Biomedical subjects

J Davignon

Publications and source records attributed to J Davignon.

At least 109 records · Page 6Linked to original sources

PubMed1994

Response to HMG CoA reductase inhibitors in heterozygous familial hypercholesterolemia due to the 10-kb deletion ("French Canadian mutation") of the LDL receptor gene.

The 10-kb deletion ("French Canadian mutation") of the low-density lipoprotein (LDL) receptor gene is the most common mutation causing familial hypercholesterolemia among subjects of French Canadian descent. In affected subjects, it results in a null allele of the LDL receptor gene and provides a unique opportunity to examine single-allele regulation of this gene in humans. We sought to ascertain the response of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase in subjects with the French Canadian mutation of the LDL receptor gene and to correlate this response with biochemical variables and the haplotype of the nondeletion LDL receptor allele. The prevalence of non-responders to high doses of HMG CoA reductase inhibitors (defined as < 15% decrease in LDL cholesterol [LDL-C] from baseline values after dietary intervention) was ascertained in 105 patients heterozygous for the 10-kb deletion after excluding first-degree relatives and those on combined lipid-lowering therapy or other lipid-lowering agents. Lipoprotein cholesterol levels were examined after a diet period (30% calories as fat) and after receiving HMG CoA reductase inhibitors as mono-therapy for a minimum of 3 months. The mean reduction in total cholesterol was 45 +/- 23%, in LDL-C 33 +/- 15%, and in triglycerides 32 +/- 49% (all P < .005). There was a slight increase in high-density lipoprotein cholesterol of 8.5 +/- 18% (P > .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1993

Familial hypercholesterolemia in French-Canadians: taking advantage of the presence of a "founder effect".

The frequency of familial hypercholesterolemia (FH) in the Province of Quebec is twice that observed in most population samples. In the French-Canadian population, 5 mutations in the low density lipoprotein (LDL) receptor gene account for 76% of FH cases diagnosed using clinical and biochemical criteria. One of these mutations, a > 10 kilobase (kb) deletion at the 5' end of the gene involving the promoter and exon 1, is present in 60% of FH patients studied in Montréal. This high frequency is attributable to a "founder effect." Contribution to this founder effect included strategies in 17th century France for the settlement of a small number of pioneers, local incentives for early marriages and large families, and geographic and cultural isolation; these factors also favored endogamy. The > 10 kb deletion is present on only one haplotype in all patients studied so far (homozygotes and heterozygotes), a major advantage for studies relating phenotypic variation to haplotype variation in the normal LDL receptor allele of these hemizygous patients. Indeed, the presence of founder effects facilitates screening, genetic counseling, and treatment. It also confers a number of advantages for research: (1) the search for new causes of FH in the 24% unaccounted for to date; (2) the study of the geographic distribution of mutations and population movements; (3) the identification of gene-gene interactions in the etiology of disease; (4) the evaluation of factors modulating phenotypic expression and search for LDL-lowering genes; and (5) the study of genetic determinants of therapeutic response.

Consanguinity↗

PubMed1993

Apolipoprotein E polymorphism and Alzheimer's disease.

Apolipoprotein E (apoE) is associated with Alzheimer's neurofibrillary tangles and beta-amyloid protein in senile plaques. It also appears to play an important part in the redistribution of lipids that follows deafferentation and neurodegeneration in the brain. The gene for apoE is on chromosome 19, within the genomic region previously associated with late-onset familial Alzheimer's disease (AD). We have studied apoE phenotype expression and the corresponding allele frequencies (epsilon 2, epsilon 3, epsilon 4) in 91 patients with sporadic AD and 74 controls. There was a significant association between epsilon 4 and sporadic AD (epsilon 4 frequency 0.380 in AD and 0.122 in controls, p < 0.01). Analysis of epsilon 4 in whom AD develops this tended to happen earlier in life than in those with epsilon 3 or epsilon 2. The epsilon 4/AD association was more pronounced in women. Octogenarians with AD had an epsilon 4 allele frequency that was 3 times higher than one reported, in a different study, in healthy octogenarians. ApoE may be an important susceptibility factor in the aetiopathology of sporadic AD.

