Non-Steady-State Studies of Low-Density-Liproprotein Turnover in Familial Hypercholesterolaemia

Thompson, Gilbert R.; Spinks, T.J.; Ranicar, A.; Myant, N. B.

doi:10.1042/cs0520361

Cited by 19 publications

(12 citation statements)

References 14 publications

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“…Statistical analysis (one-way analysis of variance with repeated measures) indicated a significant (P < 0.05) further decrease in total cholesterol between wk 2 and 4 on the 5 mg twice daily dosage of mevinolin but no statistical significance between the values at 4 and 6 wk. For all other mevinolin doses (10,20, and 40 mg twice daily) the lipid values after 2 wk on each dose were not statistically different from those at 4 and 6 wk.…”

Section: Methodsmentioning

confidence: 79%

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Hypocholesterolemic effects of mevinolin in patients with heterozygous familial hypercholesterolemia.

Illingworth¹,

Sexton²

1984

J. Clin. Invest.

176

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Section: Methodsmentioning

confidence: 79%

“…Kinetic studies of '251-labeled LDL in patients with heterozygous FH have indicated that the reduced number of high affinity LDL receptors expressed on their cells results in a reduced fractional rate of catabolism of LDL from plasma (8)(9)(10) and is associated with lifelong hypercholesterolemia.…”

Section: Introductionmentioning

confidence: 99%

Hypocholesterolemic effects of mevinolin in patients with heterozygous familial hypercholesterolemia.

Illingworth¹,

Sexton²

1984

J. Clin. Invest.

176

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“…Third, observations that portacaval shunt surgery ( Fig. 1) (11) and plasmapheresis (24) (3,14). The mechanism by which a deficiency of LDL receptors causes an increased synthesis of LDL has not been defined.…”

Section: Resultsmentioning

confidence: 99%

Metabolic Studies in Familial Hypercholesterolemia

Bilheimer¹,

Stone²,

Grundy³

1979

J. Clin. Invest.

199

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A B S T R A C T To investigate the gene-dosage effect in familial hypercholesterolemia (FH), metabolic studies were conducted in a group of well-characterized patients with either heterozygous (n = 7) or homozygous (n = 7) FH and the results were compared to those obtained in normal subjects (n = 6). 524 these seven patients is caused by variation in the plasma apoLDL synthetic rates. Consistent with this conclusion was the finding that the correlation between the plasma LDL level and the apoLDL synthetic rates in the seven FH homozygotes was 0.943.The rate of total body cholesterol synthesis determined by chemical cholesterol balance did not appear to clearly differ between normals and patients with either one or two mutant FH genes. Two of the youngest FH homozygotes exhibited cholesterol overproduction but the other five did not. No consistent abnormality of bile acid metabolism was observed in these patients. Because the daily plasma flux of cholesterol on LDL is about threefold greater than the amount of cholesterol produced per day, a significant amount ofthe cholesterol liberated from LDL degradation must be reused.

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“…One of the homozygotes (D. L.) and one of the controls each underwent plasma exchange with plasma protein fraction (PPF) during the course of their turnover study as described (13). The other control subject received cholestyramine (24 g/day) during the last 6 days of his turnover study, during which period both urinary and fecal radioactivity were measured.…”

mentioning

confidence: 99%

Defects of receptor-mediated low density lipoprotein catabolism in homozygous familial hypercholesterolemia and hypothyroidism in vivo.

Thompson¹,

Soutar²,

Spengel³

et al. 1981

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

244

110

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The role of low density lipoprotein (LDL) receptors in the pathogenesis of hereditary and acquired forms of hypercholesterolemia has been investigated in vivo by simultaneously determining total and receptor-independent LDL catabolism with "MI-labeled LDL and "'I-labeled LDL coupled with cyclohexanedione. Receptor-mediated catabolism of LDL, determined as the difference between the turnover of 125I and 1311, was found to be virtually absent in two homozygotes with familial hypercholesterolemia and markedly reduced in a hypothyroid patient. Treatment of the latter with L-thyroxine markedly stimulated receptor-mediated catabolism and reduced LDL levels as did cholestyramine administration in a control subject. Reduction of LDL levels by plasma exchange in a control subject and homozygote had no such effect. These results demonstrate the existence of an intrinsic and almost total defect of receptor-mediated LDL catabolism in homozygous familial hypercholesterolemia and demonstrate an analogous but reversible abnormality in hypothyroidism.Hypocatabolism of low density lipoprotein (LDL) characterizes both familial hypercholesterolemia (FH) and hypothyroidism (1, 2). Studies with cultured fibroblasts have revealed an inherited deficiency of LDL receptors in FH, more marked in homozygotes than in heterozygotes, which has been assumed to be the cause of the catabolic defect in vivo (3, 4). Stimulation of high affinity binding and degradation of LDL in normal fibroblasts by triiodothyronine (5) suggests the possibility of an analogous but acquired deficiency of LDL receptors in hypothyroidism. Recently, Shepherd et al. (6) provided in vivo evidence of a decrease in receptor-mediated LDL catabolism in FH heterozygotes, using the technique developed by Mahley et al. (7). This involves the simultaneous administration of 125I-labeled native LDL (l2I-LDL) and '311-labeled LDL (131I-LDL) treated with 1,2-cyclohexanedione (Chd); the latter modification blocks arginine residues and thus inhibits binding of LDL to receptors on fibroblasts and smooth muscle cells (8). Using this approach, we have been able to demonstrate the virtual absence of receptor-mediated LDL catabolism in homozygous FH and the presence of a similar but reversible abnormality in hypothyroidism. Our observations, published previously only as abstracts (9, 10), help validate a novel method ofquantitating receptor-mediated LDL catabolism and illustrate the importance of that pathway in regulating serum cholesterol levels in man.SUBJECTS AND METHODS Two male FH homozygotes (M.M., D.L.), both ages 16 years and with receptor-defective fibroblasts on established criteria (11), whose clinical details are given elsewhere (12), were studied after having discontinued cholesterol-lowering drugs and plasma exchange for 5-6 wk. A 30-year-old woman (E. P.) with overt primary hypothyroidism was studied twice, before and after being rendered euthyroid by a 6-wk treatment with L-thyroxine (0.2 mg/day). Two of the authors, both normolipidemic men, aged 34 and 47, act...

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Non-Steady-State Studies of Low-Density-Liproprotein Turnover in Familial Hypercholesterolaemia

Cited by 19 publications

References 14 publications

Hypocholesterolemic effects of mevinolin in patients with heterozygous familial hypercholesterolemia.

Hypocholesterolemic effects of mevinolin in patients with heterozygous familial hypercholesterolemia.

Metabolic Studies in Familial Hypercholesterolemia

Defects of receptor-mediated low density lipoprotein catabolism in homozygous familial hypercholesterolemia and hypothyroidism in vivo.

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