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At least 19 recordsLinked to original sources
PubMed1976

Studies of the lipid binding characteristics of the apolipoproteins from human high density lipoprotein. II. Calorimetry of the binding of apo AI and apo AII with phospholipids.

The interactions of lysophosphatidylcholine and synthetic 1,2-dimyristoyl-sn-glycerophosphocholine (DMPC) liposomes with the isolated HDL-apolipoproteins, apo AI and apo AII, has been studied by microcalorimetry. Complex formation is a highly exothermal process characterized by a maximal enthalpy of about --200 kcal/mol of apoprotein when added to DMPC at 28 degrees C in 0.05 M sodium carbonate/bicarbonate buffer, pH 9.6. For the apo AI apoprotein, the binding consists of two processes, one endothermal occurring at low phospholipid/protein ratios and one exothermal predominant at higher phospholipid levels. The endothermal process has been attributed to a lipid-induced disaggregation of the apo AI while the exothermal process is similar to the binding of apo AII or apo HDL to phospholipids. The binding of a constant AI and apo AII, demonstrates the existence of a maximal association at a 1 : 1 molar ratio of the apolipoproteins. The sequential binding of DMPC to apo AI and apo AII suggests the existence of cooperativity between the two apoproteins in phospholipid binding as apo AII promotes the incorporation of apo AI into a protein-phospholipid complex.

Apoproteins↗
PubMed1976

In vitro growth inhibition of mastitis-causing coliform bacteria by bovine apo-lactoferrin and reversal of inhibition by citrate and high concentrations of apo-lactoferin.

Bovine apo-lactoferrin (apo-Lf) was added to in vitro cultures of eight strains of coliform bacteria associated with bovine mastitis. As little as 0.02 mg of APO-Lf per ml resulted in marked inhibition of growth of all coliforms. Growth inhibition was lost if saturated Lf or iron plus apo-Lf was added to the synthetic medium. The inhibition of growth increased as the concentration of apo-Lf increased from 0.02 to 0.2 mg/ml for Klebsiella pneumoniae (OARDC-A1), Klebsiella spp. (K1-21), and Aerobacter aerogenes (55-12222) and 2 mg/ml for A. aerogenes (76-2414-1), Escherichia coli (60-Lilly), E. coli (66-S16), and Klebsiella spp. (K6-24). As the concentration of apo-Lf was increased above 0.2 or 2 mg/ml, there was less inhibition of growth except for E. coli (33-C4). Apo-Lf at 20 mg/ml was bactericidal for E. coli (33-C4). Results are compatible with the hypothesis that coliform bacteria respond to low-iron environments by production of iron-sequestering agents that complete effectively with apo-Lf for free iron. Addition of apo-Lf plus citrate resulted in loss of growth inhibition. The molar ratio (citrate to apo-Lf) was found to be more important than the absolute concentration of either component. A ratio of 75 resulted in 50% growth inhibition, whereas ratios of 300 and greater resulted in less than 10% growth inhibition. These results suggest that the ratio of citrate to Lf would be important in evaluating Lf as a nonspecific protective factor of bovine mammary secretions.

Animals↗
PubMed1979

Ultrastructural localization of apo-b and apo-c binding to very low density lipoproteins in rat liver.

Hepatic synthesis of apo-B and apo-C and their binding to nascent very low density lipoproteins (VLDL) have been studied in fat-fed rats. Apolipoproteins were located in hepatocyte organelles by light and electron microscopy after immunoenzymatic staining using peroxidase-conjugated antibodies. Our results indicate that apo-B and apo-C are synthesized by membrane-bound ribosomes. Both apoproteins seem to be adsorbed simultaneously to the lipid core of VLDL in the lumen of the endoplasmic reticulum channels, at the junction zone between rough and smooth endoplasmic reticulum. Some additional protein presumably binds nascent VLDL in the Golgi apparatus as judged by the strong positive reaction of lipoprotein particles with peroxidase-labeled antibodies. Finally our data show that significant amounts of apo-B and apo-C are bound to the sinusoidal plasma membrane in fed rat livers which probably represent remnants of lipoprotein of intestinal origin since membrane-bound apolipoproteins virtually disappeared 24 h after lymphatic duct cannulation. It is suggested that nascent VLDL (apo-C poor) could be enriched in apo-C from lipoprotein remnants at the space of Disse.

