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Biomedical subjects

R McPherson

Publications and source records attributed to R McPherson.

At least 55 records · Page 3Linked to original sources
PubMed1996

Role of Lp A-I and Lp A-I/A-II in cholesteryl ester transfer protein-mediated neutral lipid transfer. Studies in normal subjects and in hypertriglyceridemic patients before and after fenofibrate therapy.

The two major subclasses of HDL contain apo A-I only (Lp A-I) or both apo A-I and apo A-II (Lp A-I/A-II). We have carried out experiments to quantify the participation of Lp A-I and Lp A-I/A-II in the neutral lipid transfer reaction in normal and hypertriglyceridemic subjects. Thirteen hypertriglyceridemic subjects were studied before and after fenofibrate therapy. Fenofibrate treatment resulted in decreases in total cholesterol, triglycerides (TG), and VLDL cholesterol of 19%, 48%, and 70%, respectively, and a 28% increase in HDL cholesterol, with no significant change in the proportion of Lp A-I and Lp A-I/A-II particles. The abundance of cholesteryl ester transfer protein (CETP) mRNA in peripheral adipose tissue decreased with treatment in four of five patients studied; however, no change occurred in plasma CETP mass. Using an isotopic transfer assay, we demonstrated that both Lp A-I and Lp A-I/A-II participated in the CE transfer reaction, with no change after fenofibrate therapy. This finding suggests that the marked increase in HDL cholesterol during fenofibrate therapy is due to normalization of plasma TG and hence decreased opportunity for mass transfer of lipid between HDL and TG-rich proteins in vivo. In this population of hypertriglyceridemic subjects, CETP was distributed in both the Lp A-I and Lp A-I/A-II subfractions of HDL, with preferential association with the smaller Lp A-I poor. In contrast, in nine normal subjects studied, negligible amounts of CETP were associated with Lp A-I/A-II. Nonetheless, the Lp A-I/A-II fraction of HDL contributed significantly to total CE mass transfer in normolipidemic plasma. Lp A-I/A-II is an efficient donor for CE transfer to TG-rich lipoproteins, and its low affinity for CETP may in fact facilitate neutral lipid transfer either by a shuttle mechanism or by formation of a ternary complex.

Adult↗
PubMed1996

Analysis of cholesteryl ester transfer activity in adipose tissue.

Transfer of cholesteryl ester (CE) between lipoproteins is mediated by a plasma glycoprotein called cholesteryl ester transfer protein (CETP) which plays an important role in reverse cholesterol transport between peripheral tissues and the liver. Adipose tissue is a major site of cholesterol storage and lipoprotein interactions. CE transfer activity in cultured adipose tissue from several species was analyzed by using a CE transfer assay in vitro. Significant amounts of CE transfer activity were detected in conditioned media of cultured adipose tissues from human, hamster and transgenic mice expressing CETP. The amount of CE transfer activity released from cultured adipose tissue varied among species and adipose regions. Monoclonal antibodies against human CETP (subclone TP2) inhibited CE transfer activity released from cultured adipose tissue of hamsters and CETP transgenic mice. CE transfer activity was also assayed in the aqueous phase of adipose tissue homogenates. Accumulation of CE transfer activity in the medium was associated with a reciprocal decrease in adipose tissue activity positively correlated to the amount of CETP mass in the conditioned medium and the aqueous phase of tissue homogenates from cultured hamster adipose tissue. The results of the present study indicate that the measurement of CE transfer activity in adipose tissue reliably characterizes the secretion and storage of CETP in adipose tissue.

Adipose Tissue↗
PubMed1996

Allelic variation in the gene encoding the cholesteryl ester transfer protein is associated with variation in the plasma concentrations of cholesteryl ester transfer protein.

The cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl esters from high density lipoproteins (HDL) to triglyceride-rich lipoproteins. Mutations that abolish CETP function are associated with very high levels of HDL cholesterol, but the effect of more common allelic variation at this locus is less clear. In this study, we have measured plasma CETP concentration and plasma HDL cholesterol concentrations in 694 individuals from 106 nuclear families. Robust sibling-pair methods indicated linkage between the CETP locus and inter-individual variation in plasma CETP concentrations. Allelic variation at the CETP locus accounted for 20% of the variation in plasma CETP concentration. No relation between allelic variation at the CETP locus and plasma HDL cholesterol levels was detected. These data indicate that polymorphism in the CETP gene confers variation in plasma CETP concentration. However, this degree of variation in CETP function is not systematically associated with variation in plasma HDL-C concentrations.

