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Biomedical subjects

A Gaw

Publications and source records attributed to A Gaw.

At least 55 records · Page 3Linked to original sources
PubMed1995

Overproduction of small very low density lipoproteins (Sf 20-60) in moderate hypercholesterolemia: relationships between apolipoprotein B kinetics and plasma lipoproteins.

An analysis of apolipoprotein (apo) B turnovers conducted in subjects with moderate hypercholesterolemia was performed to discover relationships that may exist between apoB kinetic parameters and plasma lipid and lipoprotein levels. A group of 21 subjects with plasma cholesterol in the range 250-300 mg/dl and triglyceride < 265 mg/dl were injected with tracers of 131I-labeled very low density lipoprotein 1 (VLDL1, Sf 60-400) and 125I-labeled VLDL2 (Sf 20-60) prepared by cumulative flotation ultracentrifugation. The metabolism of apoB in these fractions was followed through intermediate density (IDL, Sf 12-20) to low density (LDL, Sf 0-12) lipoprotein. The most consistent feature giving rise to the higher apoB levels that occurred in VLDL2, IDL, and LDL in the hypercholesterolemic group was increased input of VLDL2 (787 +/- 607 (SD) mg/day vs. 349 +/- 213 in normals, P < 0.01). VLDL1 apoB input was variably affected and not significantly different from normal. However, the plasma residence time of this subfraction was increased (0.15 +/- 0.07 days vs. 0.08 +/- 0.03 days in normals, (P < 0.001) due to a decreased fractional rate of direct catabolism. Fractional transfer rates (FTR) down the delipidation cascade and other fractional rates of direct catabolism were, overall, not significantly different from normal. The plasma residence time of VLDL2 apoB and LDL apoB was similar in hypercholesterolemic and normal subjects, while that of IDL apoB was slightly increased. Variation in LDL apoB mass within the hypercholesterolemic group correlated with VLDL1 apoB input (r = 0.58, P = 0.006), the fractional rate of transfer from IDL to LDL (r = 0.61, P = 0.003), and direct LDL input (r = 0.64, P = 0.002). The proportion of LDL apoB mass derived by direct, i.e., VLDL-independent input, varied from 5 to 50% and was inversely correlated with plasma triglyceride (r = -0.53, P = 0.014) and positively with HDL2 (r = 0.66, P = 0.002). In addition, the amount of direct LDL input was related to the amount of VLDL1 removed by direct catabolism (r = 0.53, P = 0.013). The analysis indicated that moderate hypercholesterolemia arose principally from overproduction of small VLDL, while variation in VLDL1 input and the IDL to LDL conversion rate (presumably hepatic lipase-mediated) modulated the extent of the elevation in LDL apoB.

Apolipoproteins B↗
PubMed1995

Development and application of a multicompartmental model to study very low density lipoprotein subfraction metabolism.

A multicompartmental model has been devised to explain apolipoprotein B (apoB) kinetics in very low density lipoprotein subfractions (VLDL1 Sf 60-400 and VLDL2 Sf 20-60), intermediate density (IDL Sf 12-20) and low density lipoproteins (LDL Sf 0-12). Normal and hyperlipemic subjects were given tracer doses of 131I-labeled VLDL1 and 125I-labeled VLDL2 and the metabolism of apoB in VLDL1, VLDL2, IDL, and LDL was followed over a period of 13 days. VLDL1 apoB and VLDL2 apoB clearance curves had an initial shoulder, a rapid decay, and a 'tail' of slowly metabolized lipoprotein. ApoB derived from VLDL1 appeared in IDL over 10-50 h and exhibited bi-exponential decay that was attributed to the presence of two metabolically distinct species. A further compartment was required to explain the observation that a substantial proportion of apoB from VLDL2 appeared and disappeared from the IDL density range faster than apoB derived from VLDL1 delipidation. Both of the more rapidly removed IDL species gave rise to LDL apoB that was also modeled as a heterogeneous entity with two plasma compartments. The final model, which has much in common with previous versions (M. Berman et al. 1978. J. Lipid Res. 19: 38-56), a multi-step delipidation pathway and slowly metabolized remnant compartments in VLDL, incorporates parallel delipidation routes in VLDL2, IDL, and LDL. These parallel pathways linked kinetic heterogeneity in VLDL with that in IDL and LDL.