Animals↗
PubMed1979

Values of APO-1 and APO-B in humans according to age and sex.

Two series of 100 subjects each, males and females, have been studied for the determination of plasma values of apo-A1, the major peptide of HDL, and of apo-B, the major peptide of LDL. To minimize a possible influence of variations in plasma lipid levels, two series of subjects were selected with very similar mean values of plasma cholesterol and triglyceride. Despite this criterion of selection apo-A1 was significantly lower in males (127 +/- 18 mg/l) than in females (137 +/- 15 mg/l) while the reverse was true for apo-B (99 +/- 16 mg/l in males vs. 91 +/- mg/l in females). Both apo-B and apo-A1 showed a tendency to increase with advancing age with the greatest increase for apo-A1 (in both sexes) and for apo-B (only in males) from the 3rd to the 4th decade of age.

Adult↗
PubMed1979

Rate and equilibrium constants for binding of apo-E HDLc (a cholesterol-induced lipoprotein) and low density lipoproteins to human fibroblasts: evidence for multiple receptor binding of apo-E HDLc.

Competitive binding assays have demonstrated that a cholesterol-induced canine lipoprotein containing only the E apoprotein (apo-E HDL(c)) binds to the same cell surface receptors of human fibroblasts as human low density lipoproteins (LDL). However, the apo-E HDL(c) have a much greater binding activity than LDL. Equilibrium and kinetic binding studies were conducted at 4 degrees C to determine the mechanism for this enhanced receptor binding activity. Based on the data, the binding of both LDL and apo-E HDL(c) appears to be a simple bimolecular receptor interaction, and no heterogeneity of binding sites or cooperative effects among the receptor sites were observed. Equilibrium dissociation constants determined by Scatchard analysis of the equilibrium binding data for apo-E HDL(c) (K(d) = 0.12 x 10(-9) M) and LDL (K(d) = 2.8 x 10(-9) M) revealed a 23-fold greater affinity of HDL(c) for the receptors. Association and dissociation rate constants for the lipoprotein-receptor complex were determined from the time course of binding at various lipoprotein concentrations. The equilibrium dissociation constants calculated from these kinetic data confirmed that apo-E HDL(c) had a much higher affinity for the receptor than LDL. Furthermore, the kinetic studies indicated that apo-E HDL(c) bound more rapidly than LDL with rates of association of 18.0 x 10(4) and 5.5 x 10(4) M(-1) sec(-1), respectively. The rate of dissociation of the apo-E HDL(c)-receptor complex (1.7 x 10(-5) sec(-1)) was slower than that of the LDL receptor complex (6.3 x 10(-5) sec(-1)). An additional important difference between the binding of apo-E HDL(c) and LDL was that 4 times (3.6 +/- 0.4) as many LDL particles as HDL(c) particles were required for saturation of the receptors at maximal binding. These data indicate that each HDL(c) particle binds to multiple cell surface receptors at a ratio of 4:1 for LDL receptor binding.

Apolipoproteins↗
PubMed1978

Cross-linking studies of the self-association properties of apo-A-I and apo-A-II from human high density lipoprotein.

The state of self-association of the apoprotein components of human high density lipoprotein have been studied by use of the cross-linking reagent dimethyl-suberimidate. Analusis of the cross-linked products was carried out by soduim dodecyl sulfate-gel electrophoresis and by agarose column chromatography in 6 M guanidine hydrochloride. Apo-A-I was found to exist as a monomer at low concentration, but associates to tetrameric and pentameric forms at concentrations of 0.5 mg/ml or higher. The self-association was found to be ionic strength-dependent, with association promoted by the presence of salt. Apo-A-II was also found to associate, but the major oligomeric form observed was dimeric (Mr = 34,000), and the association was less dependent on ionic strength than for apo-A-I. Cross-linking in the presence of various concentrations of guanidine hydrochloride showed that apo-A-II self-association persisted at higher concentrations of the denaturant than for apo-A-I. Studies of the effect of temperature demonstrated that the self-association of both proteins was diminished at temperatures above 30 degrees C. Recombination of apo-A-II with phospholipid resulted in the formation of particles which yielded primarily trimers upon cross-linking. This suggests that phospholipid binding causes major reorganization of the self-associated forms of apo-A-II.