Age Factors↗

PubMed1993

Mutations of low-density-lipoprotein-receptor gene, variation in plasma cholesterol, and expression of coronary heart disease in homozygous familial hypercholesterolaemia.

Variation in plasma-cholesterol concentration and the expression of coronary heart disease in patients with homozygous familial hypercholesterolaemia (FH) is well documented, but the underlying reasons for variation are not clearly defined. Because FH is caused by mutations at the low-density-lipoprotein-gene locus, we compared plasma-cholesterol concentrations in 21 FH homozygotes with either the greater than 10 kb deletion (promoter region and exon 1) (11 subjects) or the exon 3 missense (trp66-->gly) mutation (10 subjects) of the low-density-lipoprotein gene. Subjects with the greater than 10 kb deletion had a higher mean plasma-cholesterol concentration than those with the exon 3 mutations (26.7 vs 16.1 mmol/L; p = 0.000006), and there was no overlap in individual plasma-cholesterol concentrations between subjects in the two groups. Although the frequency of coronary heart disease was similar in the two groups, age-of-onset was earlier in subjects with the greater than 10 kb deletion (p = 0.059). Also, coronary deaths were more frequent (p = 0.044) and occurred at an earlier age (p = 0.009) in subjects with the greater than 10 kb deletion. Our results provide evidence that there is less variation in plasma-cholesterol concentrations among FH homozygotes when they are subdivided into groups according to low-density-lipoprotein-receptor-gene defect. Furthermore, differences in plasma-cholesterol concentrations are reflected in the severity of coronary heart disease expression.

Adolescent↗

PubMed1993

Simvastatin inhibits the oxidation of low-density lipoproteins by activated human monocyte-derived macrophages.

Human monocyte-derived macrophages treated with increasing concentrations of the HMG-CoA reductase inhibitor, simvastatin, showed a dose-dependent decrease in superoxide formation in response to activation by phorbol myristate acetate. As a consequence, they oxidized LDL much less than untreated cells. Addition of exogenous mevalonic acid to simvastatin-treated macrophages restored their ability for superoxide production and for oxidative modification of LDL. These results indicate that simvastatin might prevent atherosclerosis by additional mechanisms besides its hypocholesterolemic activity.

Drug Interactions↗

PubMed1993

Apolipoprotein(a) is present in the triglyceride-rich fraction in type IV hypertriglyceridemia.

This study was designed to quantify the levels of apo(a) and assess their distribution among lipoprotein fractions in type IV hypertriglyceridemia. Plasma density < 1.006 g/mL fraction (VLDL) was obtained by preparative and zonal ultracentrifugation. Apo(a) was detected by immunoblotting with anti-apo(a) antibodies of agarose gel electrophoresed lipoproteins. Apo(a) was consistently found in VLDL in 30 hypertriglyceridemic subjects, but not in 10 normolipidemic or 10 hypercholesterolemic subjects with normal triglyceride levels. Apo(a)B particle concentrations were then measured using a selective 'sandwich' ELISA with anti-apo(a) as the capture antibody and anti-apoB as the detecting antibody. The mean apo(a)B level of VLDL in six hypertriglyceridemic patients was 30% (range 1.3-50%) of the total plasma concentration. Apo(a)-containing particles of both plasma, d < 1.006 g/mL and d > 1.006 g/mL, had the same pre-beta mobility on agarose gel electrophoresis and a similar apparent molecular weight on non-denaturing 2-16% gradient polyacrylamide gel electrophoresis. Fractionation of plasma by zonal ultracentrifugation confirmed the presence of a heterogeneous distribution of apo(a) in hypertriglyceridemic subjects. Apo(a) was present throughout the density range from VLDL to Lp(a). After normalization of plasma triglyceride levels with dietary fish oil, apo(a) was no longer detected in VLDL suggesting that detection of apo(a) in the plasma, d < 1.006 g/mL, density fraction is related to type IV hypertriglyceridemia.

