Genetics of the low density lipoprotein receptor. Diminished receptor activity in lymphocytes from heterozygotes with familial hypercholesterolemia.

Bilheimer, David W.; Ho, Y. K.; Brown, Michael S.; Anderson, R. G.; Goldstein, Joseph L.

doi:10.1172/jci108980

Cited by 137 publications

(49 citation statements)

References 20 publications

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“…On many occasions, patients may initially consult a dermatologist. When it is difficult to differentiate homozygous from severe heterozygous FH, it is possible to make a definitive diagnosis based on the detection of reduced LDL receptor activity in fibroblasts/lymphocytes (20% or less of the normal activity) 58) and LDL-receptor, ApoB or PCSK9 gene mutations.…”

Section: Diagnosis Of Homozygous Fhmentioning

confidence: 99%

Guidelines for the Management of Familial Hypercholesterolemia

Harada‐Shiba

Arai

Oikawa

et al. 2012

JAT

167

164

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Familial hypercholesterolemia (FH) is a highly prevalent autosomal dominant hereditary disease, generally characterized by three major signs, hyper-low-density-lipoprotein (LDL) cholesterolemia, tendon/skin xanthomas and premature coronary artery disease (CAD). Because the risk of CAD is very high in these patients, they should be identified at an early stage of their lives and started on intensive treatment to control LDL-cholesterol. We here introduce a new guideline for the management of FH patients in Japan intending to achieve better control to prevent CAD. Diagnostic criteria for heterozygous FH are 2 or more of 1) LDL-cholesterol ≥ 180 mg/dL, 2) tendon/skin xanthoma(s), and 3) family history of FH or premature CAD within second degree relatives, for adults; and to have both 1) LDL-cholesterol ≥ 140 mg/dL and 2) family history of FH or premature CAD within second degree relatives, for children. For the treatment of adult heterozygous FH, intensive lipid control with statins and other drugs is necessary. Other risks of CAD, such as smoking, diabetes mellitus, hypertension etc., should also be controlled strictly. Atherosclerosis in coronary, carotid, or peripheral arteries, the aorta and aortic valve should be screened periodically. FH in children, pregnant women, and women who wish to bear a child should be referred to specialists. For homozygotes and severe heterozygotes resistant to drug therapies, LDL apheresis should be performed. The treatment cost of homozygous FH is authorized to be covered under the program of Research on Measures against Intractable Diseases by the Japanese Ministry of Health, Labour, and Welfare.

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Section: Diagnosis Of Homozygous Fhmentioning

confidence: 99%

Guidelines for the Management of Familial Hypercholesterolemia

Harada‐Shiba

Arai

Oikawa

et al. 2012

JAT

167

164

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“…2). Brown and Goldstein and co-workers, who obtained similar results with both fibroblasts and lymphocytes (3)(4)(5), have designated the more concentration-sensitive part of the curve "high-affinity" degradation and the less concentration-sensitive part "low-affinity" degradation (5). The differences in LDL degradation between cells from heterozygotes on or not on colestipol were more marked at higher LDL concentrations ( Fig.…”

Section: Methodsmentioning

confidence: 93%

“…After preincubation in LPDS, the contents of the flasks for each subject were pooled, leaving behind monocytes, which adhered to the sides of the flask (4). Differential counts of stained smears showed that the preincubated cell preparations contained less than 1% monocytes.…”

Section: Methodsmentioning

confidence: 99%

“…(3). These investigators, using cells incubated without lipoproteins ("induced" cells), demonstrated defective binding and degradation of LDL by both fibroblasts and lymphocytes from FH patients (3)(4)(5)(6)(7). This defect was particularly marked in-receptor-negative homozygous FH patients and was attributed to a genetic absence of high-affinity LDL binding sites or receptors on their cells (6).…”

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confidence: 99%

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Low density lipoprotein degradation by mononuclear cells from normal and dyslipoproteinemic subjects.

Lees¹,

Lees²

1983

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

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Three major characteristics of cell surface low density lipoprotein (LDL) receptor activity in fibroblasts or lymphocytes are high-affinity LDL binding or degradation, specificity for LDL, and "inducibility"-that is, the ability to increase when cells are cultured in the absence of lipoproteins. Cells from patients with receptor-negative homozygous familial hypercholesterolemia (FH) have been reported to express none of these characteristics, and the patients are thought-to have a genetic absence of LDL receptors. We found that, although induced receptor-negative lymphocytes degraded less LDL than did normal lymphocytes, the curves for LDL degradation versus LDL concentration were biphasic, with greater concentration-dependence at LDL concentrations < 60 jug/ml, indicating high-affinity LDL degradation. The percentage of specific LDL degradation by induced receptor-negative lymphocytes was two-thirds of normal with LDL at 10 jug/ml and increased to normal at 50 Iug/ml, an LDL concentration still within the range of high-affinity degradation. Receptor-negative lymphocytes could be induced by incubation in the absence of lipoproteins to degrade twice as much LDL as they did when freshly isolated. Freshly isolated cells from abetalipoproteinemic patients and one receptor-negative patient degraded as much LDL as did fresh normal cells. The findings indicate that receptor-negative lymphocytes have a mechanism for facilitated uptake of LDL that resembles that of normal lymphocytes, although it is not as efficient. (LPDS) for cells from both normal subjects and receptor-negative patients, and (iv) treatment of heterozygous FH patients with the lipid-lowering drug colestipol before lymphocyte isolation. We also examined the degree to which LDL degradation by induced lymphocytes was specific for LDL. Lymphocytes were used. to study LDL receptor activity because lymphocyte LDL receptors are genetically identical to fibroblast LDL receptors (3). Familial hypercholesterolemia (FH) is METHODSSubjects. Lymphocytes were obtained from 16 normal volunteers, 9 FH heterozygotes on no drugs, 3 FH heterozygotes on the bile acid-binding resin colestipol (10-20 g daily), 2 receptor-negative FH homozygotes (O.C. and D.R.), and 2 patients with abetalipoproteinemia (1). Before blood was drawn for the studies, informed consent in writing was obtained from the subjects or their parents. The homozygous FH patients were two of the six patients from the original group of receptor-negative FH homozygotes described by Goldstein et al. (8). The determination of FH in those subjects designated as heterozygotes was based on criteria used previously to distinguish bet tween FH and familial combined hyperlipidemia (2). The three FH heterozygotes on colestipol had a 22% decrease in mean (±SD) plasma total cholesterol from 325 ± 27 mg/100 ml before treatment to 255 ± 21 mg'/100 ml during treatment, which compares favorably with the average 12-17% decrease in plasma total cholesterol reported in a previous study of the drug's efficacy (9).L...

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“…The degradation of IHI-Iabelled human LDL by freshly isolated blood mononuclear cells was measured as described by Bilheimer et 01. 3 Plant sterols in plasma were quantitated by gas chromatography (GC) after hydrolysis and extraction." Coprostanol (Steraloids Ltd, Croydon, UK) was used as the internal standard and taken through the complete procedure.…”

Section: Xanthomata Of the Achilles Tendons (A Bj And Extensor Tendomentioning

confidence: 99%