Alleles↗
PubMed1995

Cholesteryl ester transfer protein (CETP) mRNA abundance in human adipose tissue: relationship to cell size and membrane cholesterol content.

Cholesteryl ester transfer protein (CETP) has a well-defined role in plasma neutral lipid transport. CETP synthesized by human adipose tissue may contribute to the plasma CETP pool. CETP mRNA abundance increases in subcutaneous adipose tissue in response to cholesterol feeding and we have hypothesized that CETP gene expression is regulated by a specific pool of cellular sterol. In the present study, we have quantified CETP mRNA levels in subcutaneous adipose tissue of 10 female subjects using a solution hybridization RNase protection assay. Particulate (membrane cholesterol) and lipid droplet cholesterol (core cholesterol) were determined by gas chromatography. CETP mRNA abundance in these adipose tissue specimens correlated significantly with membrane cholesterol expressed as a fraction of membrane protein (r = 0.67, P = 0.031). There was also a linear relationship between CETP mRNA abundance and membrane cholesterol to core triglyceride ratio (r = 0.77, P = 0.009) and a strong correlation between the percentage of cellular cholesterol in the membrane fraction (ratio of membrane to core cholesterol) and CETP mRNA abundance (r = 0.91, P = 0.0002). In contrast, there was a negative relationship between each of lipid droplet cholesterol and triglyceride and CETP mRNA levels. Human adipose tissue maintained in organ culture for several days was shown to secrete CETP into the culture medium. Incubation with cholesterol-rich chylomicron remnants elicited a dose-dependent increase in both membrane and core cholesterol and a concomitant increase in the level of CETP mRNA. These studies demonstrate that adipose tissue CETP mRNA abundance is a function of membrane cholesterol concentration rather than lipid droplet cholesterol and that CETP mRNA increases with adipocyte cholesterol enrichment via chylomicron remnants. CETP gene expression is highest in small lipid-poor adipocytes, suggesting that CETP synthesized and secreted by adipocytes may have a role in promoting cellular cholesterol accumulation.

Adipose Tissue↗
PubMed1994

Effect of postmenopausal estrogen replacement on plasma Lp(a) lipoprotein concentrations.

BACKGROUND: Women who receive postmenopausal estrogen replacement experience a lower rate of coronary heart disease than women who do not receive these hormones. Evidence suggests that mechanisms in addition to decreases in plasma low-density lipoprotein levels and increases in high-density lipoprotein concentrations are responsible for the apparent beneficial effect of estrogens. Therefore, we studied the effect of estrogen on plasma Lp(a) lipoprotein, newly suggested to be a risk factor for coronary heart disease in postmenopausal women. METHODS: The 31 healthy, normolipidemic subjects received placebo and conjugated equine estrogens (0.625 and 1.25 mg/d) for 3-month periods in a randomized, double-blind, crossover trial. RESULTS: The mean Lp(a) lipoprotein concentration was 20.4 +/- 14.6 mg/dL during placebo treatment; it decreased by 14% (P < .01) with 0.625 mg of conjugated estrogens and by 16% (P < .005) with 1.25 mg. The Lp(a) lipoprotein concentration during placebo treatment was not significantly correlated with the responses to either dose of estrogen. There was no effect of estrogen on the plasma concentration of cholesterol ester transfer protein, suggesting that this protein is not involved in estrogen-induced changes in very-low-density lipoprotein or high-density lipoprotein concentrations and composition. CONCLUSIONS: Estrogen decreases the plasma Lp(a) lipoprotein concentration, which could explain some of the protective effect of estrogen replacement therapy on coronary heart disease.

Carrier Proteins↗
PubMed1994

Comparative efficacy and safety of pravastatin, nicotinic acid and the two combined in patients with hypercholesterolemia.