Cholesterol↗

PubMed1993

The response to lovastatin treatment in patients with heterozygous familial hypercholesterolemia is modulated by apolipoprotein E polymorphism.

In a retrospective study, we examined the influence of apolipoprotein (apo) E polymorphism and gender on the response to treatment with 80 mg/d lovastatin in a homogeneous population of patients with familial hypercholesterolemia (FH), most of whom were carriers of the 10-kb deletion of the low-density lipoprotein (LDL) receptor gene. Apo E phenotype distribution among the 189 FH patients was not different from that of a normal population sample. The total and LDL cholesterol (LDL-C) response to lovastatin in the overall group (men and women) was significantly lower in the E4 subset compared with E2 and E3 subsets. This finding is in agreement with trends observed in previous reports. On the other hand, the response of LDL-C to lovastatin was significantly lower in E4 men than in E4 women, whereas the high-density lipoprotein cholesterol (HDL-C) concentration in the E4 group increased significantly more in men than in women, suggesting a role of gender in modulating the response to lovastatin. Hence, apo E polymorphism influenced LDL-C (and HDL-C) response to lovastatin in men, but not in women, revealing the existence of a gene-by-gender interaction. These findings were independent of the nature of the LDL receptor defect. We conclude that male FH patients carrying the epsilon 4 allele respond less efficiently to lovastatin than men carrying the epsilon 3 or epsilon 2 allele or women of any apo E phenotype with respect to decreasing total cholesterol and LDL-C levels, but respond more efficiently with respect to increasing HDL-C levels. The full practical implication of these findings remains to be explored.

Adult↗

PubMed1993

Influence of probucol on enhanced LDL oxidation after fish oil treatment of hypertriglyceridemic patients.

The susceptibility of low-density lipoprotein (LDL) to oxidation was studied in hypertriglyceridemic men (5 with type III and 5 with type IV) at baseline on a low-saturated-fat, low-cholesterol diet, after 6 weeks of dietary supplementation with fish oil (Promega, 12 g/d), and after 6 weeks of fish oil combined with probucol (500 mg BID). The relative content of n-3 polyunsaturated fatty acids in plasma and LDL was increased during the two treatment periods, and a low alpha-tocopherol to n-3 polyunsaturated fatty acids ratio was observed. Plasma thiobarbituric acid-reactive substances (TBARS) levels were unchanged after 6 weeks of fish oil, but the ratio of lipid peroxides to the reduced triglyceride (TG) levels (MDA:TG) was significantly higher (P < .01). Addition of probucol lowered both absolute levels of TBARS (P < .01) and the MDA to TG ratio (P < .001). The susceptibility of LDL to Cu(2+)-catalyzed oxidation was evaluated over a 5-hour time course by determining TBARS formation, free amino group levels, and changes in LDL electrophoretic mobility. TBARS levels that were higher in native LDL (1.019 < d < 1.050 g/mL) after 6 weeks of fish oil than at baseline (P < .01) were reduced 52.3 +/- 11.3% by the addition of probucol (P < .001). With fish oil alone, TBARS production after exposure of LDL to Cu2+ for 5 hours was increased 17.0 +/- 5.8% compared with corresponding baseline values (P < .001), whereas a 64.1 +/- 14.3% reduction from the previous period was observed with fish oil + probucol (P < .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1993

Comparison of the short term efficacy and tolerability of lovastatin and simvastatin in the management of primary hypercholesterolemia.