Amino Acids↗
PubMed1975

The self-association of the apo-Gln-I and apo-Gln-II polypeptides of human high density serum lipoproteins.

The major polypeptide components of human high density lipoprotein, apo-Gln-I and apo-Gln-II, self-associate at pH 8.3 and ionic strength 0.045. The dimeric (MW = 56,800) association constant for apo-Gln-I is 1.3 X 10(4)liters/mol. apo-Gln-II is tetrameric at all experimentally accessible concentrations. Self-association of apo-Gln-I is accompanied by minor conformational alterations distinct from that induced by saturating levels of bound amphiphilic ligands. These results are discussed with respect to the design of reconstitution experiments between the apoproteins and lipids.

Apoproteins↗
PubMed1979

Correlation in the human aorta of APO B fractions with tissue cholesterol and collagen content.

The amounts of buffer- and Triton-extracted apo B (LDL-protein), as well as the sum of these two fractions, were correlated with the total tissue cholesterol and hydroxyproline content (as a measure of collagen) in grossly normal intima, fatty streaks, and fibrous plaques of human aortas obtained at autopsy. Quantitative values of buffer- and Triton-extracted apo B were obtained by sequentially extracting homogenates of aortic intima with an aqueous buffer and one containing Triton X-100, and measuring the apo B content in each extract by an electroimmunoassay relative to plasma LDL or Triton-treated LDL. Significant positive correlations were obtained between the following: tissue cholesterol and both buffer-extracted and total-extracted apo B in grossly normal intima; tissue cholesterol and Triton-extracted apo B in microdissected fibrotic caps and cores of fibrous plaques, as well as in whole plaques. A positive correlation was also obtained between tissue cholesterol and total-extracted apo B in the necrotic core. A significant negative correlation was found between Triton-extracted apo B and collagen in whole plaques. The calculated mean percent of total tissue cholesterol in the different aortic regions that could be present as part of an intact LDL particle were: 100% in grossly normal intima, 16% in fatty streaks, and 11% in fibrous plaques. The positive correlation between Triton-extracted apo B and cholesterol in plaques suggests one or both of the following: the extracellular pool of cholesterol or some material increasing concurrently with cholesterol interacts with apo B or another part of the LDL particle; or the apo B containing lipoprotein is trapped in the hydrophobic environment of extracellular lipid. Both possibilities would render the particle less soluble in aqueous buffers. The negative correlation between Triton-extracted apo B and tissue collagen and the lack of a significant correlation between buffer-extracted apo B and collagen content suggests that collagen is probably not responsible for apo B retention in the aortic intima.

Adult↗
PubMed2025

Elevated plasma GFAP levels in MCI link APOE ε4 allele with impaired gait speed.

The presence of at least one copy of the apolipoprotein ε4 allele (APOE ε4) is a known predictor of gait impairment risk among older adults. However, the mechanisms by which APOE ε4 affects gait performance remain unclear. This cross-sectional study aimed to reveal underlying pathological mechanisms linking APOE ε4 carriage to slow gait. This secondary analysis used baseline assessments from the J-MINT multicenter intervention trial, focusing on older adults with mild cognitive impairment. Gait speed was measured at baseline, with slow gait (SG) defined as speeds one standard deviation below the age- and sex-specific mean. APOE phenotype and plasma biomarkers related to Alzheimer's disease (AD), including amyloid-β composite biomarker, phosphorylated Tau 181, neurofilament light, and glial fibrillary acidic protein (GFAP), were also measured. The analysis included 236 non-APOE ε4 carriers and 84 carriers of at least one APOE ε4. APOE ε4 carriers exhibited significantly slower gait speed than non-carriers (1.20 m/s [SD = 0.22] vs 1.26 m/s [SD = 0.23], p = 0.042). Significant interaction between APOE ε4 carriage and SG was observed only in plasma GFAP levels (F1, 312 = 7.17, p = 0.008), indicating that individuals with APOE ε4 and SG had significantly higher plasma GFAP levels. Elevated plasma GFAP levels fully mediated the association between APOE ε4 carriage and gait speed (partially standardized indirect effect = -0.059: -0.12 to -0.013]). No other AD-related biomarkers mediated this association. Our results suggest that APOE ε4-related gait changes may reflect AD pathology, as indicated by elevated GFAP levels, and could potentially accelerate dementia symptoms.

