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Biomedical subjects

N B Myant

Publications and source records attributed to N B Myant.

At least 37 records · Page 2Linked to original sources
PubMed1984

The distribution of cholesterol and apoprotein A-I between the lipoproteins in plasma and peripheral lymph from normal human subjects.

The lipoproteins of peripheral lymph and plasma from normal human subjects were separated according to their density by sequential ultracentrifugation and according to their size by gradient gel electrophoresis and gel exclusion chromatography. High density lipoproteins (HDL) carried a higher proportion of the total cholesterol in lymph than in plasma. Within the HDL fraction, the less dense and more lipid-rich component (HDL2) carried a higher proportion of the total HDL cholesterol in lymph than in plasma. Gradient gel electrophoresis showed (1) a higher proportion of large to small HDL particles in lymph than in plasma and (2) the presence of at least three populations of apo A-I-containing lipoproteins with Stokes diameters larger than the Stokes diameter of HDL2. Separation by gel exclusion chromatography showed that the proportion of large HDL particles with a high cholester: apo A-I ratio was greater in lymph than in plasma. In view of the sieving effect of the blood capillaries, which favours the passage across the capillary walls of smaller vs larger particles, we suggest that the higher ratio of large to small HDL particles in lymph than in plasma is due to the conversion of small to large HDL in the interstitial fluid by incorporation of cholesterol and other lipids from extravascular cells into the smaller particles.

Apolipoprotein A-I↗
PubMed1983

The transport of cholesterol through the plasma in normal man.

This review includes a brief account of the routes of entry of cholesterol into the plasma by (a) secretion of lipoproteins and (b) uptake of tissue free cholesterol by lipoproteins in the interstitial fluid, the metabolic transformation undergone by cholesterol within the plasma, with particular reference to the esterification of plasma free cholesterol by lecithin:cholesteryl acyltransferase and the redistribution of esterified cholesterol from high-density to low-density and very-low-density lipoprotein, and the routes by which cholesterol is removed from the plasma by bulk transport. The review end with a balance sheet showing the approximate amounts of cholesterol entering and leaving the plasma by different routes.

Animals↗
PubMed1983

The metabolic basis of familial hypercholesterolemia.

Familial hypercholesterolaemia (FH) is a dominantly inherited error of metabolism characterised by a raised plasma low-density lipoprotein (LDL) concentration, xanthomas of skin and tendons, and a tendency to premature heart disease due to atherosclerosis of the coronary arteries. The clinical and biochemical abnormalities are more marked in homozygotes than in heterozygotes. Other biochemical changes include an increased concentration of very-low-density lipoprotein (VLDL) remnants and of a minor subfraction of high-density lipoproteins. Measurement of plasma lipoprotein turnover shows reduced fractional rates of catabolism of LDL and VLDL remnants, and increased production of LDL. Similar abnormalities are found in Watanabe rabbits, an inbred strain carrying a mutation similar to that responsible for FH. Cultured cells from human and animal tissues express surface receptors with high binding affinity for LDL. Binding of LDL to LDL receptors is followed by endocytosis and lysosomal digestion of the lipoprotein. Cultured cells from FH heterozygotes express only half the normal number of LDL receptors; those from homozygotes have little or no receptor activity and are therefore unable to degrade significant amounts of LDL by the LDL-receptor pathway. The LDL receptor has been isolated from cell membranes; it has a molecular weight of about 160 kd. Several different mutant forms of the receptor have been identified in the cells of FH homozygotes. The LDL-receptor pathway for the catabolism of LDL accounts for at least 1/3 of the total LDL catabolised by normal human subjects in vivo and almost none of that catabolised by FH homozygotes. Deficiency of LDL receptors accounts for the increased plasma concentrations of LDL and VLDL remnants in FH. The increased plasma concentration in these lipoproteins is the cause of deposition of lipid in xanthomas and arterial wall, but the mechanism by which lipoprotein enters the cells in which lipid accumulates is not yet understood.

Adult↗
PubMed1983

Normal adrenocortical response to adrenocorticotrophic hormone in patients with homozygous familial hypercholesterolaemia.