OBJECTIVES: To compare the safety and efficacy of lovastatin and simvastatin in patients with primary hypercholesterolemia. METHODS: Fourteen Canadian centres participated in this double-blind, randomized, parallel-design study with a six-week screening period, a four-week placebo baseline period and an 18-week active treatment period. Patients were included in the study if their total cholesterol (TC) was at least 6.2 mmol/L and total triglycerides (TG) were 4.0 mmol/L or less at baseline. Half of the patients were in stratum I (TC 6.2 to 7.8 mmol/L at baseline and placebo period) and half in stratum II (TC greater than 7.8 mmol/L). The initial dose of lovastatin or simvastatin (20 and 10 mg/day, respectively) was doubled if the patient's cholesterol was greater than 5.2 mmol/L after six and/or 12 weeks, to a maximum of 80 mg/day lovastatin or 40 mg/day simvastatin. Of 298 randomized patients, two had baseline data only (and were excluded from the efficacy analysis), while 77 were treated with lovastatin and 74 with simvastatin in stratum I, and 72 were on lovastatin and 75 on simvastatin in stratum II. RESULTS: In stratum I, both lovastatin and simvastatin lowered TC (-26.0% in both the lovastatin and simvastatin groups), low density lipoprotein (LDL) cholesterol (-33.4% in lovastatin and -34.4% in simvastatin), TG (-11.4% in lovastatin and -16.2% in simvastatin), apolipoprotein (apo)-B (-24.8% in lovastatin and -26.3% in simvastatin) and the TC:high density lipoprotein (HDL) cholesterol ratio (from 6.65 to 4.73 in lovastatin and from 6.45 to 4.46 in simvastatin), and increased HDL cholesterol (+3.6% in lovastatin and +7.8% in simvastatin) and apo-A1 (+6.3% in lovastatin and +9.0% in simvastatin) with P < 0.001 in all within-group tests except for HDL cholesterol (P < 0.05). Similar results were obtained in stratum II for TC (-30.7% in lovastatin and -30.3% in simvastatin), LDL cholesterol (-37.6% in lovastatin and -36.8% in simvastatin), TG (-21.9% in lovastatin and -16.9% in simvastatin), apo-B (-32.0% in lovastatin and -31.7% in simvastatin), TC:HDL cholesterol ratio (from 8.62 to 5.47 in lovastatin and from 8.96 to 5.77 in simvastatin), HDL cholesterol (+9.7% in lovastatin and +7.5% in simvastatin) and apo-A1 (+7.2% in lovastatin and +8.8% in simvastatin), with P < 0.001 in all within-group tests. Serious adverse events (clinical and laboratory) were reported in four patients in the lovastatin group and three in the simvastatin group. The most reported nonserious adverse effects were gastrointestinal tract (15 patients in the lovastatin group and 16 in the simvastatin group) and musculoskeletal (14 patients in the lovastatin group and 11 in the simvastatin group). Medication was withdrawn in eight patients. CONCLUSIONS: Both lovastatin and simvastatin were found to be effective and well tolerated in each stratum. However, there were no significant differences between lovastatin and simvastatin in the treatment of moderate or severe primary hypercholesterolemia.

Anticholesteremic Agents↗

PubMed1993

Genealogy and regional distribution of lipoprotein lipase deficiency in French-Canadians of Quebec.

Lipoprotein lipase (LPL) deficiency, an autosomal recessive disorder causing chylomicronemia, has a high prevalence in the French-Canadian population of Quebec. The molecular basis of LPL deficiency has been defined, and two major mutations have been shown to have an uneven geographic distribution. Two mutations, one at residue 188 (M-188) and the other at residue 207 (M-207), are described here; they account for 95% of the mutant alleles. The carrier rate of M-188 was highest in western Quebec (1/326) but that of M-207 was much higher in the eastern part of the province (1/85). Genealogical reconstruction has revealed that both mutations were introduced to the French-Canadian population by migrants from France in the seventeenth century. M-188 is likely to have a Scottish ancestor, whereas M-207 appears to be of French origin.

France↗

PubMed1992

Two naturally occurring mutations at the first and second bases of codon aspartic acid 156 in the proposed catalytic triad of human lipoprotein lipase. In vivo evidence that aspartic acid 156 is essential for catalysis.

