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Biomedical subjects

N H Fidge

Publications and source records attributed to N H Fidge.

At least 55 records · Page 3Linked to original sources
PubMed1982

Changes in the plasma lipoprotein distribution of apolipoproteins C-II, C-III1, C-III2 and apolipoprotein B after heparin-induced lipolysis.

The group of C apolipoproteins are involved in the catabolism of triacylglycerol-rich lipoproteins, C-II activating triacyglycerol lipolysis and C-III possibly preventing premature removal of the particle. In normal subjects, C-II, C-III1 and C-III2 exchange between very low density (VLDL) and high density lipoprotein (HDL) at similar rates and catabolism appears to occur with HDL. In the present studies in one normal and in four subjects with moderate-to-severe hypertriglyceridemia, the metabolism of the C apolipoproteins was studied before and during maximal lipolysis induced with heparin. Radioiodinated triacylglycerol-rich lipoproteins were injected and the specific activity-time curves for C-II, C-III1, C-III2 and B proteins were analyzed in triacylglycerol-rich lipoproteins and HDL. Heparin infusion caused rapid and proportional transfer of each C apolipoprotein from triacylglycerol-rich lipoproteins to HDL. In the two most hyperlipemic men, a substantial fraction (over 90%) of apolipoprotein C mass lost from triacylglycerol-rich lipoproteins was not recoverable in HDL, whereas in the normal subject this was less than 15% and intermediate in the other two hypertriglyceridemic men. This indicates a new potential catabolic pathway for C apolipoproteins, direct loss from the circulation during remnant particle removal, which was also evident from B apolipoprotein studies. Furthermore, unlike in the normal subject transfer of C apolipoprotein radioactivity from triacylglycerol-rich lipoproteins to HDL was greater than that of mass, also suggesting heterogeneity in C apolipoprotein catabolism. The studies show that C apolipoprotein metabolism may be disturbed in severely hypertriglyceridemic subjects: the lack of conservation of these proteins within HDL may exacerbate the degree of hyperlipoproteinemia.

Adult↗
PubMed1982

Specific, saturable binding and uptake of rat chylomicron remnants by rat skin fibroblasts.

To investigate the possible contribution of chylomicron remnants to the accumulation of cholesterol in non-hepatic tissues, rat chylomicron remnants were incubated with rat skin fibroblasts. The binding of remnants was saturable and specific. Native, undegraded chylomicrons were almost as effective as unlabeled remnants in displacing the uptake of labeled remnants. Rat low density and high density lipoproteins were relatively ineffective in displacing the uptake of labeled remnants. Accumulation of radioactive unesterified fatty acids occurred in proportion to the uptake of labeled remnants, indicating probable internalization and degradation of the particles after binding. The incorporation of added [14C]acetate into cell non-saponifiable lipids was not significantly suppressed by added remnants, indicating an apparent lack of feedback regulation of cholesterol biosynthesis after remnant uptake. Our results show that the physiological mechanism underlying uptake of remnants by hepatic parenchymal cells might not be accounted for by tissue or cellular specificity, but may perhaps arise because of the lower capillary permeability of extra-hepatic sites compared with the hepatic sinusoid.

Animals↗
PubMed1981

Studies on the apoproteins of rat lymph chylomicrons: characterization and metabolism of a new chylomicron-associated apoprotein.