1. Plasma cortisol concentration was measured in three subjects with homozygous familial hypercholesterolaemia immediately before, and 30 and 60 min after, an intramuscular injection of adrenocorticotrophic hormone. The baseline values and the values at 30 and 60 min were within the normal range. 2. We conclude that in the presence of a genetic deficiency of low-density lipoprotein receptors, the human adrenal cortex can respond to a single injection of adrenocorticotrophic hormone with a normal increase in corticosteroid production.

Adolescent↗
PubMed1982

The effect of partial ileal bypass on receptor-mediated uptake and catabolism of low density lipoprotein in the rhesus monkey.

The fractional rates of catabolism (FCR) of 125I-labelled low-density lipoprotein (LDL) and 131I-labelled LDL coupled with 1,2-cyclohexanedione (LDL-CHD) were determined before and 6 weeks after partial ileal bypass in three Rhesus monkeys. Receptor-mediated catabolism, determined as the difference between the FCRs of 125I-LDL and 131I-LDL-CHD, increased significantly after partial ileal bypass. Analysis of tissue distribution of radioactivity in one monkey, killed at the conclusion of a third turnover study 6 months after partial ileal bypass, suggested that the liver was the main tissue site of accumulation of LDL, and that uptake had occurred mainly via a receptor-mediated mechanism. It is concluded that partial ileal bypass stimulates receptor-mediated LDL catabolism in the Rhesus monkey as in man, and that this increase is probably mediated via hepatic LDL receptors.

Animals↗
PubMed1982

The metabolism of very low density and intermediate density lipoproteins in patients with familial hypercholesterolaemia.

The metabolism of apolipoprotein B (apoB) in very low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL) was studied in normal subjects and in patients with familial hypercholesterolaemia (FH) after an intravenous injection of autologous VLDL labelled with 125I. There were no significant differences in half life, pool size and turnover rate (mg/kg/h) of VLDL-apoB between the normal subjects, the FH heterozygotes and the FH homozygotes. IDL-apoB metabolism in the FH patients differed significantly from that in the normal subjects. In the FH patients, the rise to the maximum of the specific activity curve was slower, the half life of the descending limb of the specific-activity curve was longer, the fractional rate of turnover was lower and the plasma concentration was higher than in the normals. The effect of cholestyramine on IDL-apoB metabolism in the normal subjects did not differ from that in the FH heterozygotes and homozygotes, though cholestyramine is known to stimulate hepatic uptake of low density lipoprotein (LDL) by the LDL receptor. It is suggested that in normal human subjects the LDL receptor makes some contribution to the hepatic uptake of IDL-apoB derived from VLDL, but that IDL uptake is mediated partly by a separate receptor that recognizes apolipoprotein E but not apoB.

Adolescent↗
PubMed1982

Further evidence for the role of high density lipoprotein in the removal of tissue cholesterol in vivo.

The lipoproteins of human peripheral lymph and plasma were separated according to particle size by polyacrylamide gradient gel electrophoresis. All samples of lymph contained lipoproteins that moved to the same positions on the gel as plasma LDL and plasma HDL. Some samples of lymph also contained lipoproteins with the mobility of VLDL and IDL. The lymph lipoproteins corresponding to plasma LDL reacted with anti-LDL serum and those corresponding to plasma HDL reacted with anti-HDL serum. In the lipoprotein fraction with the mobility of HDL, the proportion of particles larger than catalase was greater in lymph than in plasma. It is suggested that the shift in size distribution towards larger HDL particles in lymph compared with plasma is due to uptake of cholesterol from extravascular tissue by HDL particles after they have reached the interstitial fluid from the plasma, rather than to preferential movement of larger particles across the capillary walls.

Cholesterol↗
PubMed1982

Difference in saturable binding of low density lipoprotein to liver membranes from normocholesterolemic subjects and patients with heterozygous familial hypercholesterolemia.

To investigate the possible role of the low density lipoprotein (LDL) receptor in the catabolism of LDL by the human liver, the binding of 125I-labeled LDL to membrane fractions prepared from human liver biopsies was determined. Biopsy samples taken for routine histology were obtained from seven patients with heterozygous familial hypercholesterolemia, one with non-familial hypercholesterolemia, and seven normocholesterolemic subjects. LDL was bound by the membranes from normal subjects in a saturable manner that was inhibited by 56% in the presence of excess LDL. Binding of LDL was also inhibited by modification of the lipoproteins with 1,2-cyclohexanedione. The amount of 125I-labeled LDL bound to membranes from familial hypercholesterolemic livers that could be displaced with excess LDL was significantly less than that bound by normocholesterolemic membranes. These observations suggest that LDL receptors are expressed in normal human liver and are defective in the livers of familial hypercholesterolemic patients.