Apolipoproteins B↗
PubMed1994

Effects of ciprofibrate on LDL metabolism in man.

This study examined the effects of ciprofibrate therapy (100 mg/day) on plasma lipids, lipoproteins and low density lipoprotein (LDL) kinetic heterogeneity in moderately hypercholesterolaemic subjects. The drug lowered plasma triglyceride and cholesterol by 41% and 17%, respectively. Very low density lipoprotein (VLDL) cholesterol fell by 38%, LDL cholesterol fell by 22%, while the content of the lipid in high density lipoprotein (HDL) increased by 11%. LDL structural and metabolic heterogeneity were assessed before and during therapy in eight subjects. Density gradient centrifugation was used to fractionate LDL into three species. LDL-I, the least dense, was not affected by therapy whereas LDL-II and LDL-III were decreased by 28% (P < 0.01) and 31% (N.S.). Baseline turnover studies revealed that LDL catabolism was subnormal and this was the cause of the raised cholesterol in these subjects. Ciprofibrate therapy increased the apoLDL fractional catabolic rate (FCR) by 19%, principally by inducing a 38% enhancement (P < 0.03) in apoLDL removal by the receptor pathway. ApoLDL kinetics exhibited metabolic heterogeneity both before and during drug therapy. Analysis of plasma decay curves for the LDL tracer and urinary excretion data indicated that the lipoprotein comprised two metabolically distinct species, one with an FCR of about 0.50 pools/day (Pool A), the other with an FCR of about 0.18 pools/day (Pool B). Drug therapy decreased synthesis of and hence reduced the plasma mass of apoLDL in the slow metabolised pool B. This perturbation in synthesis was linked to the change in plasma triglyceride concentration. The resultant reduced proportion of pool B vs. pool A material accounted for the observed promotion of LDL receptor-mediated clearance. Ciprofibrate, therefore, produced beneficial changes in the plasma levels of VLDL, LDL and HDL and in the metabolism of LDL.

Adult↗
PubMed1994

Molecular genetics of lipoprotein (a): new pieces to the puzzle.

Important advances have been made in the past year in our understanding of the genetics of lipoprotein (a) [Lp(a)]. The apolipoprotein (a) [APO(a)] gene has been cloned and mice have been engineered to express apo(a) and Lp(a). These developments have provided the tools to answer many fundamental questions concerning the genetics, metabolism, and atherogenicity of Lp(a).

Animals↗
PubMed1994

Comparative analysis of the apo(a) gene, apo(a) glycoprotein, and plasma concentrations of Lp(a) in three ethnic groups. Evidence for no common "null" allele at the apo(a) locus.

Distributions of plasma lipoprotein(a) (Lp[a]) concentrations exhibit marked interracial differences. Apolipoprotein(a) (apo[a]), the unique constituent of Lp(a), is highly polymorphic in length due to allelic variations in the number of kringle 4(K-4)-encoding sequences. Plasma Lp(a) concentrations are inversely related to the number of K-4 repeats in the apo(a) alleles. To determine the contribution of this length variation to the interracial variation in plasma Lp(a) levels, we compared apo(a) allele size, glycoprotein size, and plasma Lp(a) concentrations in Caucasians, Chinese, and African Americans. Caucasians and African Americans had very different distributions of plasma Lp(a) concentrations yet there was no significant difference in the overall frequency distributions of their apo(a) alleles. Over the entire size spectrum of apo(a) alleles, the plasma Lp(a) levels were higher in African Americans than in Caucasians. Conversely, Caucasians and Chinese had similar plasma Lp(a) concentrations but significantly different apo(a) allele size distributions. Therefore, interracial differences in the plasma concentrations of Lp(a) are not due to differences in the frequency distributions of apo(a) alleles. We also examined the relationship between apo(a) allele size and the presence of detectable plasma apo(a) protein in plasma. Apo(a) alleles associated with no detectable plasma protein were not of uniformly large size, as had been expected, but were distributed over the entire size spectrum. From this analysis, we conclude that there is no common "null" allele at the apo(a) locus.

