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PubMed2006

Apolipoproteins AI and B as therapeutic targets.

Currently the apolipoprotein B:AI ratio integrates information about the potential for cardiovascular disease (CVD) risk reduction better than any other lipid or lipoprotein index. Certainly it could, with benefit, replace serum cholesterol and HDL cholesterol in the estimation of CVD risk. Defining the therapeutic target of statin therapy in terms of serum apolipoprotein B (apo B) rather than LDL cholesterol could also help to optimize statin treatment. Deciding whether a therapeutic response is adequate also requires knowledge of whether there is persisting hypertriglyceridaemia, because this gives an indication of whether small dense LDL is likely to have been satisfactorily reduced. Raising low levels of HDL, probably best measured as apo AI, may also prove to be an important aim of treatment. This is, however, a more complex issue and also depends on the mechanism by which a particular therapy alters HDL levels and on whether the capacity of HDL to perform its anti-inflammatory and antioxidative functions is restored. A meta-analysis of randomized clinical trials of statins in which apo B and apo AI have been reported could provide valuable information.

Anticholesteremic Agents↗

PubMed2006

Measurement and meaning of apolipoprotein AI and apolipoprotein B plasma levels.

Apolipoproteins AI and B are structural components of lipoprotein particles, and also determinants of the metabolic fate of the encapsulated lipid, cholesterol and triglyceride. Development of accurate assays for these apolipoproteins has opened the way for their use as predictors of coronary heart disease risk. Interpretation of AI and apo B levels is best undertaken with background knowledge of the metabolic status of an individual, especially the lipolytic capacity as reflected in the triglyceride concentration. Those with raised triglyceride, in general, not only have an elevated apo B/apo AI ratio, but also apo B-containing lipoproteins with a prolonged residence time and hence ample opportunity for modification and damage. Assessment of apolipoprotein levels is an aid to risk prediction and can be useful in tailoring treatment.

Apolipoprotein A-I↗

PubMed2005

Association between MspI polymorphism of the APO AI gene and Type 2 diabetes mellitus.

AIMS: Genes of the Apo AI/CIII/AIV cluster on chromosome 11 have been related to plasma lipid patterns. The close relationship between carbohydrate metabolism and lipid metabolism warrants investigation of the association between this cluster and Type 2 diabetes mellitus. We therefore examined the possible association between polymorphisms of this cluster and Type 2 diabetes mellitus as part of a study of the prevalence of diabetes and the metabolic syndrome in southern Spain. METHODS: A total of 1224 persons were selected randomly from the town of Pizarra in the province of Malaga, southern Spain. The sample errors for the prevalence of Type 2 diabetes mellitus and the three polymorphisms studied were all < or = 4%. All subjects underwent phenotyping after an oral glucose tolerance test (75 g) (WHO 1998 criteria) and the XmnI and MspI polymorphisms of Apo AI and the SstI polymorphism of Apo CIII were genotyped. RESULTS: Those subjects with the mutated AA genotype of the MspI polymorphism (-75 G-->A) of Apo AI had a greater risk of impaired glucose tolerance [odds ratio (OR) = 1.95, CI = 1.02-3.8, P = 0.05], Type 2 diabetes mellitus, both known (OR = 7.38, CI = 1.3-39.7, P = 0.02) and unknown (OR = 3.7, CI = 1.4-9.9, P = 0.009). This risk was independent of age, sex, obesity, triglyceride level, HDL cholesterol and pattern of insulin resistance. CONCLUSIONS: Pending confirmation in prospective studies, the AA genotype of the MspI polymorphism of the Apo AI gene, within the Apo A-I/C-III/A-IV cluster, seems to be a risk factor for Type 2 diabetes mellitus.

Adult↗

PubMed2001

Hepatic familial amyloidosis caused by a new mutation in the apolipoprotein AI gene: clinical and pathological features.