Aged↗
PubMed1976

Apo-lipoprotein localization in human atherosclerotic arteries.

A study documenting the localization in human arteries of apoproteins from human plasma high density (HDL, low density (LDL), and very low density (VLDL) lipoproteins was undertaken in light of their possible roles in the pathogenesis and regression of the atherosclerotic process in man. Apo A-I from HDL, apo B from LDL, apo C-III from VLDL were all localized by immunohistochemical techniques to generally the same areas of athersclerotic lesions. These consisted of certain bands of collagen and elastic fibers in fatty streaks and fibrous plaques, and extracellular pools of neutral lipid in fibrous plaques. Apoproteins were also occasionally present in areas of diffuse intimal thickening in coronary arteries. Extensiveness and frequency of appearance of apo B in atherosclerotic lesions was greatest in type II hyperlipoproteinemics, thus correlating with the plasma apo B levels. Employing an immuno-peroxidase procedure, apo B was localized ultrastructurally in atherosclerotic lesions to the outer surface of spheres ranging in diameter between 250 and 700 A. These spheres, localized predominantly in lipid cores and between collagen bands, were also seen in negatively-stained preparations of arterial extracts which also reacted positively against anti-apo B, SUGGESTING THAT THE SPHERES MAY REPRESENT NATIVE LDL and VLDL. The superimposed localization of apo A-I, apo B, and apo C-III in atherosclerotic lesions suggests that a specific interaction exists between certain lesion components and these apoproteins.

Apoproteins↗
PubMed2026

Divergent Biological Consequences of APOE Isoforms Across Industrialized and Non-Industrial Environments.

The apolipoprotein ε4 (APOE ε4) isoform directly alters cholesterol and immune biology and is associated with an increased risk of neurodegenerative and cardiometabolic disease in industrialized settings; nevertheless, APOE ε4-which is ancestral in humans-has persisted over evolutionary time. One potential explanation is that the costs and benefits of APOE ε4 were significantly different in the environments in which humans evolved compared to those we experience today. In support, previous work has suggested that living in a high pathogen environment, engaging in high levels of physical activity, or eating a low fat diet can dampen the detrimental effects of APOE ε4, and has revealed positive effects for fertility. However, direct tests of whether APOE isoforms are associated with different biological outcomes in non-industrial versus industrialized contexts are lacking. Working with the Turkana of Kenya and the Orang Asli of Peninsular Malaysia-two Indigenous groups in which individuals of shared ancestry span a continuum of subsistence, non-industrial to urban, industrialized lifestyles-we investigated how APOE genotypes impact cholesterol, immunological, and reproductive traits and tested for genotype x environment (GxE) interactions. First, we confirmed established genotype effects across lifestyles, showing that more APOE ε4 alleles are associated with higher total cholesterol, higher LDL cholesterol, and lower HDL cholesterol. Second, we tested for lifestyle interactions, finding lifestyle-dependent effects of genotype on innate immune biomarkers in the Orang Asli but not Turkana. Finally, we show that more APOE ε4 alleles are correlated with an extended reproductive lifespan, however this effect is relatively weak, is not consistent across populations, and does not correspond with a higher reproductive output. Together, our study provides evidence that industrialized environments can modify the biology of APOE ε4; however, we find that APOE ε4 is not universally beneficial in non-industrial contexts, highlighting the role of local environmental variation in determining its specific costs and benefits.

Journal Article↗
PubMed1979

Use of an incisor diagnostic triangle for evaluating incisor positions relative to the APo line.

