Biomedical subjects

H B Brewer

Publications and source records attributed to H B Brewer.

At least 73 records · Page 4Linked to original sources

PubMed1995

Increased catabolic rate of low density lipoproteins in humans with cholesteryl ester transfer protein deficiency.

The cholesteryl ester transfer protein (CETP) transfers lipids among lipoprotein particles and plays a central role in lipoprotein metabolism. Humans with genetic deficiency of CETP have both elevated HDL cholesterol and apolipoprotein A-I concentrations as well as decreased LDL cholesterol and apolipoprotein B levels. The present study was undertaken to elucidate the metabolic basis for the decreased LDL cholesterol and apo B levels in CETP deficiency. We conducted a series of in vivo apo B kinetic studies in tow unrelated homozygotes with CETP deficiency and in control subjects. A primed constant infusion of stable isotopically labeled phenylalanine was administered to the two CETP deficient subjects and control subjects and apo B kinetic parameters in VLDL, intermediate density lipoproteins, and LDL were obtained by using a multicompartmental model. The fractional catabolic rates (FCR) of LDL apo B were significantly increased in the CETP-deficient subjects (0.56 and 0.75/d) compared with the controls (mean FCR of 0.39/d). Furthermore, the production rates of apo B in VLDL and intermediate density lipoprotein were decreased by 55% and 81%, respectively, in CETP deficiency compared with the controls. In conclusion, CETP-deficient subjects were demonstrated to have substantially increased catabolic rates of LDL apo B as the primary metabolic basis for the low plasma levels of LDL apo B. This result indicates that the LDL receptor pathway may be up-regulated in CETP deficiency.

Adult↗

PubMed1995

Apolipoprotein E deficiency in mice: gene replacement and prevention of atherosclerosis using adenovirus vectors.

Apolipoprotein E (apoE)-deficient mice develop marked hyperlipidemia as well as atherosclerosis and thus are an excellent animal model for evaluating the potential for gene therapy in human genetic dyslipoproteinemias. Recombinant adenovirus containing either human apoE (rAdv.apoE) or the reporter gene luciferase (rAdv.luc) were generated and infused intravenously in apoE-deficient mice with preinfusion plasma total cholesterol of 644 +/- 149 mg/dl an cholesterol rich VLDL/IDL. After a single infusion of rAdv.apoE, plasma concentrations of human apoE ranging from 1.5 to 650 mg/dl were achieved. Adenovirus-mediated apoE replacement resulted in normalization of the lipid and lipoprotein profile with markedly decreased total cholesterol (103 +/- 18mg/dl), VLDL, IDL, and LDL, as well as increased HDL. Measurement of aortic atherosclerosis 1 mo after adenoviral infusion demonstrated a marked reduction in the mean lesion area of mice infused with rAdv.apoE (58 +/- 8 x 10(3) microns2) when compared with control mice infused with rAdv.luc (161 +/- 10 x 10(3) microns2; P < 0.0001). Thus, apoE expression for 4 wk was sufficient to markedly reduce atherosclerosis, demonstrating the feasibility of gene therapy for correction of genetic hyperlipidemias resulting in atherosclerosis. The combined use of adenovirus vectors and the apoE-deficient mouse represents a new in vivo approach that will permit rapid screening of candidate genes for the prevention of atherosclerosis.

Adenoviridae↗

PubMed1995

Identification of novel differentially expressed hepatic genes in cholesterol-fed rabbits by a non-targeted gene approach.