OBJECTIVE: Recently, we reported a nondescribed deletion/insertion mutation in the apolipoprotein AI gene as the cause of hereditary amyloidosis with hepatic presentation. We describe the clinical and pathological features of this type of amyloidosis in one affected family. METHODS: Demographic, clinical, and biochemical data were obtained from 33 members of the family in whom the apolipoprotein AI gene was studied. Diagnosis was based on the detection of the apolipoprotein AI gene mutation, scintigraphy using radioionated serum amyloid P component, and histological and immunohistochemical studies. RESULTS: Eight members with the mutation had hepatic involvement. Six patients were practically asymptomatic, presented with an elevation of alkaline phosphatase and gamma-glutamyl transpeptidase, and remained stable during follow-up (7.6 +/- 4.9 yr). One patient had jaundice, developed ascites and encephalopathy, and died of hepatorenal syndrome a few months after diagnosis. Jaundice and portal hypertension appeared in the remaining patient, who died 4 yr later. CONCLUSION: This form of familial amyloidosis is characterized by elevation in serum alkaline phosphatase and gamma-glutamyl transpeptidase secondary to amyloid deposits in the portal tracts. Patients remain stable and asymptomatic for many years, but portal hypertension and liver failure can develop later in life and lead to death. Thus, patients should be observed regularly and liver transplantation should be indicated when progression is detected.

Adult↗

PubMed2005

Evidence for a functional quorum-sensing type AI-1 system in the extremophilic bacterium Acidithiobacillus ferrooxidans.

Acidithiobacillus ferrooxidans is one of the main acidophilic chemolithotrophic bacteria involved in the bioleaching of metal sulfide ores. The bacterium-mineral interaction requires the development of biofilms, whose formation is regulated in many microorganisms by type AI-1 quorum sensing. Here, we report the existence and characterization of a functional type AI-1 quorum-sensing system in A. ferrooxidans. This microorganism produced mainly acyl-homoserine lactones (AHL) with medium and large acyl chains and different C-3 substitutions, including 3-hydroxy-C8-AHL, 3-hydroxy-C10-AHL, C12-AHL, 3-oxo-C12-AHL, 3-hydroxy-C12-AHL, C14-AHL, 3-oxo-C14-AHL, 3-hydroxy-C14-AHL, and 3-hydroxy-C16-AHL. A quorum-sensing genetic locus that includes two open reading frames, afeI and afeR, which have opposite orientations and code for proteins with high levels of similarity to members of the acyl synthase (I) and transcriptional regulator (R) protein families, respectively, was identified. Overexpression of AfeI in Escherichia coli and the associated synthesis of AHLs confirmed that AfeI is an AHL synthase. As determined by reverse transcription-PCR, the afeI and afeR genes were transcribed in A. ferrooxidans. The transcription levels of the afeI gene were higher in cells grown in sulfur and thiosulfate media than in iron-grown cells. Phosphate starvation induced an increase in the transcription levels of afeI which correlated with an increase in AHL levels. Two afe boxes which could correspond to the AfeR binding sites were identified upstream of the afeI gene. This is the first report of a functional type AI-1 quorum-sensing system in an acidophilic chemolithotrophic microorganism, and our results provide a very interesting opportunity to explore the control and regulation of biofilm formation during the bioleaching process.

4-Butyrolactone↗

PubMed2005

Proteomics analysis by two-dimensional differential gel electrophoresis reveals the lack of a broad response of Neisseria meningitidis to in vitro-produced AI-2.

To investigate the effect of the autoinducer AI-2 on protein expression in Neisseria meningitidis, a luxS mutant of strain MC58 was grown in the presence and absence of in vitro-produced AI-2, and differential protein expression was assessed by two-dimensional differential gel electrophoresis. N. meningitidis did not show a global response to AI-2 signaling activity.

Bacterial Proteins↗

PubMed1986

Serum apolipoproteins AI and B and lipoproteins in middle aged men with and without previous myocardial infarction.

