels, normal LDL cholesterol levels, and often strikingly premature CHD (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Other patients with marked HDL deficiency have mutations affecting the apoA-I sequence that can affect the activity of lecithin:cholesterol acyl transferase activity (19)(20)(21)(22)(23)(24)(25)(26).…”

mentioning

confidence: 99%

Characterization of high density lipoprotein particles in familial apolipoprotein A-I deficiency

Santos

Schaefer

Asztalos

et al. 2008

Journal of Lipid Research

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Our aim was to characterize HDL subspecies and fat-soluble vitamin levels in a kindred with familial apolipoprotein A-I (apoA-I) deficiency. Sequencing of the APOA1 gene revealed a nonsense mutation at codon 22, Q[22]X, with two documented homozygotes, eight heterozygotes, and two normal subjects in the kindred. Homozygotes presented markedly decreased HDL cholesterol levels, undetectable plasma apoA-1, tuboeruptive and planar xanthomas, mild corneal arcus and opacification, and severe premature coronary artery disease. In both homozygotes, analysis of HDL particles by two-dimensional gel electrophoresis revealed undetectable apoA-I, decreased amounts of small a-3 migrating apoA-II particles, and only modestly decreased normal amounts of slow a migrating apoA-IV-and apoEcontaining HDL, while in the eight heterozygotes, there was loss of large a-1 HDL particles. There were no significant decreases in plasma fat-soluble vitamin levels noted in either homozygotes or heterozygotes compared with normal control subjects. Our data indicate that isolated apoA-I deficiency results in marked HDL deficiency with very low apoA-II a-3 HDL particles, modest reductions in the separate and distinct plasma apoA-IV and apoE HDL particles, tuboeruptive xanthomas, premature coronary atherosclerosis, and no evidence of fat malabsorption. Decreased plasma HDL cholesterol levels (,40 mg/dl in men and ,50 mg/dl in women) have been associated with an increased risk of coronary heart disease (CHD) (1). Marked HDL deficiency states (HDL cholesterol , 5 mg/dl) and undetectable plasma apolipoprotein A-I (apoA-I) levels have been reported in humans as a result of mutations at the APOA1/C3/A4 gene locus (2-18). Such patients lack apoA-I-containing HDL in plasma, with normal or decreased triglyceride levels, normal LDL cholesterol levels, and often strikingly premature CHD (2-18). Other patients with marked HDL deficiency have mutations affecting the apoA-I sequence that can affect the activity of lecithin:cholesterol acyl transferase activity (19)(20)(21)(22)(23)(24)(25)(26). In this regard, they differ from patients with homozygous Tangier disease caused by mutations in ABCA1, who have defective cellular cholesterol efflux, detectable plasma apoA-I in preb-1 HDL only, hypertriglyceridemia, and decreased LDL cholesterol (27-29). Previously, defects involving the APOA1/C3/A4 gene cluster, the contiguous APOA1 and APOC3 genes, and the APOA1 gene in isolation have been described (2-26). Here, we report a kindred with isolated apoA-I deficiency, with precise lipoprotein and clinical characterization and characterization of fat-soluble vitamin levels, and document differences between this type of apoA-I deficiency and those combined with other apolipoprotein deficiencies in humans. These data provide us with important insights about the function of these apolipoproteins in human health and disease as well as about HDL particle subspecies. METHODS KindredThe index case presented to the Lipid Clinic at the Heart Institute (InCor) of the Uni...

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

Cited by 162 publications

References 131 publications

Coordinate changes in levels of human serum low and high density lipoprotein subclasses in healthy men.

Coordinate changes in levels of human serum low and high density lipoprotein subclasses in healthy men.

Characterization of apolipoprotein A-I- and A-II-containing lipoproteins in a new case of high density lipoprotein deficiency resembling Tangier disease and their effects on intracellular cholesterol efflux.

Characterization of high density lipoprotein particles in familial apolipoprotein A-I deficiency

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