Several key genes involved in cholesterol metabolism are known to be directly regulated by cholesterol. The possible indirect effect, however, of increased levels of cellular cholesterol on gene expression and its possible role in cholesterol metabolism and atherosclerosis has not been thoroughly explored. In order to determine the overall effect of cholesterol on gene expression, we isolated differentially expressed genes from a PCR-based subtraction library prepared from the liver of chow-fed and cholesterol-fed rabbits. A total of nine upregulated and four down-regulated cDNA fragments were isolated. As determined by Northern blot analysis, the expression of the isolated cDNAs began to change as early as the first week on the cholesterol-rich diet or as late as 4 weeks, which corresponded with hepatic cholesterol accumulation. Three of the cDNAs were identified by DNA sequence homology, whereas the remaining cDNAs had no significant homology match. CYP1A1, a cytochrome P450 isoenzyme, was found to be down-regulated in hepatocytes by cholesterol feeding. Osteopontin and Mac-2, which are produced by macrophages, were found to be up-regulated in Kupffer cells by cholesterol feeding. Overall these results demonstrate the usefulness of the subtraction library approach for identifying new candidate genes for exploring the pathogenesis of atherosclerosis.

Animals↗

PubMed1994

A naturally occurring mutation at the second base of codon asparagine 43 in the proposed N-linked glycosylation site of human lipoprotein lipase: in vivo evidence that asparagine 43 is essential for catalysis and secretion.

The patient was a 20-year-old male. His fasting plasma triglyceride and cholesterol levels were 1258 mg/dl and 138 mg/dl, respectively. The lipoprotein lipase (LPL) activity and mass from postheparin plasma of the patient were 0.00 mumol/ml/h (normal range: 5.51 +/- 1.12) and 23 ng/ml (normal range: 220 +/- 42), respectively. DNA sequence analysis of the LPL gene from the patient revealed a homozygous nucleotide change: a A-->G transition at nucleotide position 383, resulting in an amino acid substitution of Ser for Asn43, which is believed to be an N-linked glycosylation site of the LPL mature protein. Expression studies of this mutant LPL cDNA produced an inactive LPL protein which was not secreted into the media.

Adult↗

PubMed1994

Amyloid-associated proteins alpha 1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer beta-protein into filaments.

The protease inhibitor alpha 1-antichymotrypsin and the lipid transport protein apolipoprotein E (apoE) are intimately associated with the 42-amino-acid beta-peptide (A beta) in the filamentous amyloid deposits of Alzheimer's disease. We report here that these two amyloid-associated proteins serve a strong stimulatory role in the polymerization of A beta into amyloid filaments. Addition of either alpha 1-anti-chymotrypsin or apoE to the A beta peptide promoted a 10- to 20-fold increase in filament formation, with apoE-4, the isoform recently linked to the development of late-onset Alzheimer's disease, showing the highest catalytic activity. These and other experiments suggest that Alzheimer amyloid deposits arise when A beta is induced to form filaments by amyloid-promoting factors (pathological chaperones) expressed in certain brain regions.

Alzheimer Disease↗

PubMed1994

Quantitation of plasma apolipoproteins in the primary and secondary prevention of coronary artery disease.

PURPOSE: To review current knowledge of apolipoprotein quantitation used in the clinical management of persons with or at risk for the development of premature coronary artery disease. DATA SOURCES: The English-language literature was analyzed using MEDLINE (1975 to 1993) with key words "apolipoproteins," "quantitation," and "coronary artery disease." Article bibliographies were also reviewed to obtain additional references. STUDY SELECTION: Published, peer-reviewed retrospective and prospective studies relevant to the association of plasma apolipoprotein levels with coronary artery disease in humans. DATA SYNTHESIS: Most studies concerned apolipoprotein A-I (apo A-I), apolipoprotein B (apo B), and lipoprotein(a) [Lp(a)]. In retrospective cross-sectional studies, apo A-l levels were not substantially more predictive of coronary artery disease than were high-density lipoprotein (HDL) cholesterol levels. In contrast, levels of apo B and Lp(a) were often more strongly associated with coronary artery disease than were traditional lipid measurements. In studies of the relation between apolipoprotein levels in children and premature coronary artery disease in their parents, Lp(a) levels, but not apo A-l and apo B levels, were consistently predictive of familial coronary artery disease. Prospective studies have yielded variable results for all three apolipoproteins. Low apo A-l levels were consistently associated with coronary artery disease in six prospective studies but were not more predictive than HDL levels. Apolipoprotein B levels were strongly associated with coronary artery disease in four of five prospective studies but were more predictive of coronary artery disease than were total cholesterol levels in only two of the four studies. Lipoprotein(a) levels were strongly associated with coronary artery disease in five of seven prospective studies but were not associated in two of the four largest studies. CONCLUSIONS: Too few large prospective studies of apolipoprotein quantitation using validated assay methods, both in general unselected populations and in subgroups of persons with premature coronary artery disease or family histories of premature coronary artery disease, are available to make definitive recommendations concerning clinical utility. The data do not support use of apolipoprotein quantitation as a screening tool to predict coronary artery disease risk in the general population. However, the data suggest that quantitation of apo B and Lp(a) may be indicated in subgroups of persons with premature coronary artery disease or with family histories of premature coronary artery disease. In these persons, an increased apo B or Lp(a) level or both could be a clinical indication for more aggressive treatment of low-density lipoprotein cholesterol.