We are studying naturally occurring mutations in the gene for lipoprotein lipase (LPL) to advance our knowledge about the structure/function relationships for this enzyme. We and others have previously described 11 mutations in human LPL gene and until now none of these directly involves any of the residues in the proposed Asp156-His241-Ser132 catalytic triad. Here we report two separate probands who are deficient in LPL activity and have three different LPL gene haplotypes, suggesting three distinct mutations. Using polymerase chain reaction cloning and DNA sequencing we have identified that proband 1 is a compound heterozygote for a G----A transition at nucleotide 721, resulting in a substitution of asparagine for aspartic acid at residue 156, and a T----A transversion, resulting in a substitution of serine for cysteine at residues 216. Proband 2 is homozygous for an A----G base change at nucleotide 722, leading to a substitution of glycine for aspartic acid at residue 156. The presence of these mutations in the patients and available family members was confirmed by restriction analysis of polymerase chain reaction-amplified DNA. In vitro site-directed mutagenesis and subsequent expression in COS cells have confirmed that all three mutations result in catalytically defective LPL. The two naturally occurring mutations, which both alter the same aspartic acid residue in the proposed Asp156-His241-Ser132 catalytic triad of human LPL, indicate that Asp156 plays a significant role in LPL catalysis. The Cys216----Ser mutation destroys a conserved disulfide bridge that is apparently critical for maintaining LPL structure and function.

Amino Acid Sequence↗

PubMed1992

Phenotypic heterogeneity associated with defective apolipoprotein B-100 and occurrence of the familial hypercholesterolemia phenotype in the absence of an LDL-receptor defect within a Canadian kindred.

Of 163 individuals with a diagnosis of heterozygous familial hypercholesterolemia (FH), only one subject was found to be positive for familial defective apo B-100 (FDB). The eight-member kindred ascertained through this subject who presented with both a clinical phenotype of FH and the FDB apo B-100 (Arg3500----Gln) mutation was studied. Plasma lipid and lipoprotein profiles, apo E phenotypes, apo B gene markers at the 3' hypervariable region and LDL-receptor haplotypes (ApaLI, PvuII, NcoI), were determined, together with LDL-receptor activity on freshly isolated blood lymphocytes. The FDB mutation, present in four relatives, was associated with three different phenotypes: FH and severe hypercholesterolemia, moderate hypercholesterolemia and normolipidemia. The FH phenotype occurred in the absence of any functional LDL-receptor defect. In homozygotes for the absence of the PvuII cutting site who had the apo B mutation, LDL-cholesterol levels were low in the presence of the apo E3/2 phenotype and high in the presence of the apo E4/4 phenotype. None of the major known environmental influences accounted for the wide range of variation in LDL-cholesterol among the affected members. Further observations in the spouse and offspring of the normolipidemic FDB subject confirmed the association of apo E4, the FDB mutation and the PvuII(-/-) genotype with high cholesterol levels. It is concluded that the phenotypic expression of the FDB mutation may vary widely as a function of the genetic environment within a family.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1992

Molecular genetic evidence for a founder effect in familial hypercholesterolemia among French Canadians.

Familial hypercholesterolemia (FH), at a prevalence of about 1 in 200 in the French-Canadian population, is caused by a 10-kb deletion in the low-density lipoprotein (LDL) receptor gene in 60% of French-Canadian FH heterozygotes. We genotyped 159 FH patients who carry this common mutation and 221 healthy French-Canadian controls for five DNA restriction fragment length polymorphisms (RFLPs) of the LDL receptor gene. The allele numbers for four of the five RFLPs differed significantly (P less than 0.001) between FH patients and control subjects. Our results suggest that the 10-kb deletion carrier allele is associated with a single haplotype (called the B haplotype). In a family study including a patient homozygous for the 10-kb deletion, we showed that the B haplotype cosegregates with the deletion in affected members and that the B haplotype is also associated with the normal allele in some members of the family. We identified 15 different haplotypes for the normal allele in 10-kb deletion carrier FH heterozygotes. These results offer strong support, at a molecular level, for the hypothesis of a founder effect for the 10-kb deletion in the French-Canadian population.

Alleles↗

PubMed1992

Acute influence of smoking on platelet behaviour, endothelium and plasma lipids and normalization by aspirin.