The apoprotein composition of rat lymph chylomicrons and very low density lipoprotein (VLDL) was investigated following isolation and purification by preparative gel electrophoresis. The medium molecular weight apoproteins in the 27,000-60,000 range were characterized by electrophoretic mobility, immunochemical identification, amino acid composition, and molecular weight determination. In addition to three previously identified apoproteins, A-I, E, and A-IV, present in both rat serum high density lipoproteins (HDL) and lymph chylomicrons, a fourth peptide of molecular weight 59,000 was always a consistent major component of lymph VLDL washed free of serum protein contaminants by repeated ultracentrifugation. The protein formed complexes with phosphatidylcholine vesicles, was amphipathic in nature, and, when injected into rats, became associated with serum HDL and lymph chylomicrons. It was removed from chylomicrons after gel filtration through agarose columns but not after repeated ultracentrifugation; it differed slightly in amino acid composition and did not show immunochemical identity against antisera to any other apoprotein. The results of in vivo studies suggest that the protein preferentially associates with lymph chylomicrons and thus may play some important role in the metabolism of exogenous triglyceride transport. Since A-I, A-II, and A-IV apoproteins are also integral components of lymph chylomicrons, we suggest that the protein be designated A-V apoprotein. The distribution of A-I, E, A-IV, and A-V in serum HDL and lymph VLDL was approximately 54, 10, 12, and 0%, and 22, 3, 19, and 22%, prospectively.

Amino Acids↗
PubMed1981

Metabolism of C-apolipoproteins: kinetics of C-II, C-III1 and C-III2, and VLDL-apolipoprotein B in normal and hyperlipoproteinemic subjects.

The turnover and metabolism of the individual C apolipoproteins (C-II, C-III1, and C-III2) were studied following the injection of 125I-labeled VLDL into 15 normal and hyperlipoproteinemic subjects. The C apolipoproteins from very low density lipoprotein (VLDL) and high density lipoprotein (HDL) were separated by analytical isoelectric focusing, and subsequent densitometric scanning and radioassay of the stained bands yielded values for specific activity. In 13 of 15 subjects, kinetics of C-II, C-III1, and C-III2 were best described by a one-pool model, whereas two subjects showed biexponential kinetics. The specific activity-time curves for VLDL and HDL were super-imposable, indicating rapid exchange of all C apolipoproteins in hyperlipidemic as well as in normal subjects. In each subject the half-life was similar for C-II, C-III1, and C-III2, which suggests similar synthesis and catabolic mechanisms for each C apolipoprotein. The mass of exchangeable C-II (range 1.0-5.8 mg/kg), C-III1 (2.6-20 mg/kg), and C-III2 (2.0-13 mg/kg) increased with plasma triglyceride concentrations. Values for flux of C-II were 1.0-2.8 mg/d per kg, for C-III1 1.6-5.6 mg/d per kg, and for C-III2 1.2-3.1 mg/d per kg, but they were not related to levels of plasma triglyceride. However the irreversible fractional catabolic rates were inversely related to C apolipoprotein (and triglyceride) mass, suggesting that expansion in C apolipoprotein pool size is related to slower removal, due to the longer residence time of triglyceride-rich VLDL particles in plasma. This was confirmed by similar findings for B apolipoprotein kinetics in VLDL carried out simultaneously.

Adult↗
PubMed1980

The redistribution and metabolism of iodinated apolipoprotein A-IV in rats.

The metabolic fate of 125I-labeled apolipoprotein A-IV has been studied in rats. This was achieved by incorporating labeled apolipoprotein A-IV into lymph chylomicrons and plasma high density lipoprotein by in vitro exchange or by association, in vivo of apolipoprotein A-IV with plasma chylomicrons and high density lipoprotein following injection of 125I-labelled apolipoprotein A-IV into fat-fed rats. After separating lipoprotein-bound from unbound apolipoprotein A-IV, the interrelationship of apolipoprotein A-IV between lipoproteins was studied by administering 125I-labeled apolipoprotein A-IV/lipoproteins into rats and bleeding at various times thereafter. Apolipoprotein A-IV was rapidly removed from chylomicrons and transferred into high density lipoprotein and lipoprotein-free fractions. The time course of transfer, measured both as absolute radioactivity and as specific radioactivity was consistent with a precursor-product relationship between apolipoprotein A-IV in the lipoprotein-free fraction and high density lipoprotein, suggesting that the rapid transfer of apolipoprotein A-IV from chylomicrons into the lipoprotein-free form precedes transfer into the high density lipoprotein fraction. Since it could be demonstrated by electroimmunoassay that approximately half the total apolipoprotein A-IV in rat plasma was not associated with lipoproteins, it is concluded that a pool of lipoprotein-free apolipoprotein A-IV exists which may have an important physiological role in the lipoprotein transport system.