Apolipoproteins↗

PubMed1994

Lipoprotein lipase: structure, function and mechanism of action.

Lipoprotein lipase (LPL) plays a central role in the hydrolysis of circulating triglycerides present in chylomicrons, and very low density lipoproteins. The active form of the enzyme is a non-covalent homodimer which contains multiple functional domains required for normal hydrolytic activity including a catalytic domain, as well as sites involved in co-factor, heparin and lipid binding. Recent studies involving site-directed mutagenesis, the elucidation of the three dimensional crystallographic structure of different lipases, as well as analysis of the molecular defects that result in the expression of the familial chylomicronemia syndrome have provided new insights into the structure-function relationship of LPL. As a result, our understanding of structural domains involved in catalysis, heparin, lipid binding, and enzyme-cofactor interaction as well as the mechanism of action of LPL as an acylglycerol hydrolase has been greatly enhanced.

Chylomicrons↗

PubMed1994

A comparison of Lp(a) levels in fresh and frozen plasma using ELISAs with either anti-apo(a) or anti-apoB reporting antibodies.

Sandwich ELISAs with an anti-apo(a) trapping antibody and either an anti-apolipoprotein B or anti-apolipoprotein(a) reporting antibody, were used to measure the concentrations of Lp(a) in 230 plasma samples that were either freshly drawn or stored at -20 degrees C for 4-6 weeks. The assays produced significantly different results for the fresh and frozen samples, however, the magnitudes of these differences were small, about 8% higher for the frozen samples, and independent of total cholesterol, HDL cholesterol, triglyceride, apolipoprotein B or Lp(a) concentration or assay configuration. A similar difference was seen for a freshly drawn plasma sample assayed at the time as the fresh and frozen samples, indicating the differences were due to inherent differences in the assays at the times the assays were performed. The assay configuration was an important factor in determining the Lp(a) concentrations for identically treated samples. ELISAs using the apoB reporting antibody yielded concentrations that were significantly less than those determined by ELISAs using the anti-apo(a) reporting antibody. The assay differences did not correlate with total cholesterol, HDL cholesterol, triglyceride, or apoB concentration. However, the magnitude of the difference did correlate well with Lp(a) amount. Low Lp(a) concentrations produced greater assay differences than high Lp(a) concentrations.

Antibodies↗

PubMed1994

Discrimination between RRR- and all-racemic-alpha-tocopherols labeled with deuterium by patients with abetalipoproteinemia.

The ability to discriminate between stereoisomers of alpha-tocopherol was studied in five patients with abetalipoproteinemia (ABL) because an impairment in secretion of apolipoprotein B-containing lipoproteins might impede the normally enhanced plasma transport of RRR-alpha-tocopherol. An oral dose containing 3.7 g of each 2R, 4'R,8'R-alpha-[5-C2H3]tocopheryl acetate (d3RRR-alpha-tocopheryl acetate) and 2RS,4'RS,8'RS-alpha-[5,7-(C2H3)2]tocopheryl acetate (d6 all rac-alpha-tocopheryl acetate) was administered, then the labeled and unlabeled alpha-tocopherol contents of plasma and red blood cells from multiple blood samples obtained at selected times up to 72 h following the dose were quantitated. ABL plasma contained about 1%-10% of the d3-RRR-alpha-tocopherol concentrations of normal subjects given only 150 mg of each isotope. Three of the patients discriminated between forms of alpha-tocopherol with ratios of RRR-/allrac-alpha-tocopherol > or = 1.8, similar to normals. These data suggest that the hepatic tocopherol binding protein is present and functional in ABL patients. Although two of the patients did not discriminate between stereoisomers of alpha-tocopherol, it is likely that this resulted from nearly a complete block in very low density lipoprotein (VLDL) secretion. Thus, the ability of ABL patients to absorb and transport orally administered vitamin E is markedly impaired and variable among patients.