Cell Membrane↗
PubMed1982

The characterization of lipoproteins in the high density fraction obtained from patients with familial lecithin:cholesterol acyltransferase deficiency and their interaction with cultured human fibroblasts.

Lipoproteins of density 1.063--1.21 g/ml were isolated from the plasma of three sisters of Irish origin with familial LCAT deficiency. Fractionation of the lipoproteins on the basis of particle size by chromatography on Sephacryl S-300 permitted partial separation of two major and at least three other minor components which differed in their lipid:protein ratio and their apolipoprotein content. One of the major components was a small spherical lipoprotein whose sole apolipoprotein was apoA-I; the second major component contained predominantly apoA-I, together with apoE, and in addition, an apolipoprotein of molecular weight 46,000 that was not cleaved by reduction of disulfide bonds, and which was identified as apoA-IV. This apoprotein has not previously been detected in the lipoproteins of LCAT-deficient patients. A second apoE-containing lipoprotein, which contained apoA-I and apoE in a ratio of approximately 2:1, was also present as a minor component, together with two or more minor components whose apoproteins were comprised of apoA-I and apoC. The apoE-containing lipoproteins competed efficiently with 125I-labeled LDL for binding to high affinity LDL-receptor sites on the surface of cultured human skin fibroblasts. The ability to bind to the LDL-receptor was directly proportional to the apoE content of the lipoproteins, even when other apoproteins, with the exception of apoB, were present in relatively large proportions. ApoE-containing 125I-labeled lipoproteins from an LCAT-deficient subject were also taken up and degraded by the cultured cells.

Apolipoproteins↗
PubMed1981

Analytical fractionation of human liver microsomal fractions: localization of cholesterol and of the enzymes relevant to its metabolism.

1. The submicrosomal distribution of three enzymes concerned in cholesterol metabolism, and of free and esterified cholesterol, was determined in human liver by analytical isopycnic centrifugation on sucrose gradients. 2. The distribution profile and median density of acyl-CoA:cholesterol O-acyltransferase was similar to that of RNA, showing that this enzyme is confined largely to the ribosome-rich membranes of the endoplasmic reticulum. The distribution profiles and median densities of 3-hydroxy-3-methylglutaryl-CoA reductase and cholesterol 7 alpha-mono-oxygenase showed that both enzymes are confined to the smooth, ribosome-poor, endoplasmic reticulum. 3. Most of the free cholesterol in the microsomal preparations was present in smooth membranes from the Golgi apparatus and in vesicles from plasma-membrane fragments. The distribution of esterified cholesterol was multimodal and extended throughout the whole gradient.

Adult↗
PubMed1981

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

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 125I-labeled LDL and 131I-labeled LDL coupled with cyclohexanedione. Receptor-mediated catabolism of LDL, determined as the difference between the turnover of 125I and 131I, 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 demontrate an analogous but reversible abnormality in hypothyroidism.

Biological Transport↗
PubMed1980

Evidence for the presence of tissue-free cholesterol in low density and high density lipoproteins of human peripheral lymph.

The specific radioactivity of free and esterified cholesterol in the lipoproteins of human peripheral lymph was measured in 4 normal human subjects at various intervals after labelling the tissue cholesterol by a single intravenous injection of [14C]cholesterol. The free : esterified cholesterol specific-activity ratios in lymph LDL and HDL at short and long intervals after labelling in vivo suggest that both lipoproteins were capable of acting as acceptors for tissue-free cholesterol, but that in 3 of the 4 subjects the predominant acceptor was HDL.

Carbon Radioisotopes↗
PubMed1980

Effect of lipoprotein concentration and lecithin: cholesterol acyltransferase activity on cholesterol esterification in human plasma after plasma exchange.