The serum high density lipoprotein (HDL) subfractions, HDL2, and HDL3, and serum apolipoprotein AI and B (apo AI and B) were evaluated as potential indicators of the risk of ischaemic heart disease in men aged less than 60 years who had previously had a myocardial infarction and in controls with a similar socioeconomic background who had no history of myocardial ischaemia. Discriminant analysis confirmed that the combination of serum cholesterol, triglycerides, and total HDL cholesterol distinguished poorly between patients and controls. The best single discriminating variable was apo B. Stepwise discriminant analysis showed that this discrimination could be improved to a small extent by combining apo B with apo AI and parental history, but nothing was gained by measurement of serum cholesterol triglycerides, very low density lipoprotein cholesterol, low density lipoprotein cholesterol, HDL cholesterol, HDL2 or HDL3 cholesterol. Significantly more patients than controls with type IV hyperlipoproteinaemia had raised concentrations of serum apolipoprotein B, but the frequency of raised apolipoprotein B concentrations was no greater in patients with type IV hyperlipoproteinaemia than in those with normal serum lipids. The value of apo B as an indicator of cardiovascular risk should be assessed in prospective studies.

Apolipoprotein A-I↗

PubMed1999

High apolipoprotein AI concentrations are associated with lower mortality and myocardial infarction five years after coronary artery bypass graft surgery.

OBJECTIVE: To examine mortality and myocardial infarction five years after coronary artery bypass graft (CABG) surgery and the association with different lipid fractions and haemostatic, glycaemic, and demographic risk factors. SETTING: A regional cardiothoracic centre, Freeman Hospital, and the University Clinical Investigation Unit, Royal Victoria Infirmary, Newcastle upon Tyne, UK. DESIGN: 353 consecutive patients (297 male, mean age 57.2 years) undergoing first time CABG for stable angina were recruited to a prospective cohort study and studied to five years. MAIN OUTCOME MEASURES: All cause mortality, late cardiac mortality (beyond 30 days) alone and in combination with non-fatal myocardial infarction. Risk factor assessments before operation and 3, 6, 12, 24, and 60 months after surgery. For each laboratory variable a weighted mean for the period of exposure was calculated from the concentration at each time interval and the time between measurements. The distribution was divided into tertiles. RESULTS: 41 patients died (16 late cardiac deaths) and eight had a myocardial infarct. An adverse outcome occurred more frequently in the lower tertile of weighted apolipoprotein AI compared with the upper tertile. An adverse outcome was also more common in patients in the upper tertile of weighted total white blood cell count and less consistently so in patients in the upper tertile of the haemostatic covariates, factor VIIc and factor VIIIc. There was no association with other lipid fractions except for total mortality and apolipoprotein B (owing to low levels in five patients with carcinoma). CONCLUSIONS: Low apolipoprotein AI concentrations, but no other markers of an adverse lipid profile, were associated with mortality and myocardial infarction five years after CABG. Apolipoprotein AI is associated with paraoxonase, an enzyme located on high density lipoprotein, which may limit the oxidation of low density lipoprotein. An association between outcome and other covariates such as white cell count provides a credible pointer to inflammation mediating a component of cardiovascular risk.

Apolipoprotein A-I↗

PubMed1983

Some features of binaural input to single neurons in physiologically defined area AI of cat cerebral cortex.

1. In the ectosylvian cortex of 24 barbiturate-anesthetized cats, area AI was identified by its frequency organization and the responses to tonal stimuli of single neurons in that field were examined using sealed stimulating systems incorporating calibrated probe microphone assemblies. 2. The responsiveness to monaural and binaural best-frequency stimuli was examined quantitatively for 282 single units in AI. One hundred thirty-nine cells (49%) were excited by independent stimulation of only one ear and were classified as EO cells. In general, the effective monaural excitatory input was derived from the contralateral ear. One hundred ten (39%) neurons were excited by independent stimulation of each ear and were classified as EE units. For these neurons, the contralateral responses were generally stronger, shorter in latency, and lower in threshold than were their ipsilateral responses. Thirty-three cells (12%) gave weak or no responses to monaural stimuli but responded securely to binaural stimuli. These cells were classified as predominantly binaural (PB). 3. Binaural interactions were examined by comparison of the response to binaural, equally intense stimuli to the stronger monaural response. Among EO cells suppression was the most common form of interaction, while for EE cells summation was the more common. Less than 8% of cells were found to be monaural. 4. In electrode penetrations radial to the cortex surface, cells received their stronger or sole monaural excitatory input from a common ear, generally the contralateral. Within such penetrations, however, cells commonly differed with regard to the nature of their input from the other ear and/or in their binaural interactions. 5. Comparison of these data with data previously reported for subcortical auditory nuclei revealed that AI preserves many of the stimulus specificity characteristics of the lower nuclei. The reasons for the preservation of these characteristics at the cortex and the implications of the present data for the binaural column hypothesis are discussed.