Abetalipoproteinemia↗

PubMed1994

Decreased plasma levels of lipoprotein(a) in patients with hypertriglyceridemia.

Lipoprotein(a) (Lp(a)) is an atherogenic lipoprotein which is similar in structure to, but metabolically distinct from, LDL. Factors modulating plasma Lp(a) concentrations are poorly understood. To investigate the possible interaction of Lp(a) with triglycerides, we determined the apo(a) phenotype, Lp(a) concentration, and distribution of Lp(a) in a group of patients with triglycerides > 400 mg/dl (n = 60) compared with a control group (n = 128). Lp(a) concentrations were significantly lower in hypertriglyceridemic patients (mean +/- S.E., 13 +/- 4 mg/dl; median, 6 mg/dl; 25/75 percentile, 2-13 mg/dl) as compared with the controls (mean, 22 +/- 2 mg/dl; median, 10 mg/dl; 25/75 percentile, 7-30 mg/dl). Plasma Lp(a) concentrations in the hypertriglyceridemic patients correlated negatively with triglyceride levels (r = -0.69, P = 0.03). The difference in Lp(a) levels between patients and controls was maintained when subjects were stratified by apo(a) phenotype and type of hyperlipidemia. After subdividing the hypertriglyceridemic patients into one group with apo(a) isoforms < or = S2 and one group with apo(a) isoforms > or = S3, we found that the differences in plasma Lp(a) concentrations between patients and controls were more pronounced in the group with the lower molecular weight apo(a) isoforms. These data indicate that hypertriglyceridemia is associated with lower plasma Lp(a) concentrations and suggest that increased levels of triglyceride-rich lipoproteins may influence the metabolism of Lp(a).

Adolescent↗

PubMed1994

Distribution of subclasses of HDL containing apoA-I without apoA-II (LpA-I) in normolipidemic men and women.

Women have significantly higher plasma concentrations of high-density lipoprotein (HDL) and apolipoprotein (apo) A-I than men. Human HDL consists of two major species of apoA-I-containing lipoproteins: LpA-I (lipoprotein containing apoA-I but not apoA-II) and LpA-I:A-II (lipoprotein containing both apoA-I and apoA-II). LpA-I is itself heterogeneous and contains several subclasses of different size and composition. We analyzed LpA-I subclasses in 12 male and 12 female healthy normolipidemic adults. LpA-I concentrations were significantly higher in women (72.4 +/- 5.6 mg/dL) than in men (50.2 +/- 2.2 mg/dL) (P < .05). LpA-I was preparatively isolated from fasting plasma by immunoaffinity chromatography. Gel filtration chromatography was then used to isolate LpA-I subclasses based on size. Three major subclasses were eluted: large, medium, and small LpA-I. No differences between men and women in the size or composition of individual LpA-I subclasses were observed. In contrast, the distribution and plasma concentration of LpA-I subclasses were significantly different between men and women. As a fraction of total LpA-I, the large LpA-I was significantly higher (68.0% to 48.4%) and the medium LpA-I was significantly lower (26.4% to 44.9%) in women than in men. The fraction of small LpA-I was not significantly different. Plasma concentrations of large LpA-I in women (49.2 mg/dL) were twice that in men (24.3 mg/dL), whereas plasma concentrations of medium LpA-I (19.1 mg/dL versus 22.5 mg/dL) and small LpA-I (4.0 mg/dL versus 3.0 mg/dL) were similar in women and men.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1994

The inverse association of plasma lipoprotein(a) concentrations with apolipoprotein(a) isoform size is not due to differences in Lp(a) catabolism but to differences in production rate.