This study was conducted to investigate acute effects of smoking on platelet function, endothelial cells and plasma lipids and to follow these parameters after Aspirin ingestion. Twelve fasting smokers each inhaled the smoke of one cigarette. Blood was drawn before and 10 min after smoking. Plasma nicotine, measured by gas chromatography, increased from 13.48 before smoking to 78.41 nM after smoking. Platelet aggregation to thrombin and ADP increased significantly (P less than 0.001). The platelet aggregate ratio decreased from 0.95 to 0.75 (P less than 0.005). Plasma beta-thromboglobulin also increased in post-smoking samples as measured using radioimmunoassay. 'Circulating endothelial cells' increased significantly after smoking (P less than 0.005). Triglycerides decreased (P less than 0.005) in plasma and in the VLDL fraction (P less than 0.05). Both post-smoking plasma free fatty acids and free glycerol increased, respectively, as compared with respective values. Lipase activity ascribable to lipoprotein lipase and hepatic lipase, absent in pre-smoking plasma samples, could be detected in post-smoking plasma without heparin injection. At least 1 week later, the subjects returned to follow an identical protocol except that they had ingested Aspirin (650 mg) 10-14 h before blood sampling. The same parameters were measured before and after smoking the same cigarette. Except for plasma nicotine, all the smoking-induced changes were abolished by ingestion of Aspirin. The results of this study indicate an interrelationship between platelet hyperactivity, endothelial injury and plasma lipids. They also demonstrate an inhibition of the major smoking-induced changes by Aspirin in the presence of high plasma nicotine levels. It is concluded that Aspirin may offset several of the deleterious acute effects of smoking. However, our conclusions cannot be, in any way, extended for long-term effects of both smoking and Aspirin treatment. Based on these data, it is suggested that there may be some links between platelet hyperactivity, endothelium injury and plasma lipids.

Adult↗

PubMed1992

Oxidative modification of lipoprotein(a) and the effect of beta-carotene.

Lipoprotein (a) [Lp(a)] particles isolated and purified from human plasma were found to be oxidatively modified when incubated in vitro with human mononuclear cells or Cu2+. This modification, which involved lipid peroxidation measured as thiobarbituric acid-reactive substances (TBARS), caused marked changes in the structure and biological properties of Lp(a). Relative to native Lp(a), oxidized particles showed decreases of free amino groups, protein fragmentation, increased negative charge, and high aggregation ability. They were taken up and degraded readily by macrophages in vitro, inducing cholesteryl ester accumulation. When apolipoprotein (a) [apo(a)] was clipped off by exposure to dithiothreitol (DTT), the remaining particle was degraded by macrophages at a significantly lower rate. This observation implies that oxidative modification of apo(a) may have an influence on Lp(a) recognition by scavenger receptors of macrophages. Under the same experimental conditions, low-density lipoprotein (LDL) concentrations equal to those of Lp(a) showed a lower susceptibility to oxidation. This was probably due to higher vitamin E (30% more) and beta-carotene (40% more) content compared with Lp(a), when expressed as a function of cholesterol concentration and measured in the same subject. The addition of beta-carotene to Lp(a) in vitro partially protected Lp(a) against oxidation and aggregation. As a result, uptake of oxidized Lp(a) by macrophages decreased markedly. We conclude that Lp(a) particles are prone to oxidation and that the increased risk of coronary artery disease associated with elevated Lp(a) levels may be related in part to their oxidative modification and uptake by macrophages, resulting in the formation of macrophage-derived foam cells.

Adult↗

PubMed1992

Probucol protects lipoprotein (a) against oxidative modification.

Probucol, which decreases cholesterol levels and has antioxidant properties, was administered orally to patients with familial combined hyperlipidemia and high plasma lipoprotein(a) [Lp(a)] levels. The drug had no effect on Lp(a) concentrations after 4 weeks, but was found to be distributed in both Lp(a) and low-density lipoprotein (LDL). Before treatment, in each case LDL and Lp(a) isolated from the same individual were readily oxidized by copper, resulting in increased electrophoretic mobility and enhanced uptake and degradation by macrophages of both lipoproteins. After probucol treatment, both lipoproteins acquired resistance to in vitro oxidation by copper. Furthermore, probucol prevented their enhanced uptake and degradation by the macrophages. It is surmised that oxidized Lp(a) may carry an atherogenic potential that could be opposed by probucol administration.