Animals↗

PubMed1986

Apolipoproteins AI, AII and HDL phospholipids but not APO-B are risk indicators for occlusive cerebrovascular disease.

A variety of lipids, lipoprotein (Lp) lipids and APO-Lp were measured in 72 patients of both sexes suffering from cerebrovascular arteriopathy and compared with a control group matched for age and sex. The best discriminators by univariate analysis were serum concentrations of APO-AI, followed by APO-AII, high density lipoprotein phospholipids and HDL cholesterol (HDL-C). Low density lipoprotein cholesterol and serum APO-B values were lower in the patients than in the controls. With APO-AI only, patients and controls could be classified with 88-91% certainty. By combination of some of the variables which were selected by a stepwise discriminant analysis, several models were calculated resulting in 93-97% segregation of patients from controls. By multivariate analysis, APO-AI, APO-AII, HDL-C, and triglycerides in combination with the blood pressure or the body weight index were independent variables (in a mathematical sense). By comparing the present data with published results of previous studies it is concluded that cerebral atherosclerosis differs from other forms of atherosclerosis by several major risk indicators.

Adult↗

PubMed1984

Plasma lipids, lipoproteins and apolipoproteins AI, AII, and B in renal transplanted children: what risk for accelerated atherosclerosis?

The aim of the study was to investigate the atherosclerosis risk factors related to hyperlipidemia in renal transplanted children. Plasma cholesterol, triglycerides, apolipoproteins (Apo) AI, AII and B, and the major lipoprotein classes separated by gradient ultracentrifugation were compared in 30 renal transplanted patients and 14 healthy children. Hyperlipidemia was present in 66% of the transplanted children. 'Positive' risk factors for atherosclerosis (high plasma cholesterol and Apo B) were present in hypercholesterolemic and combined hyperlipidemic subgroups. All transplanted children, whether normo- or hyperlipidemic, presented essentially 'negative' risk factors for atherosclerosis, i.e. significantly higher levels of Apo AI and AII in plasma and in high-density lipoprotein HDL2 and higher Apo AI/Apo B and/or Apo AII/B ratios. Repeated evaluations (over a 12-month period) in transplanted children indicated relatively frequent individual changes in the lipid pattern, but not in Apo AI and AII content. These results suggest that the risks for accelerated atherosclerosis related to hyperlipidemia may be considered as moderate in transplanted children.

Adolescent↗

PubMed1987

Serum HDL cholesterol and apolipoprotein AI, AII and B levels in Singapore newborns.

The mortality from coronary artery disease (CAD) in Indians is more than three times that in the Chinese and Malays of Singapore. Serum total and HDL cholesterol as well as apolipoprotein (Apo) AI, AII and B levels were determined in a group of 349 newborns (cord blood) from both sexes in these three ethnic groups in order to examine if a trend is reflected at birth. Both serum LDL cholesterol and Apo B levels were low in the newborn, while HDL cholesterol and Apo AII levels were almost the same as in adults. Serum Apo AI levels were also low in newborns. No consistent difference as to ethnic group or sex was observed in any of the parameters investigated, except that the females had significantly higher levels of serum Apo AI in all the ethnic groups. Serum total and HDL cholesterol levels in Singapore newborns were comparable to those reported in Caucasians and Asians. The trends of incidence of CAD were not reflected in the lipid profiles studied at birth.

Apolipoprotein A-I↗

PubMed1984

Changes in apolipoprotein AI after treatment with high-dose medroxyprogesterone acetate.