Lipoprotein(a) (Lp[a]) is an atherogenic lipoprotein which is similar in structure to low density lipoproteins (LDL) but contains an additional protein called apolipoprotein(a) (apo[a]). Apo(a) is highly polymorphic in size, and there is a strong inverse association between the size of the apo(a) isoform and the plasma concentration of Lp(a). We directly compared the in vivo catabolism of Lp(a) particles containing different size apo(a) isoforms to establish whether there is an effect of apo(a) isoform size on the catabolic rate of Lp(a). In the first series of studies, four normal subjects were injected with radio-labeled S1-Lp(a) and S2-Lp(a) and another four subjects were injected with radiolabeled S2-Lp(a) and S4-Lp(a). No significant differences in fractional catabolic rate were found between Lp(a) particles containing different apo(a) isoforms. To confirm that apo(a) isoform size does not influence the rate of Lp(a) catabolism, three subjects heterozygous for apo(a) were selected for preparative isolation of both Lp(a) particles. The first was a B/S3-apo(a) subject, the second a S4/S6-apo(a) subject, and the third an F/S3-apo(a) subject. From each subject, both Lp(a) particles were preparatively isolated, radiolabeled, and injected into donor subjects and normal volunteers. In all cases, the catabolic rates of the two forms of Lp(a) were not significantly different. In contrast, the allele-specific apo(a) production rates were more than twice as great for the smaller apo(a) isoforms than for the larger apo(a) isoforms. In a total of 17 studies directly comparing Lp(a) particles of different apo(a) isoform size, the mean fractional catabolic rate of the Lp(a) with smaller size apo(a) was 0.329 +/- 0.090 day-1 and of the Lp(a) with the larger size apo(a) 0.306 +/- 0.079 day-1, not significantly different. In summary, the inverse association of plasma Lp(a) concentrations with apo(a) isoform size is not due to differences in the catabolic rates of Lp(a) but rather to differences in Lp(a) production rates.

Adult↗

PubMed1994

A novel missense mutation in the C-terminal domain of lipoprotein lipase (Glu410-->Val) leads to enzyme inactivation and familial chylomicronemia.

Lipoprotein lipase (LPL) is a complex enzyme consisting of multiple functional domains essential for the initial hydrolysis of triglycerides present in plasma lipoproteins. Previous studies have localized the catalytic domain of LPL, responsible for the hydrolytic function of the enzyme, to the N-terminus whereas the C-terminal end may play a role in lipid and heparin binding. To date, most described missense mutations resulting in a nonfunctional LPL have been located in the N-terminal region of the enzyme. In this manuscript we describe the defect in the LPL gene of a patient with triglycerides ranging from normal to 12,000 mg/dl, low LPL mass, and no LPL activity in post-heparin plasma. Sequencing of patient PCR-amplified DNA identified two separate mutations in the C-terminal domain of LPL: an A-->T transversion at nucleotide 1484 resulting in a Glu410-->Val substitution and a C-->G mutation at position 1595 that introduces a premature stop codon at position 447. Digestion with MaeIII and MnII established that the patient is a true homozygote for both mutations. In order to investigate the functional significance of these defects, mutant enzymes containing either the Val410 or the Ter447 mutations as well as both Val410 and Ter447, were expressed in vitro. Compared to the wild-type enzyme, LPL447 demonstrated a moderate reduction of specific activity using triolein (70% of normal) and tributyrin (74% of normal) substrates, while LPL410 had a significant (11% and 23% of normal) reduction of the normal lipase and esterase specific activities, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMed1994

In vivo metabolism of apolipoproteins A-I and E in patients with abetalipoproteinemia: implications for the roles of apolipoproteins B and E in HDL metabolism.