Animals↗
PubMed1980

Increased catabolism of high density lipoprotein in alcoholic hepatitis.

The kinetics of high density lipoprotein apoprotein A-I were determined in three subjects with severe alcoholic hepatitis. Lipoprotein was obtained from three healthy subjects, radioiodinated, and injected into the patients and the donors. The catabolic rate of A-I was two to four times higher in the patients compared to a group of 18 control subjects studied previously. In the patients only, about 20% of the radiolabeled apoproteins rapidly appeared in the lipoprotein-poor fraction of plasma, which also contained substantial amounts of unlabeled A-I. The findings show that the reduced concentration of A-I in alcoholic hepatitis (less than half-normal), is due not to diminished synthesis (synthesis was normal) but to rapid degradation. This may reflect disruption of abnormal high density lipoproteins due to lack of cofactors.

Adult↗
PubMed1979

Marked increase in high density lipoproteins in mountaineers.

Apoprotein-AI concentrations were measured in whole blood in 13 male mountaineers before, during and after a strenuous climb of 8 weeks' duration. The AI concentration almost doubled in 3 weeks and remained elevated at that level for the full period of the climb. This study demonstrates the rapid rate at which high density lipoproteins can rise and the very high levels (148 +/- 29 mg/dl in whole blood) that can be reached. The rise can be attributed at least in part to exercise though other factors such as exposure to cold, hypoxia and mental stress might also have contributed.

Adult↗
PubMed1979

Sucrose-induced changes in VLDL- and LDL-B apoprotein removal rates.

Dietary sucrose has been shown to increase triglyceride transport in very-low-density lipoproteins (VLDL), but it is not known whether the metabolism of the entire particle is affected. Measurements were therefore carried out on VLDL-B apoprotein flux and removal rate before and after the consumption of high sucrose diets (55% of calories). Autologous 125I-labeled VLDL were injected and the specific activity-time curves analyzed by two-pool kinetics. Two kinds of response to sucrose were seen. In two subjects, the pool of VLDL-B apoprotein decreased by 20% and 14% (despite increased fluxes) due to substantial increases in removal rates of 42% and 116%. In four subjects, pool size expanded by 154%, 426%, 50% and 105%, primarily as the result of decreased removal rates (decreases of 55%, 67%, 30%, and 43%). Changes in flux were inconstant, suggesting that accumulation of VLDL particles was related to delayed clearance rather than to increased formation. This may reflect the longer time required to remove the larger load of triglyceride from each particle. The catabolic rate of low-density lipoprotein (LDL) was also measured in five subjects: in four, the clearance of LDL increased with sucrose and was associated with decreases in LDL-B apoprotein and plasma cholesterol.

Administration, Oral↗
PubMed1978

Catabolism of very low density lipoprotein B apoprotein in man.

The turnover and the catabolic fate of the B apoprotein of very low density lipoprotein (VLDL-B) was studied in 15 normal and hyperlipidemic subjects using reinjected autologous VLDL labeled with radioiodine. The specific radioactivity-time curve of the B apoprotein in total VLDL (S(f)20-400) was multiexponential but conformed to a two-pool model during the first 48 h of catabolism. The flux was highest in several hypertriglyceridemic subjects. The mass of pool A exceeded the intravascular content of VLDL-B by 30% on average, indicating extravascular metabolism of VLDL. The two-pool model might reflect the input of several populations of particles or heterogeneity of catabolic processes or pools. The flux of B apoprotein was also measured in several subclasses of VLDL, in smaller intermediate density lipoproteins, and in low density lipoproteins (LDL). In three subjects the flux was similar in S(f) 60-400 and in S(f) 12-60 lipoproteins, suggesting that VLDL was catabolized at least to a particle in the density range S(f) 12-60. Subsequent catabolism appeared to proceed by two pathways: in normotriglyceridemic subjects, B apoprotein flux in the S(f) 20-400 and in S(f) 12-20 lipoproteins was similar, whereas in hypertriglyceridemic subjects flux through S(f) 12-20 accounted for only part of the VLDL-B flux. The flux of low density lipoprotein B apoprotein (LDL-B), which is believed to be derived from VLDL catabolism, was calculated from the area between the specific activity time curves of VLDL-B and LDL-B. In subjects with normal plasma triglyceride concentration, LDL-B flux was from 91% to 113% of that of VLDL-B; but in three hypertriglyceridemic subjects showing high rates of VLDL-B transport, LDL-B flux was only one-third that of VLDL-B. This suggests that when VLDL-B flux is high, VLDL is substantially catabolized by a route other than through LDL and possibly leaves the circulation as a particle in the S(f) 20-60 density range.