In a comparative study, 158 patients with type IIa or IIb primary hypercholesterolemia received either placebo, nicotinic acid extended-release capsules (0.5 to 1.0 g twice daily), pravastatin (40 mg at bedtime), or the combination for a short-term, 8-week period. A long-term, 88-week phase followed in which the addition of other lipid-lowering agents was permitted. During the short-term phase, low-density lipoprotein cholesterol levels were lower, in relation to baseline, with nicotinic acid treatment (-21%) than with placebo (P < or = 0.05), with pravastatin (-33%) than with either placebo (p < or = 0.001) or nicotinic acid (p < or = 0.05) and with combination therapy (-49%) than with the other 3 treatments (p < or = 0.05) at all weeks measured. At week 8, high-density lipoprotein cholesterol levels were increased, in relation to placebo, by nicotinic acid treatment (12%; p < or = 0.05), pravastatin therapy (13%; p < or = 0.01) and combination therapy (16%; p < or = 0.01). Adverse events were less frequent in the pravastatin and placebo groups (p < or = 0.05). In comparison with placebo, treatment with nicotinic acid resulted in significant increases in aspartate and alanine aminotransferase. The placebo and pravastatin groups did not differ significantly regarding adverse events or laboratory parameters. Similar results were observed in the long-term phase. Therefore, pravastatin is very effective and well tolerated in the treatment of type IIa or IIb primary hypercholesterolemia, and is superior to nicotinic acid in both efficacy and adverse event profile.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Plasma lipids and cholesterol esterification in Alzheimer's disease.

Eight patients and eight age matched controls were recruited to study parameters related to plasma lipoprotein metabolism in Alzheimer's disease based on previous studies in Down's syndrome (A.G. Lacko et al., Clin. Chim. Acta, 132 (1983) 133). The fractional rate of cholesterol esterification (% cholesterol esterified per hour) was 16% lower in the patient group compared with controls. Correlational analyses of lecithin/cholesterol acyltransferase (LCAT) activity and plasma lipids revealed additional differences between the Alzheimer's patients and control subjects. These data are strikingly similar to those obtained earlier with Down's syndrome patients. These data, combined with analyses of cholesteryl ester transfer protein (CETP) levels, suggest that reverse cholesterol transport in general and CETP activity in particular may be altered in Alzheimer's disease.

Aged↗
PubMed1994

High frequency of mutations in the human lipoprotein lipase gene in pregnancy-induced chylomicronemia: possible association with apolipoprotein E2 isoform.

Partial deficiency in lipolysis usually results in only mild disturbances of lipid levels. However, when this is associated with impairment of the uptake of remnant particles and increased production of triglyceride-rich lipoproteins stimulated by environmental factors such as during normal pregnancy, chylomicronemia may ensue. We have previously reported a patient who had approximately 12% of normal LPL activity and developed severe chylomicronemia during pregnancy (Ma et al. 1993. J. Clin. Invest. 91: 1953-1958). Here we report four new patients with pregnancy-induced chylomicronemia. In the nonpregnant state, these patients had mild to modest elevation of triglyceride levels ranging from 80 to 623 mg/dl (0.9-7.0 mmol/l) but during the third trimester they became severely chylomicronemic with triglyceride levels ranging from 2314 to 14,596 mg/dl (26 to 164 mmol/l). Three of these four patients had partial lipoprotein lipase (LPL) deficiency. The molecular characterization of the LPL gene in these three patients with partial LPL deficiency revealed four novel unpublished mutations. Patient #1 is a compound heterozygote for Leu252Arg and Ala261Thr mutations which are associated with 25% of normal LPL activity. In addition, she has an apoE3/2 genotype. Patient #2 is a heterozygote for a Asn291Ser substitution with 69% of LPL activity and also has an apoE3/2 genotype, while patient #3 is a heterozygote for a Trp382Stop mutation with 54% of normal LPL activity and has an apoE4/2 genotype. The fourth patient (#4) with pregnancy-induced chylomicronemia does not have LPL deficiency and has an apoE3/3 genotype. The previously reported patient (#5) who had 12% of normal LPL activity due to homozygosity for a Ser172Cys mutation also has an E3/3 genotype. Our data suggest that mutations in the LPL gene that cause partial LPL deficiency might be a frequent factor in the pathogenesis of pregnancy-induced chylomicronemia.