The metabolism of high density lipoproteins (HDL) is tightly linked to the metabolism of apoB-containing lipoproteins through the exchange and transfer of lipids and apolipoproteins within the plasma compartment. Abetalipoproteinemia (ABL), a genetic disease in which apoB is absent from the plasma and HDL are the sole plasma lipoproteins, is a model for the investigation of HDL metabolism without modification by apoB-containing lipoproteins. Apolipoproteins A-I and E are two of the major apolipoproteins in HDL. Plasma apoA-I levels, but not apoE levels, have been reported to be decreased in patients with ABL. Furthermore, HDL from ABL patients is enriched in apoE compared with normal subjects. The purpose of the present study was: 1) to elucidate the metabolic basis of the low apoA-I levels in ABL; 2) to determine whether in vivo apoE production rates are normal in the absence of apoB-lipoprotein secretion; and 3) to test the hypothesis that apoE influences apoA-I and HDL catabolism in ABL. 131I-labeled apoA-I and 125I-labeled apoE were reassociated with autologous lipoproteins and injected into two unrelated ABL patients and control subjects. The mean residence time of apoA-I in ABL (2.4 days) was significantly decreased by nearly 50% compared with control subjects (4.7 +/- 0.6 days). ApoA-I production rates were also significantly decreased by 40% in ABL (7.1 mg/kg-d) compared with control subjects (11.8 +/- 1.7 mg/kg-d). The mean residence time of apoE in ABL (0.50 days) was somewhat shorter than that of control subjects (0.66 +/- 0.15 days), whereas the mean apoE production rate in ABL (2.14 mg/kg-d) was not substantially different from that of control subjects (1.55 +/- 0.62 mg/kg-d). HDL subfractions LpA-I and LpA-I:A-II were isolated using immunoaffinity chromatography. In contrast to the normal metabolism, apoA-I in LpA-I:A-II particles was catabolized at a faster rate than apoA-I in LpA-I, accounting for the greater decrease of plasma LpA-I:A-II relative to LpA-I in the ABL patients. HDL subfractions with and without apoE were also isolated using anti-apoE immunoaffinity chromatography. Labeled apoA-I in apoE-containing HDL was catabolized faster than that in HDL without apoE. Among the three different forms of apoE, the apoE monomer was catabolized at the fastest rate, the apoE homodimer at an intermediate rate, and the apoE-A-II heterodimer had the slowest rate of catabolism.(ABSTRACT TRUNCATED AT 400 WORDS)

Abetalipoproteinemia↗

PubMed1994

In vivo metabolism of apolipoprotein A-IV in severe hypertriglyceridemia: a combined radiotracer and stable isotope kinetic study.

Apolipoprotein (apo) A-IV is an intestinally derived apolipoprotein that plays a potentially important role in lipoprotein metabolism and reverse cholesterol transport. However, the factors that regulate its plasma concentrations are not well understood. Plasma apoA-IV levels have been previously shown to correlate with fasting triglyceride (TG) levels in humans with TG levels less than 300 mg/dl (Lagrost et al. 1989. J. Lipid Res. 30: 701-710). In this study, we established that apoA-IV levels were significantly elevated (mean 29.3 mg/dl) in a group of 15 hypertriglyceridemic patients (TG > 300 mg/dl) compared with normolipidemic controls (mean 13.4 mg/dl). In order to investigate the relationship between hypertriglyceridemia and apoA-IV metabolism, we then studied the in vivo kinetics of apoA-IV in two healthy hypertriglyceridemic patients (mean TG = 1297 mg/dl) compared with normolipidemic control subjects. Combined studies using endogenous stable isotope labeling (with a primed constant infusion of deuterated L-leucine) and exogenous radiolabeling (with 125I) of apoA-IV were performed. Both stable isotope and radiotracer studies demonstrated substantially decreased apoA-IV fractional catabolic rates (FCR) in the hypertriglyceridemic patients (1.24 +/- 0.13 day-1) compared with controls (2.33 +/- 0.08 day-1). The apoA-IV production rate was not significantly different between the two groups. Gel filtration chromatography of plasma indicated an increased proportion of apoA-IV in the triglyceride-rich lipoproteins (TRL) of the hypertriglyceridemic patients compared with controls and delayed catabolism of this TRL-associated apoA-IV. The rate of apoA-IV catabolism from the lipid deficient fraction was not different between the hypertriglyceridemic patients and controls. In summary, plasma levels of apoA-IV are significantly elevated in hypertriglyceridemic patients due to delayed catabolism of apoA-IV as demonstrated by both endogenous stable isotope labeling and exogenous radiotracer techniques.