Adult↗

PubMed1992

ACAT activity in freshly isolated human mononuclear cell homogenates from hyperlipidemic subjects.

Acyl-coenzyme A:cholesterol acyltransferase (ACAT) catalyzes the esterification of cholesterol in human mononuclear cells (MNC). In order to assess the relationship between lipid levels and ACAT activity in circulating MNC, we measured the rate of [14C]oleoyl-CoA incorporation into cholesterol ester in freshly isolated MNC homogenates from hyperlipidemic subjects. Baseline, off-treatment results obtained in 14 hypertriglyceridemic subjects (eight type IV and six type III) and seven subjects with familial hypercholesterolemia (FH) due to the same deletion of greater than 10 kb on the low-density lipoprotein (LDL)-receptor gene were compared with values determined in 12 healthy normolipidemic subjects. The rate of cholesterol esterification was 45 +/- 28 pmol/5 min/mg cell protein in healthy normolipidemic controls. This rate was significantly higher in type IV subjects (84 +/- 52 pmol/5 min/mg cell protein, P less than .05) and FH subjects (67 +/- 25 pmol/5 min/mg cell protein, P less than .05). The values were more dispersed in type III subjects; the mean value for the group (72 +/- 46 pmol/5 min/mg cell protein) was not statistically different from the control. Hypertriglyceridemic patients were then treated with 6 g/d of omega-3 fatty acids. This resulted in a significant reduction in plasma total triglycerides and very-low-density lipoprotein (VLDL)-cholesterol in both type III subjects (-57% and -51%, P less than .05) and type IV subjects (-62% and -62%, P less than .01). The reduction in VLDL concentration was associated with a significantly lower ACAT activity in MNC homogenates from type IV subjects (from 84 +/- 52 to 60 +/- 36 pmol/5 min/mg cell protein, P less than .05), but not from type III hypertriglyceridemic subjects (from 72 +/- 46 to 73 +/- 36 pmol/5 min/mg cell protein). In conclusion, we found that cholesterol esterification in human MNC is elevated in hyperlipidemic subjects and can be decreased with normalization of lipid levels. However, ACAT activity changes occurring with treatment are heterogeneous among hyperlipidemic subjects, suggesting that factors other than plasma lipid level reduction affect ACAT activity in vivo.

Cholesterol↗

PubMed1992

In vivo metabolism of apolipoprotein A-I in a patient with homozygous familial hypercholesterolemia.

Familial hypercholesterolemia (FH), caused by a defect in the low density lipoprotein (LDL) receptor, results in high plasma concentrations of LDL cholesterol due to both overproduction and delayed catabolism of LDL. FH is also associated with significantly lower levels of plasma high density lipoprotein cholesterol and apolipoprotein (apo) A-I in both heterozygous and homozygous patients. However, the metabolic basis of the hypoalphalipoproteinemia in FH has not been elucidated. We investigated the kinetics of apo A-I in a homozygous FH patient and two normal control subjects by using endogenous labeling with a stable isotopically labeled amino acid. Study subjects were administered a primed constant infusion of 13C6-phenylalanine for 12 hours. Apolipoproteins were isolated from plasma drawn at selected time points and analyzed for their isotopic enrichment by gas chromatography-mass spectrometry. The fractional catabolic rate of apo A-I in the FH subject was found to be substantially increased (0.38 day-1) compared with that of the normal subjects (mean, 0.26 day-1). In addition, the apo A-I production rate was decreased in the FH subject (6.5 mg/kg.day-1) compared with the normal subjects (mean, 11.1 mg/kg.day-1). In conclusion, the low levels of high density lipoprotein cholesterol and apo A-I in this homozygous FH patient are due to the combined metabolic defects of increased apo A-I catabolism and decreased apo A-I production.

Apolipoprotein A-I↗