Adult↗
PubMed1978

Metabolic heterogeneity in the formation of low density lipoprotein from very low density lipoprotein in the rat: evidence for the independent production of a low density lipoprotein subfraction.

The formation of low density lipoprotein (LDL) from very low density lipoprotein (VLDL) was studied after injecting 14C-radiomethylated or 125I-radioiodinated VLDL into rats. VLDL and LDL B apoprotein specific radioactivity time curves were obtained after tetramethylurea extraction of the lipoproteins. In all experiments, the specific activity of LDL B apoprotein did not intercept the VLDL curve at maximal heights, suggesting that not all LDL B apoprotein is derived from VLDL B apoprotein. Further subfractionation of LDL into the Sf 12-20, 5-12, and 0-5 ranges showed that most (65%) LDL B apoprotein was present in the Sf 0-5 fraction and that only a small proportion (6-15%) of this fraction was derived from VLDL. However, the curves obtained for the Sf 12-20 and 5-12 subfractions were consistent with a precursor-product relationship in which all of these fractions were derived entirely from VLDL catabolism. These results contrasted strikingly with similar data obtained for normal humans in which all LDL is derived from VLDL. In the rat, it appears that most of the B apoprotein in the Sf 0-5 range, which contains 65% of the total LDL B apoprotein, enters the plasma independently of VLDL secretion.

Animals↗
PubMed1977

Lipoprotein composition in hypothyroidism.

Sixteen patients with hypothyroidism have had their lipid status assessed before and during replacement therapy. More than 60% had hypercholesterolaemia and more than 60% had hypertriglyceridaemia. Significant reductions in plasma cholesterol, but not in plasma triglyceride, were seen during replacement therapy. A high cholesterol: triglyceride ratio was observed in VLDL and this relationship tended back to normal during treatment. This raises the possibility that in hypothyroidism, as in Type III hyperlipoproteinaemia, an abnormality in VLDL conversion to LDL is present.

Adolescent↗
PubMed1977

The effect of a short term saturated fat diet on the apoprotein composition and radioiodination properties of rat very low density lipoproteins.

The effect of a saturated fat diet on the apoprotein composition and radioiodination properties of plasma very low density lipoprotein (VLDL) was studied in rats. After feeding the diet for 10 days, the proportion of 125I attached to VLDL lipid decreased from 50% (control animals) to 8%, the remainder (92%) being bound to the apoprotein components. The decreased lipid labelling was associated with proportional changes in the fatty acid composition of serum and VLDL lipids, the most notable change being a reduction in linoleic acid (30-8%) content which occurred in all the major lipid classes of both serum and VLDL. Analysis of VLDL after radioiodination showed that most of the radioactivity incorporated into the lipid moiety was associated with phospholipid. The proportion of 125I bound to phospholipid decreased after feeding rats a saturated diet. The proportion of soluble (small molecular weight peptides and arginine rich peptide) to insoluble (B apoprotein) did not alter during the saturated fatty acid dietary regime and no differences in the distribution of soluble proteins were observed. It is concluded that feeding a saturated fat diet to rats for 10 days significantly improved 125I labelling of the apoprotein moiety while apparently not inducing changes in apoprotein composition.