Alleles↗
PubMed1993

Effects of simvastatin on apoB metabolism and LDL subfraction distribution.

Seven moderately hypercholesterolemic subjects were studied before and after 10 weeks of simvastatin therapy (20 mg/day). Therapy reduced low density lipoprotein (LDL) cholesterol by 39% (p < 0.001), whereas high density lipoprotein and very low density lipoprotein (VLDL) cholesterol were unchanged. Apolipoprotein (apo) B-containing lipoproteins were divided into VLDL1 (Sf 60-400), VLDL2 (Sf 20-60), intermediate density lipoprotein (IDL) (Sf 12-20), and LDL (Sf 0-12), and metabolic changes were sought in dual-tracer VLDL1 and VLDL2 turnover studies. VLDL1 apoB pool size was unaltered by therapy, as were its rates of synthesis, catabolism, and delipidation to VLDL2. Similarly, the VLDL2 apoB pool size was unchanged, but its metabolic fate was altered. The IDL pool size fell significantly (27%, p < 0.01) due entirely to an increased fractional catabolism of the lipoprotein. In our subjects, the circulating mass of LDL apoB decreased (49%, p < 0.01) primarily due to a reduction in its synthesis. Before therapy, 30% of the apoB entering the delipidation cascade in these hyperlipidemic subjects was converted to LDL. On therapy the input remained the same, but direct catabolism from VLDL2 and IDL was increased (p < 0.05), and as a result only 16% eventually appeared in LDL. These kinetic changes were associated with a fall in particle cholesteryl ester content throughout the delipidation cascade. We also observed a link between LDL kinetics and its subfraction distribution. Simvastatin influences the metabolism of LDL, IDL, and VLDL2 but not VLDL1.

Adult↗
PubMed1993

Fenofibrate and LDL metabolic heterogeneity in hypercholesterolemia.

Metabolic heterogeneity in low density lipoprotein (LDL) may be detected by examination of the daily urinary excretion rate of radioactivity after injection of trace-labeled lipoprotein. Two distinct pools are observed within LDL. The first (pool A) is cleared rapidly from the plasma, whereas the second (pool B) is catabolized more slowly. In the present study we examined LDL metabolism in seven hypercholesterolemic subjects (six women and one man) before and during fenofibrate therapy. Comparison with normocholesterolemic individuals showed that the pretreatment high LDL levels in the hypercholesterolemic subjects resulted from an accumulation of apoprotein-LDL (apo-LDL) mass in pool B (2,077 +/- 174 mg versus 787 +/- 70 mg in normal subjects, p < 0.002). Pool A apo-LDL was present at normal levels (approximately 1,000 mg), although its fractional catabolic rate was reduced (0.39 +/- 0.06 versus 0.61 +/- 0.03 pool/day in normal subjects, p < 0.01). Fenofibrate therapy (100 mg t.i.d. for 8 weeks) produced substantial reductions in plasma cholesterol (29%; p < 0.001), triglycerides (36%; p < 0.001), and LDL cholesterol (30%; p < 0.001). The latter was associated with a 30% decrease in circulating apo-LDL mass (2,312 +/- 200 mg versus 3,279 +/- 264 mg before treatment, p < 0.005). This resulted from a combination of two effects. First, although overall LDL apoprotein B production did not change, there was a shift from pool B to pool A. Pool A input was 400 +/- 74 mg/day pretreatment versus 706 +/- 62 mg/day on fenofibrate; pool B input was 422 +/- 35 mg/day pretreatment versus 258 +/- 41 mg/day on the drug. At the same time, catabolism of pool A rose from 0.39 +/- 0.06 to 0.66 +/- 0.08 pool/day (p < 0.05). We hypothesize that the shift from pool B to pool A resulted from a drug-induced decrease in the particle size of very low density lipoprotein made by the liver, which in turn favored the formation of more rapidly catabolized LDL. Overall, the rate of apo-LDL degradation by the receptor route (as detected using a combination of native and 1,2-cyclohexanedione-modified LDL tracers) rose 43% on the drug, whereas the amount cleared by the receptor-independent pathway did not change. Fenofibrate, therefore, appears not only to promote LDL catabolism via the receptor-mediated pathway but also, by lowering plasma triglyceride levels, inhibits the formation of slowly metabolized, potentially atherogenic LDL particles.