Adult↗
PubMed1993

Effects of lovastatin on natural killer cell function and other immunological parameters in man.

Suppression of cholesterol synthesis by 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, such as lovastatin, has been shown to inhibit mitogen stimulated proliferation of natural killer (NK) cells and other lymphocytes in vitro. This effect is only partially overcome by provision of exogenous free or lipoprotein cholesterol but is reversed by mevalonate, suggesting that proliferating lymphocytes have a specific requirement for a nonsterol isoprenoid product of mevalonate. The effect of lovastatin (20 mg bid) on a range of immune function parameters was determined in a randomized, placebo-controlled, double-blind ex vivo study in 52 patients with primary hypercholesterolemia. No significant differences (P < 0.05) were found between lovastatin and placebo groups for basal NK or interleukin-2 (IL-2)-induced cell-mediated cytotoxicity, PHA-stimulated lymphocyte proliferation, or relative numbers of T lymphocytes (CD3+), B lymphocytes (CD19+), total NK cells (CD3-, CD16+, CD56+) and CD57+ NK cells or in immunoglobulin levels after 4 or 8 weeks of treatment. In contrast to previous in vitro data, no statistically or clinically significant changes were observed in any parameter of lymphocyte function in patients treated with lovastatin.

Adult↗
PubMed1993

Cholesteryl ester transfer protein and high density lipoprotein responses to cholesterol feeding in men: relationship to apolipoprotein E genotype.

The apolipoprotein (apo) E isoform is an important determinant of the plasma lipoprotein distribution of apoE and of the metabolism of apoE-containing lipoproteins. We have determined the effects of apoE genotype on the plasma lipoprotein response to cholesterol feeding in 30 young normal male subjects (5 E3/2, 11 E3/3, 14 E4/3) under rigorously controlled dietary conditions. Two diets, differing only in cholesterol content (low cholesterol (LC): 80 mg cholesterol/1000 kcal and high cholesterol (HC): 320 mg cholesterol/1000 kcal), were compared using a random crossover design. At the end of the HC as compared to the LC period, total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and HDL2-C increased by an average of 15%, 21%, 7%, and 23%, respectively, for the three genotype groups combined (P < 0.001 for each). The LDL-C response to dietary cholesterol did not differ among the apoE genotypes. However, the increase in HDL-C varied significantly according to the apoE genotype (E3/2: 0 change, E3/3: +4%, E4/3: +12%; P < 0.05). The plasma cholesteryl ester transfer protein (CETP) response to cholesterol feeding also differed amongst the three apoE genotype groups (E3/2: +37%, E3/3: +18%, E4/3: +9%) (P < 0.05). ApoE genotype has significant and opposite effects on plasma CETP and HDL-C responses to dietary cholesterol in men.

Adipose Tissue↗
PubMed1993

Adipose tissue cholesteryl ester transfer protein mRNA in response to probucol treatment: cholesterol and species dependence.

Probucol treatment results in an increase in plasma concentrations of cholesteryl ester transfer protein (CETP) which may account, in part, for the effects of this agent on plasma concentrations of HDL cholesterol. We have examined the mechanism by which probucol increases plasma CETP and have determined the associated changes in the plasma distribution of high density lipoprotein (HDL) particles. Studies were carried out in nine hypercholesterolemic subjects and five normal volunteers. Probucol treatment resulted in a 31% increase in plasma concentrations of CETP and a 23% decrease in HDL cholesterol (P < 0.01). The plasma concentration of LpA-I decreased by 40% (P < 0.01) whereas no change occurred in the LpA-I/A-II subclass of HDL. Plasma CETP increased significantly by 1 week of therapy and remained stable over 10 to 14 weeks of therapy. In spite of the significant increase in plasma concentrations of CETP, the abundance of CETP mRNA in peripheral adipose tissue decreased markedly (P < 0.001). These results suggested that probucol may alter CETP synthesis in another tissue such as liver or, alternatively, may have other effects on CETP secretion into or catabolism out of the plasma pool. Further studies were carried out in hamsters because, in this species, adipose tissue is a major site and liver is a negligible site for CETP synthesis. Hamsters were fed probucol with or without dietary cholesterol because this species was previously shown to respond to dietary cholesterol with an increase in adipose tissue mRNA levels and in plasma CETP concentrations, thus providing the opportunity to determine whether probucol would alter these parameters independently of the dietary cholesterol effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1992

Analytical and experimental studies on the relationship between Na+, K+, and water uptake during volume increases associated with Fundulus oocyte maturation in vitro.