Apolipoproteins A↗

PubMed1993

Very low high-density lipoproteins without coronary atherosclerosis.

Epidemiological studies have established that concentrations of plasma high-density lipoproteins (HDL) are inversely associated with premature atherosclerosis, but the physiological basis of this relationship remains unknown. We investigated 5 probands with very low plasma HDL. None had clinical or biochemical findings typical of the known genetic disorders with low HDL nor had evidence of premature coronary atherosclerosis by sensitive diagnostic methods. All 5 probands and the son of 1 of them had rapid catabolism of the HDL apolipoproteins A-I and A-II. These results indicate that not all people with low HDL are necessarily at risk of premature coronary heart disease and that further investigation is required before decisions can be made about their management.

Adult↗

PubMed1993

Biochemical characterization of the three major subclasses of lipoprotein A-I preparatively isolated from human plasma.

Apolipoprotein (apo) A-I is the major protein constituent of plasma high-density lipoproteins (HDL). HDL consist of two major classes of apoA-I-containing lipoproteins: LpA-I and LpA-I:A-II. LpA-I includes heterogeneous lipoprotein particles that differ in size and hydrated density. LpA-I was isolated by immunoaffinity chromatography from the fasting plasma of 24 normal human subjects and separated by gel filtration chromatography. Three major subclasses of LpA-I were eluted: large (Lg-LpA-I), medium (Md-LpA-I), and small LpA-I (Sm-LpA-I). By nondenaturing gradient PAGE, Lg-LpA-I, Md-LpA-I, and Sm-LpA-I had mean Strokes diameters of 10.8 +/- 0.5, 8.9 +/- 0.5, and 7.5 +/- 0.3 nm, respectively. The lipid/protein ratios were 1.25 +/- 0.12 for Lg-LpA-I, 0.75 +/- 0.10 for Md-LpA-I, and 0.38 +/- 0.08 for Sm-LpA-I. Lg-LpA-I was relatively lipid and cholesteryl ester rich compared with Md-LpA-I and Sm-LpA-I. Sm-LpA-I contained phospholipids as the major lipid component. ApoA-I was the major apolipoprotein in all LpA-I subfractions, whereas apoE was present only in Lg-LpA-I and apoA-IV was associated with both Md-LpA-I and Sm-LpA-I. All three LpA-I subclasses exhibited predominantly alpha mobility on agarose electrophoresis. Lg-LpA-I migrated as a diffuse band in the fast alpha position, whereas Md-LpA-I and Sm-LpA-I migrated to the slow alpha position.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1993

Identification and management of heterozygous familial hypercholesterolemia: summary and recommendations from an NHLBI workshop.

Heterozygous familial hypercholesterolemia (hFH) is one of the most common monogenic disorders with serious health consequences, affecting approximately 1 in 500 persons in the United States. Persons with hFH generally manifest elevations of low density lipoprotein (LDL) cholesterol throughout their lives and have a markedly increased risk of death from coronary artery disease. The hypercholesterolemia of hFH is responsive to medication and diet, and, if detected early, aggressive LDL cholesterol control may prevent or substantially delay cardiovascular disease. However, evidence suggests that many persons with hFH are undetected and inadequately treated. On July 20-21, 1992, the National Heart, Lung, and Blood Institute sponsored a workshop to assess the current understanding of the diagnosis and management of hFH, to emphasize recommendations for identification and management that are known to be effective, and to identify opportunities and needs for intervention and research.

Heterozygote↗