21 women (mean age 60 years, range 48-72) were given depot medroxyprogesterone acetate (DMPA), 1,000 mg/week parenterally for 6 months, as part of the treatment for endometrial carcinoma in either clinical stage I or II. Before treatment and after 1, 3 and 6 months of treatment serum apolipoprotein AI was analyzed by electroimmunoassay. There was a significant decrease in apolipoprotein AI after the administration of DMPA, compared to the value before treatment. A low level of apolipoprotein AI is considered a risk factor for the development of atherosclerosis and cardiovascular disease. Such a risk might therefore be anticipated if the period of treatment was extended to several years.

Aged↗

PubMed1997

Complex genetic contribution of the Apo AI-CIII-AIV gene cluster to familial combined hyperlipidemia. Identification of different susceptibility haplotypes.

Familial combined hyperlipidemia (FCH) is a common genetic lipid disorder in Western societies. In a recent report (Dallinga-Thie, G.M., X.D. Bu, M. van Linde-Sibenius Trip, J.I. Rotter, A.J. Lusis, and T.W.A. de Bruin. J. Lipid Res., 1996, 36:136-147) we have studied three restriction enzyme polymorphisms: XmnI, and MspI sites 5' of the apo AI gene and SstI site in the 3' untranslated region of exon 4 of the apo CIII gene in 18 FCH pedigrees, including 18 probands, 178 hyperlipidemic relatives, 210 normolipidemic relatives, and 176 spouses. DNA variations in the apo AI-CIII-AIV gene cluster had a modifying effect on plasma triglycerides, LDL cholesterol, and apolipoprotein CIII levels. In this study, combinations of haplotypes were analyzed to further characterize their interactions and effect on the expression of severe hyperlipidemia in FCH subjects. A specific combination of haplotypes with one chromosome carrying the X1M1S2 (1-1-2) haplotype and the other the X2M2S1 haplotype (2-2-1) was significantly more frequent in hyperlipidemic relatives (6%) than in normolipidemic relatives (3%) and spouses (0.5%). Associated with this combination of haplotypes were significantly elevated plasma cholesterol (P < 0.0001), triglycerides (P < 0.0001), and apo CIII (P < 0.001) levels when compared to the wild type combination of haplotypes 1-1-1/1-1-1. The only spouse with this specific combination of haplotypes showed a severe hyperlipidemic phenotype, similar to FCH. Furthermore, nonparametric sibpair linkage analysis revealed significant linkage between these markers in the gene cluster and the FCH phenotype (MspI P = 0.0088, SstI P = 0.044, and XMS haplotype P = 0.037). The present findings confirm that the apo AI-CIII-IV gene cluster contributes to the FCH phenotype, but this contribution is genetically complex. An epistatic interaction between different haplotypes of the gene cluster was demonstrated. The S2 allele on one haplotype was synergistic to the X2M2 allele on the other haplotype in its hyperlipidemic effect. Therefore, two different susceptibility loci exist in the gene cluster, demonstrating the paradigm of complex genetic contribution to FCH.

Adult↗

PubMed1983

Cell-free translation of human liver apolipoprotein AI and AII mRNA. Processing of primary translation products.

Human liver apolipoprotein AI and A II poly(A+) mRNA has been translated in the cell-free rabbit reticulocyte lysate system. The structures of the two primary translation products of these two main protein components of human serum high-density lipoprotein (HDL) have been characterized. The products of the synthesis in vitro are preproapolipoproteins. The signal sequence (pre-sequence) of the primary translation product of human apo AI mRNA consists of 18 amino acids, that of apo AII of 17 amino acids. The cotranslational translocation into dog microsomal vesicles is associated with the cleavage of these sequences by the signal peptidase releasing the proapolipoproteins AI and AII, both extended by an N-terminal hexapeptide. Preproapolipoprotein AII is synthesized in its monomeric form consisting of 100 amino acids. Pro-apo AII is present in the vesicles of the endoplasmic reticulum also as monomer. Sequencing of the radiolabelled signal sequences of both pre-forms revealed their strongly hydrophobic nature. Despite the high affinity of HDL-apolipoproteins for complex lipids their secretion requires these hydrophobic signal sequences for translocation. Internal recognition sequences in the native apoproteins are not responsible for the transmembrane transport.