Angular values of the upper and lower incisors to the APo line were measured in a sample of fifty subjects with clinically acceptable occlusions, ranging from 10 to 14 years of age. Correlations were high between both upper and lower incisor angulations to the APo line and the interincisal angle. The correlation was low between the upper incisor angulations to the APo line and the lower incisor angulations to the APo line. An incisor diagnostic triangle was introduced. This is made up of the interincisal angle and the intersection of the long axes of the upper and lower incisors to the APo line. Incisor diagnostic templates were introduced and their uses as diagnostic and visual aids were enumerated. These templates were constructed by using an idealized linear position of the tip of the lower incisors on the APo line, the upper incisor angulation to the APo line, and the interincisal angle. By relating both incisors to the APo line and to each other through the interincisal angle, the orthodontist is provided with a simple, specific diagnostic aid. The incisors are positioned in relation to a skeletal reference line (APo) which is more intimately associated with the patient's facial profile than more distant skeletal reference lines or planes, such as sella-nasion, Frankfort horizontal, or the mandibular plane.

Adolescent↗
PubMed1976

Conformational and thermodynamic properties of apo A-1 of human plasma high density lipoproteins.

Conformational changes of apo A-1, the principal apoprotein of human plasma high density lipoprotein, have been studied by differential scanning calorimetry and ultraviolet difference spectroscopy as a function of temperature, pH, concentration of apoprotein, and urea concentration. Calorimetry shows that apo A-1 (5 to 40 mg/ml, pH 9.2) undergoes a two-state, reversible denaturation (enthalpy = 64 +/- 8.9 kcal/mole), between 43--71 degrees (midpoint temperature, Tm = 54 degrees), associated with a rise in heat capacity (deltaCvd) of 2.4 +/- 0.5 kcal/mole/degrees C. Apo A-1 (0.2 to 0.4 mg/ml, pH 9.2) develops a negative difference spectrum between 42--70 degrees, with Tm = 53 degrees. The enthalpy (deltaH = 59 +/- 5.7 kcal/mole at Tm) and heat capacity change (2.7 +/- 0.9 kcal/mole/degrees C) in the spectroscopic experiments were not significantly different from the calorimetric values. Below pH 9 and above pH 11, the calorimetric Tm and deltaH of denaturation are decreased. In the pH range of reversible denaturation (6.5 to 11.8), delatH and Tm are linearly related, showing that the heat capacity change (ddeltaH/dT) associated with denaturation is independent of Tm. In urea solutions, the calorimetric Tm and deltaH of denaturation are decreased. At 25 degrees, apo A-1 develops a negative difference spectrum between 1.4 and 3 M urea. Fifty per cent of the spectral change occurs in 2.4 M urea, which corresponds to the urea concentration obtained by extrapolation of the calorimetric Tm to 25 degrees. In urea solution of less than 0.75 M there is hyperchromicity at 285 nm (delta epsilon = 264 in 0.75 M urea), indicating strong interaction of aromatic amino acid residues in the native molecule with the solvent. Spectrophotometric titration of apo A-1 shows that 6.6 of the 7 tyrosine groups of apo A-1 titrate at pH less than 11.9, with similar titration curves obtained in aqueous solutions and in 6 M urea. The free energy of stabilization (deltaG) of the native conformation of apo A-1 was estimated, (a) at 37 degrees, using the calorimetric deltaA and deltaCvd, and (b) at 25 degrees, by extrapolation of spectroscopic data to zero urea concentration. The values (deltaG (37 degrees) = 2.4 and deltaG (25 degrees) = 2.7 kcal/mole) are small compared to typical globular proteins, indicating that native apo A-1 has a loosely folded tertiary structure. The low values of deltaG reflect the high degree of exposure of hydrophobic areas in the native protein molecule. The loosely folded conformation of apo A-1 allows extensive binding of lipid, since this can involve both surface hydrophobic sites and hydrophobic areas exposed by a cooperative, low energy unfolding process.

Apoproteins↗
PubMed2026

Genetic modifiers of APOE-ε4-associated cognitive decline.