Animals↗
PubMed1976

Characterisation of the small molecular weight apolipoproteins from pig plasma very low density lipoprotein.

The small molecular weight apolipoproteins of pig very low density lipoprotein were investigated following their separation by gel filtration and ion exchange chromatography. Gel filtration through Sephadex G-200 in 6 M urea, produced essentially the same elution profile to that obtained after filtration of human very low density apolipoprotein. However, separation of the pig Sephadex fraction corresponding to human C proteins on DEAE-cellulose columns revealed the presence of only one major peptide and minor quantities of several others. Some properties of three apparent homogeneous fractions and one heterogeneous DEAE fraction were investigated. Unlike human apoprotein CII apoprotein, none of the pig peptides studied activated cow's milk lipase and sialic acid was not detected in any of the three purified C peptides of pig VLDL. The amino acid compositions of the pig peptides were different to those reported for human C apoproteins. The carboxy terminal residue of the major pig C peptide was shown to be serine. The differences so far revealed between pig and human C peptides need further investigation especially since this animal is regarded as a suitable model for investigating human lipoprotein metabolism and the development of atherosclerosis.

Amino Acid Sequence↗
PubMed1975

Purification, properties and kinetics of sheep and human renin substrates.

Sheep plasma renin substrate was purified 1,200-fold by using nephrectomised sheep plasma, followed by DEAE-Sephadex chromatography and gel filtration. The purified substrate contained 8 mu-g angiotensin II/mg protein and had an estimated molecular weight of 52,000. The kinetic characteristics of the purified substrate were identical both to those of unpurified nephrectomised sheep plasma and to normal sheep plasma substrates. At pH 7.5, K-m of the human renin-sheep substrate reaction was 0.29 mu-M and for sheep renin-sheep substrate, 2.0 mu-M. Sheep substrate was susceptible to peptic digestion with generation of pepsitensin. Human renin substrate was less readily purified. DEAE-Sephadex chromatography of plasma from pregnant women at 36-40 weeks' gestation produced a 70-fold increase in purity (0.9 mu-g angiotensin II/mg protein). No further increase was achieved with gel filtration. Human renin substrate behaved as a larger (mol. wt. 82,000) more anionic protein than sheep substrate and was resistant to the proteolytic actions of both pepsin and sheep renin. K-m for the human renin-human substrate reaction was high and could not be accurately determined (range 3-8 mu-M, mean 5.7 mu-M). The presence of human substrate in a human renin-sheep substrate system did not alter the measured initial velocity. In both sheep and man, the normal concentration of renin substrate is considerably less than K-m and must therefore be considered a determinant of angiotensin production rate in vivo.

Angiotensin II↗
PubMed1973

Dependence of rates of lipolysis, esterification, and free fatty acid release in isolated fat cells on age, cell size, and nutritional state.

Rates of lipolysis, esterification, and free fatty acid release were estimated in isolated epididymal fat cells prepared from rats fed either ad lib. or with a restricted caloric intake. Basal and epinephrine- or theophylline-stimulated rates of lipolysis correlated positively with cell size in the ad lib.-fed group only. Rates of esterification, both basal and epinephrine-stimulated, correlated positively with cell size in the ad lib.-fed group but negatively in the caloric-restricted group. These findings indicate that nutritional factors can modify any possible influence of adipose cell size on lipolysis and esterification. On the other hand, in both groups of rats, epinephrine- and theophylline-stimulated rates of lipolysis correlated positively with the basal rates of lipolysis. Also, rates of esterification in the presence of epinephrine correlated positively with the basal rates of esterification, suggesting that stimulated rates of lipolysis and esterification are at least partly determined by the basal rates regardless of nutritional status. The activity of glycerokinase measured in homogenates of isolated fat cells, if applicable to intact fat cells, was sufficient to cause considerable underestimations of the basal rates of lipolysis (using glycerol production as an index). When lipolysis was stimulated, the potential errors of estimating lipolysis by glycerol production alone were negligible.

Adipocytes↗