Aged↗
PubMed1993

Thyroid replacement therapy and its influence on postheparin plasma lipases and apolipoprotein-B metabolism in hypothyroidism.

T4 replacement at 150 micrograms/day in a group of six hypothyroid subjects led to the development of a euthyroid state and produced a fall in the cholesterol content of plasma and low and high density lipoproteins (LDL and HDL). The effect of T4 on apolipoprotein-B (apoB) metabolism was followed using radioiodinated very low density lipoprotein1 (VLDL1; 60-400 Svedberg units) and VLDL2 (20-60 Svedberg units). The pretreatment plasma concentration of VLDL1 apoB and its rates of synthesis and catabolism were similar to those in normal subjects. VLDL2 apoB was synthesized at a supranormal rate in hypothyroid subjects, and this led to a doubling of its circulating mass. Treatment did not significantly alter the kinetics of apoB in either VLDL1 or VLDL2. The concentration of intermediate density lipoprotein (IDL) apoB in untreated hypothyroids was 170% of normal and fell during T4 treatment due to stimulation of conversion of LDL (from 0.46 +/- 0.14 to 0.91 +/- 0.30 pools/day; mean +/- SD; P < 0.01). Direct IDL apoB clearance was not altered by treatment, whereas the fractional catabolic rate of LDL increased 76% (from 0.17 +/- 0.06 to 0.27 +/- 0.07 pools/day), leading to a 36% decrement in LDL mass. The stimulation of IDL to LDL conversion during therapy was probably due to a 3-fold increase in hepatic lipase activity (P < 0.02). This change together with the known effects of T4 on LDL receptors largely explained the lipoprotein abnormality in hypothyroidism and the effects of replacement therapy.

Adult↗
PubMed1993

Metabolism of apoB-100-containing lipoproteins in familial hyperchylomicronemia.

The metabolism of apolipoprotein B-100 was studied in three patients with familial hyperchylomicronemia (type I hyperlipoproteinemia) using a very low density lipoprotein (VLDL) dual-tracer technique. Radioiodinated VLDL1 (Sf 60-400) and VLDL2 (Sf 20-60) were injected and their catabolism and rate of the transfer of apoB into VLDL2, intermediate density lipoprotein (IDL) (Sf 12-20), and low density lipoprotein (LDL) (Sf 0-12) were compared in patients and in five normolipidemic controls. The rates of delipidation of large triglyceride-rich VLDL1 to VLDL2 (0.26-0.54 pools/day vs. 2.5-5.2 pools/day in controls) and VLDL1 direct catabolism (0.33-0.92 pools/day vs. 4.2-14.7 pools/day in controls) were found to be significantly reduced in type I patients resulting in a tenfold increase of VLDL1 pool size. ApoB synthesis into this density interval was, however, normal as was that into smaller VLDL2. the circulating apoB mass in VLDL2 was not increased. In fact, apart from a modest decrease in the rate of VLDL2 delipidation to IDL and LDL, the behavior of apoB in this density interval was similar in hyperchylomicronemic and normal subjects. Likewise, the transfer of apoB through the IDL and LDL density ranges was not significantly different from normal. Pool sizes of these fractions, however, were reduced, the latter significantly (354-491 mg vs. 1,160-2,505 mg in controls) due to increased direct catabolism in hyperchylomicronemic patients. The results of this study indicate that lipoprotein lipase deficiency primarily affects VLDL1 metabolism, both its delipidation and direct removal from plasma. Lipolysis further down the delipidation cascade is not dependent on this enzyme. Hypercatabolism rather than a failure of synthesis of IDL and LDL was responsible for the decreased pools for both lipoproteins.