The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease. However, APOE-ε4 is not deterministic, highlighting the need to identify additional genetic and environmental factors. APOE-ε4 has been linked to accelerated cognitive decline, so we sought to investigate genetic factors that modify APOE-ε4-associated cognitive decline. We conduct cross-ancestry APOE-ε4-stratified and interaction GWAS using harmonized cognitive data from 32,778 participants, including 29,354 non-Hispanic White and 3,424 non-Hispanic Black individuals. Our primary outcome is late-life cognition, measured using harmonized composite scores for memory, executive function, and language, modeled as continuous traits reflecting both normative cognitive aging and disease-related decline. We identify two genome-wide significant loci in APOE-ε4 carriers, reaching genome-wide significance for executive function. These loci also demonstrate nominal associations across the other domains, suggesting broad effects on cognition. In non-carriers, we identify a genome-wide significant association at ITGB8 restricted to executive function, and another locus associated with language. We further link these loci to SEMA6D, GRIN3A, and ITGB8 through expression and methylation databases. Post-GWAS analyses implicate additional genes including SLCO1A2, and DNAH11. Genetic correlation analyses reveal differences by APOE-ε4 status for immune-related traits, suggesting immune-related predispositions may exacerbate cognitive risk in APOE-ε4 carriers.

Humans↗
PubMed2022

Destabilizing heterochromatin by APOE mediates senescence.

Apolipoprotein E (APOE) is a component of lipoprotein particles that function in the homeostasis of cholesterol and other lipids. Although APOE is genetically associated with human longevity and Alzheimer's disease, its mechanistic role in aging is largely unknown. Here, we used human genetic, stress-induced and physiological cellular aging models to explore APOE-driven processes in stem cell homeostasis and aging. We report that in aged human mesenchymal progenitor cells (MPCs), APOE accumulation is a driver for cellular senescence. By contrast, CRISPR-Cas9-mediated deletion of APOE endows human MPCs with resistance to cellular senescence. Mechanistically, we discovered that APOE functions as a destabilizer for heterochromatin. Specifically, increased APOE leads to the degradation of nuclear lamina proteins and a heterochromatin-associated protein KRAB-associated protein 1 via the autophagy-lysosomal pathway, thereby disrupting heterochromatin and causing senescence. Altogether, our findings uncover a role of APOE as an epigenetic mediator of senescence and provide potential targets to ameliorate aging-related diseases.

Humans↗
PubMed2025

GWAS of CRP response to statins further supports the role of APOE in statin response: A GIST consortium study.

Statins are first-line treatments in the primary and secondary prevention of cardiovascular disease. Clinical studies show statins act independently of lipid-lowering mechanisms to decrease C-reactive protein (CRP), an inflammation marker. We aim to elucidate genetic loci associated with CRP statin response. CRP statin response is the change in log-CRP between off-treatment and on-treatment measurements. Cohort-level Genome-Wide Association Studies (GWAS) of CRP response were performed using 1000 Genomes imputed data, testing &#x223c;10 million common genetic variants. GWAS meta-analysis combined results from seven cohorts and clinical trials totalling 14,070 statin-treated individuals of European ancestry within the GIST consortium. Secondary analyses included statin-by-placebo interaction analyses, and lookups in African ancestry cohorts. Our GWAS identified two genome-wide significant (P&#x202f;<&#x202f;5e-8) loci: APOE and HNF1A for CRP statin response corrected for baseline CRP. The missense lead variant rs429358 at APOE, contributing to the APOE-E4 haplotype, is a risk locus for dyslipidaemia, Alzheimer's and coronary artery disease (CAD). The HNF1A locus is associated with diabetes, cholesterol levels, and CAD. Both loci are also associated with baseline CRP levels, and neither locus achieved a significant (P&#x202f;<&#x202f;0.05) result from the statin v. placebo interaction meta-analysis using randomized clinical trial data. However, the interaction result (P-int=0.09) for APOE was suggestive and possibly underpowered. The APOE-E4 signal may therefore be associated with both CRP and LDL-cholesterol statin response. Combined with suggestions in the literature that APOE also leads to differential statin benefit in Alzheimer's, the APOE locus warrants further investigation for potential genetic effects on healthcare with statin treatment.

Humans↗