Oocytes of marine and estuarine teleosts often undergo pronounced volume increases during the maturation phase of development that precedes ovulation and fertilization. To examine the physiological correlates of these volume increases, prematuration follicles of the saltmarsh teleost, Fundulus heteroclitus, were cultured in vitro with a maturation-inducing steroid (17 alpha-hydroxy-20 beta-dihydroprogesterone). Mean follicle volume rose significantly (75%) during a 40-h incubation period. Similar to the situation previously found in vivo, uptake of water by the maturing follicle was responsible for this volume increase in vitro, with the water content increasing from 62% to 78% of the total follicle mass. The follicle contents of two probable osmotic effectors--Na+ and K(+)--also rose, the increase in K+ being twice that of Na+. The influx of K+ even exceeded water uptake, resulting in a net increase in the concentration of this cation. It thus appears that the influx of these cations, in particular K+, is a major cause of the uptake of osmotically obligated water and subsequent volume increase experienced by maturing F. heteroclitus follicles. In a search for operant mechanisms, it was found that follicle hydration, but not maturation, was strictly dependent on external K+ in a concentration-dependent manner. The mechanism by which K+ accumulates in the follicle was insensitive to ouabain, so that a typical Na+, K(+)-ATPase mechanism does not appear to be involved. The ability of external K+ to promote follicle hydration was gradually lost during the maturation process as the oocyte dissociated from the surrounding granulosa cells in preparation for ovulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Role of cholesteryl ester transfer protein in reverse cholesterol transport.

Cholesteryl ester transfer protein (CETP) and apolipoprotein E (apo E) play important roles in reverse cholesterol transport in humans. CETP transfers cholesteryl ester (CE) from high-density lipoprotein (HDL) to other lipoproteins, mainly very low-density lipoprotein (VLDL) remnants, which provide a vehicle for the delivery of HDL-derived CE to the liver via apo E or B/E receptors. Using a sensitive and specific radioimmunoassay, we have demonstrated that plasma concentrations of CETP vary dependent on gender, the concentration and composition of plasma lipoproteins, and dietary cholesterol intake. Plasma CETP appears to increase as an adaptive response to increased peripheral flux of cholesterol. Probucol therapy results in a significant increase in plasma CETP concentration, which may explain, in part, the marked effect of this agent on HDL concentration and composition.

Apolipoproteins E↗
PubMed1990

Distribution and concentration of cholesteryl ester transfer protein in plasma of normolipemic subjects.

A MAb (TP-2) directed against human cholesteryl ester transfer protein (CETP) has been applied to the development of a competitive solid-phase RIA. Experiments with immobilized CETP have shown that upon incubation with plasma or HDL in the presence of Tween (0.05%) apo A-I (but not apo A-II) binds to CETP while TP-2 binding to CETP is concomitantly decreased. With high detergent concentration (0.5% Triton), the interference is eliminated and a specific RIA in which all plasma CETP fractions have the same affinity can be obtained. Plasma levels of CETP, apo A-I, lipids, and lipoproteins were measured in 50 normolipemic, healthy subjects of both sexes. CETP levels varied nearly fourfold with a mean value of 1.7 micrograms/ml. CETP was positively correlated only with apo A-I (r = 0.38) and HDL-triglyceride (r = 0.39). In 29 other normolipemic subjects, where several apolipoproteins were also measured, significant correlations of CETP with apo A-I (0.41), apo E (0.43), and HDL-cholesterol (0.41) were observed, but there was no significant relationship between CETP and either apo A-II, B, or D. In other experiments CETP was shown to be present mostly in HDL3 and VHDL, to display exclusively an alpha 2-electrophoretic migration, and to occur within discrete particles ranging in size from 129 to 154 kD. In conclusion, the association of CETP with apo A-I-containing lipoproteins probably explains the correlation between CETP and apo A-I levels. The relationship between CETP and apo E suggests either a common metabolism or a specific cooperative role in cholesterol ester transport for these proteins.

Adult↗