Amino Acid Sequence↗

PubMed1983

A serum proteinase converts proapolipoprotein AI secreted by rat hepatocytes to the mature apolipoprotein.

Apolipoprotein AI integrated into the high-density lipoprotein particle in serum was synthesized in the rat hepatocyte in the presence of radiolabelled amino acids and isolated from the cells in primary culture (suspension) as its proform, with the N-terminus extended by a hexapeptide segment. The primary secretion product is this proform which is only further proteolytically processed in the presence of the serum fraction with density higher than 1.21 g/ml. The secretion product and the proteolytically converted product were characterized by Edman degradation of their respective amino-acid sequences after radiolabelling with [3H]valine and [3H]phenylalanine, the positions of which are well established in the preproform and in the N-terminus of mature rat apolipoprotein AI. The products from the lysed cells and their culture medium were purified by immunoprecipitation, sodium dodecyl sulfate gradient gel electrophoresis and subsequent electroelution of the apo AI band. The proform sediments associated with a particle of density 1.16-1.20 g/ml. The serum proteinase which is inhibited by phenylmethanesulfonyl fluoride, but not by sulfhydryl reagents, is presumably a serine proteinase.

Animals↗

PubMed1997

Cortical convergence originating from domains representing different frequencies in the cat AI.

In order to reveal the cortical convergence, two different anterograde tracers were injected in the cat primary auditory cortex (AI). These tracers were located side by side in AI, at loci representing different best frequencies. Patches of labeled fibers were found mainly dorsal and ventral to each injection site. Patches located immediately dorsal and ventral to the injection sites did not overlap each other, but those located most distant from the injection sites overlapped significantly. Areas where the overlapping of labeled fibers were found correspond to the dorsal zone and secondary auditory field. The results suggest that the cortical convergence representing different frequency information takes place outside AI.

Animals↗

PubMed2004

Pregnancy rates after timed AI of heifers following removal of intravaginal progesterone inserts.

Reproductive performance of dairy heifers was compared for each of 2 synchronization protocols: The first group of 54 heifers was synchronized using intravaginal progesterone inserts (CIDR) plus estradiol cypionate (ECP) on d 0, PGF(2alpha) on d 7, and ECP again on d 8 (CIDR-ECP); a second group of 56 heifers was synchronized using CIDR and ECP on d 0, PGF(2alpha) on d 7, and GnRH on d 9 (CIDR-GnRH). All heifers received timed artificial insemination (TAI) at 48, 56, or 72 h after CIDR removal on d 7. Pregnancy diagnosis was conducted by ultrasonography 32 +/- 1 d post AI to confirm pregnancy and at 60 +/- 1 d post AI to determine embryo survival. Ovaries were monitored by ultrasonography daily from d 0 to 7 and twice daily from d 8 to ovulation to examine emergence of a new wave of follicles, size of the ovulatory follicle, and timing of ovulation on 15 heifers per protocol. New follicular development was detected 3.7 +/- 0.2 d after CIDR insertion. Heifers receiving CIDR-ECP had a shorter interval from CIDR removal to ovulation than heifers receiving CIDR-GnRH (63.8 +/- 3.0 vs. 71.6 +/- 2.3 h, respectively); however, ovulation occurred 39.8 +/- 3.0 h after ECP or 23.6 +/- 2.3 h after GnRH. Diameters of ovulatory follicles did not differ between treatments. Overall pregnancy rate for synchronized heifers was 60.1%, and embryo survival was 98%. Pregnancy rate for heifers synchronized with CIDR-ECP was 63.0% and similar to that in heifers synchronized with CIDR-GnRH (57.1%). Pregnancy rate was affected by time of AI for heifers synchronized using CIDR-ECP but not for those synchronized with CIDR-GnRH. Heifers in the CIDR-ECP group that were inseminated 56 h after CIDR removal had a higher pregnancy rate (81.0%) compared with heifers inseminated 48 (66.7%) or 72 h (50.0%) after CIDR removal. Either ECP or GnRH used in a CIDR-based TAI program in dairy heifers can achieve acceptable reproductive performance.

Administration, Intravaginal↗