The rate of cholesterol esterification in plasma, plasma lecithin cholesterol acyltransferase (LCAT) activity and plasma lipoprotein levels have been measured in five subjects who underwent therapeutic plasma exchange to reduce their plasma cholesterol concentration. In the week following the exchange the cholesterol esterification rate and the plasma triglyceride concentration returned rapidly in parallel to pre-exchange levels, while high density lipoprotein (HDL) cholesterol and LCAT activity returned to normal more slowly but also in parallel. The data suggest that the rate-limiting factor for cholesterol esterification in plasma is unlikely to be solely the enzyme levels, but is probably a combination of factors, including the enzyme level and either substrate availabiltiy or product removal. Plasma very low density lipoprotein (VLDL) may either provide substrates for the reaction or provide a means of removing one of the products from the site of reaction.

Adult↗
PubMed1980

Assessment of long-term plasma exchange for familial hypercholesterolaemia.

The effectiveness of repeated plasma exchange with 2 to 4 litres of plasma protein fraction as long-term treatment for familial hypercholesterolaemia has been evaluated in six severely affected patients receiving conventional cholesterol lowering treatment. Cell-separator mediated exchange at monthly intervals for one to two years reduced mean serum cholesterol levels from 18.5 mmol/l (715 mg/dl) to 12.4 mmol/l (480 mg/dl) in two female homozygotes but failed to influence xanthomata or prevent a two- to threefold increase in their left ventricular aortic systolic pressure gradients. More effective reduction of mean serum cholesterol levels from 15.7 mmol/l (608 mg/dl) to 8.6 mmol/l (333 mg/dl) in two male homozygotes by plasma exchange at fortnightly intervals for two to three years was accompanied by resolution of xanthomata and by stabilisation of aortocoronary lesions. In two male heterozygotes with angina, coronary angiographic appearances were unaltered or improved after one to two years of thrice-monthly plasma exchange, which reduced mean serum cholesterol levels from 6.4 mmol/l (248 mg/dl) to 4.7 mmol/l (182 mg/dl). We conclude that plasma exchange every one to two weeks, combined with oral nicotinic acid and/or cholestyramine, retards the rate of progression of atheroma in homozygotes and possibly induces regression in heterozygotes.

Adult↗
PubMed1980

Cadiovascular complications of homozygous familial hypercholesterolaemia.

Seven patients with homozygous familial hypercholesterolaemia, two female and five male, aged 12 to 25 years, underwent clinical and angiographic assessment to define the associated cardiovascular abnormalities. Four patients had angina, two of whom also had syncope on exertion. All had an ejection systolic murmur but no ejection click and a loud aortic second sound. All but one had a systolic gradient between the left ventricle and aorta, ranging from 20 to 80 mmHg at the time of presentation. Angiography showed a characteristic narrowing of the aortic root in all and five of the seven patients had coronary ostial stenosis. One patient died after an aortocoronary bypass and aortic valvotomy and two others underwent aortocoronary bypass and aortic valve replacement, one of whom also died after operation. The survivor and three other patients are now undergoing regular plasma exchange and remain well. The seventh patient died suddenly before the latter form of treatment could be started. These findings confirm that premature, severe atheroma of the aortic valve and root is a characteristic feature of homozygous familial hypercholesterolaemia and carries a high mortality.

Adolescent↗
PubMed1979

Metabolism of apolipoprotein B-containing lipoproteins in familial hypercholesterolaemia: effects of plasma exchange.

The turnover of apolipoprotein B (apo B) in very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein (LDL) was investigated in 2 homozygous and 3 heterozygous patients with familial hypercholesterolaemia. The effects of a marked reduction in plasma LDL concentration, brought about by plasma exchange, upon apo B turnover were studied in 4 patients. Specific activity-time curves for the the plasma apo B after intravenous radioactive VLDL before plasma exchange indicated that in the heterozygotes all IDL-apo B was derived from VLDL and all LDL-apo B was derived from IDL, but the curves from the homozygotes showed that a significant fraction of the LDL in the plasma was not derived from IDL. Plasma exchange did not increase the rates of synthesis of LDL-apo B or VLDL-apo B and had no significant effect on the precursor--product relationship between IDL-apo B and LDL-apo B in heterozygous or homozygous patients. These findings provide no support for the hypothesis that apo B synthesis is controlled by the plasma LDL.

Apolipoproteins↗