Adult↗
PubMed1992

Effects of cholestyramine and acipimox on subfractions of plasma low density lipoprotein. Studies in normolipidaemic and hypercholesterolaemic subjects.

Two independent studies were designed to investigate the separate and combined effects of acipimox and cholestyramine on plasma low density lipoprotein subfractions. In the first study, normolipidaemic subjects were given cholestyramine (16 g day-1, 4 weeks), followed, after an 8-week wash-out period, by acipimox (750mg day-1, 4 weeks). In the second study, moderately hypercholesterolaemic subjects were prescribed acipimox (1250mg day-1, 10 weeks), followed by acipimox in combination with low dose cholestyramine (12g day-1) for a further 10 weeks. In the normal subjects, cholestyramine decreased total LDL mass (density (d) = 1.019-1.063g ml-1) by selectively reducing the largest, least dense LDL-I (d 1.025-1.034 g ml-1, P less than 0.05) and LDL-II (d 1.034-1.044 g ml-1, P less than 0.005) subfractions. The small, dense LDL-III (d 1.044-1060 g ml-1) showed a variable response to the resin. In the same subjects acipimox produced no overall change in total LDL mass but showed a tendency to redistribute LDL towards LDL-I (+10%) and LDL-II (+10%) in a manner related to the changes in plasma triglyceride (TG) (TG vs. LDL-III r = 0.75, P less than 0.05). In the hypercholesterolaemic subjects acipimox induced a substantial redistribution of LDL subfractions (LDL-I +84% P less than 0.05; LDL-III -50%) without affecting total LDL mass. The addition of cholestyramine produced a significant decrease in total LDL mass which was again confined to the LDL-I (-28%) and LDL-II (-23%) subfractions.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Acipimox in combination with low dose cholestyramine for the treatment of type II hyperlipidaemia.

1. This study was designed to examine the effects of acipimox 250 mg three times daily and cholestyramine 4 g three times daily on plasma lipids and lipoproteins in 28 hypercholesterolaemic individuals in a prospective double-blind placebo controlled parallel group fashion. 2. Combined treatment with the two agents produced a mean reduction of 27% in plasma total cholesterol and a 32% fall in LDL cholesterol. Plasma triglyceride was reduced by 13% due to a 38% decrement in VLDL cholesterol. 3. In comparison treatment with cholestyramine alone resulted in a 12% fall in plasma cholesterol and a 15% fall in LDL cholesterol. In this group triglycerides and VLDL showed no significant change. 4. Studies of HDL subfraction mass showed that the addition of acipimox to resin therapy produced a mean increment of 45% in HDL2. 5. These results demonstrate the effectiveness of such a well tolerated low dosage combination therapy.

Cholesterol↗
PubMedDate not supplied

Setting up a helpline on heart disease.

This article describes how the first nurse-led national telephone helpline for the prevention of coronary heart disease (CHD) was set up and presents the results after the first year of operation. The free service was well received. Most callers were seeking advice on CHD prevention for the first time and traditional risk factors and general healthy lifestyle advice remained major areas of concern.

Adult↗