John Albers - Academia.edu (original) (raw)
Papers by John Albers
Journal of Lipid Research, Jul 1, 2015
Supplementary key words phospholipid transfer protein • coronary artery disease • paraoxonase 1 C... more Supplementary key words phospholipid transfer protein • coronary artery disease • paraoxonase 1 Cholesterol carried on HDL (HDL-C) has long been believed to be cardioprotective, based on consistent epidemiologic fi ndings of an inverse relationship between incident CVD and HDL-C levels in subjects healthy at baseline (1, 2). Estimates from the Framingham Heart Study found that risk of myocardial infarction (MI) increased by 25% for each 5 mg/dl decrease in HDL-C below median values of HDL-C for both healthy men and women (2). Similar fi ndings of the cardioprotective effects of HDL-C have also been reported in subjects with CVD at baseline (3). In confl ict with these epidemiologic fi ndings, recent attempts to establish a causal relationship between HDL-C Abstract Recent studies have failed to demonstrate a causal cardioprotective effect of HDL cholesterol levels, shifting focus to the functional aspects of HDL. Phospholipid transfer protein (PLTP) is an HDL-associated protein involved in reverse cholesterol transport. This study sought to determine the genetic and nongenetic predictors of plasma PLTP activity (PLTPa), and separately, to determine whether PLTPa predicted carotid artery disease (CAAD). PLTPa was measured in 1,115 European ancestry participants from a casecontrol study of CAAD. A multivariate logistic regression model was used to elucidate the relationship between PLTPa and CAAD. Separately, a stepwise linear regression determined the nongenetic clinical and laboratory characteristics that best predicted PLTPa. A fi nal stepwise regression considering both nongenetic and genetic variables identifi ed the combination of covariates that explained maximal PLTPa variance. PLTPa was signifi cantly associated with CAAD (7.90 × 10 ؊ 9), with a 9% decrease in odds of CAAD per 1 unit increase in PLTPa (odds ratio = 0.91). Triglyceride levels (P = 0.0042), diabetes (P = 7.28 × 10 ؊ 5), paraoxonase 1 (PON1) activity (P = 0.019), statin use (P = 0.026), PLTP SNP rs4810479 (P = 6.38 × 10 ؊ 7), and PCIF1 SNP rs181914932 (P = 0.041) were all signifi cantly associated with PLTPa. PLTPa is signifi cantly inversely correlated with CAAD. Furthermore, we report a novel association between PLTPa and PON1 activity, a known predictor of CAAD.
Apolipoprotein E Highly Correlates with AβPP- and Tau-Related Markers in Human Cerebrospinal Fluid
Journal of Alzheimer's Disease, 2008
Journal of Lipid Research, 1990
Two types of A-I-containing lipoproteins are found in human high density lipoproteins (HDL): part... more Two types of A-I-containing lipoproteins are found in human high density lipoproteins (HDL): particles with A-I1 (Lp(A-I with A-11)) and particles without A-I1 (Lp(A-I without A-11)). We have studied the distribution of 1ecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer (CET) activities in these particles. Lp(A-I with A-11) and Lp(A-I without A-11) particles were isolated from ten normolipidemic subjects by anti-A-I and anti-A-I1 immunosorbents. Most plasma LCAT mass (70 k 15%), LCAT (69 f 16%), and CET (81 2 15%) activites were detected in Lp(A-I without A-11). Some LCAT (mass: 16 k 776, activity: 17 f 8%) and CET activities (7 f 8%) were detected in Lp(A-I with A-11). To determine the size subspecies that contain LCAT and CET activities, isolated Lp(A-I with All) and Lp(A-I without A-11) particles of six subjects were further fractionated by gel filtration column chromatography. In Lp(A-I without All), most LCAT and CET activities were associated with different size particles, with the majority of the LCAT and CET activities located in particles with hydrated Stokes diameters of 11.6 f 0.4 nm and 10.0 f 0.6 nm, respectively. In Lp(A-I with A-Il), most of the LCAT and CET activities were located in particles similar in size: 11.1 f 0.4 nm and 10.6 2 0.3 nm, respectively. Ultracentrifugation of A-I-containing lipoproteins resulted in dissociation of both LCAT and CET activities from the particles. Furthermore, essentially all CET and LCAT activities were recovered in the non-B-containing plasma obtained by anti-LDL immunoaffinity chromatography. I This report, therefore, provides direct evidence for the association of LCAT and CET protein with A-I-containing lipoproteins. Our conclusions pertain to fasting normolipidemic subjects and may not be applicable to hyperlipidemic or nonfasting subjects.-Cheung,
Atherosclerosis, Aug 11, 2016
Previous results of the AIM-HIGH trial showed that baseline levels of the conventional lipid para... more Previous results of the AIM-HIGH trial showed that baseline levels of the conventional lipid parameters were not predictive of future cardiovascular (CV) outcomes. The aims of this secondary analysis were to examine the levels of cholesterol in high density lipoprotein (HDL) subclasses (HDL2-C and HDL3-C), small dense low density lipoprotein (sdLDL-C), and LDL triglyceride (LDL-TG) at baseline, as well as the relationship between these levels and CV outcomes. Individuals with CV disease and low baseline HDL-C levels were randomized to simvastatin plus placebo or simvastatin plus extended release niacin (ERN), 1500 to 2000 mg/day, with ezetimibe added as needed in both groups to maintain an on-treatment LDL-C in the range of 40-80 mg/dL. The primary composite endpoint was death from coronary disease, nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome, or symptom-driven coronary or cerebrovascular revascularization. HDL-C, HDL3-C, sdLDL-C and ...
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2011
Phospholipid transfer protein (PLTP) facilitates the transfer of phospholipids among lipoproteins... more Phospholipid transfer protein (PLTP) facilitates the transfer of phospholipids among lipoproteins. Over half of the PLTP in human plasma has been found to have little phospholipid transfer activity (inactive PLTP). We recently observed that plasma PLTP specific activity is inversely correlated with high-density lipoprotein (HDL) level and particle size in healthy adults. The purpose of this study was to evaluate the factors that contribute to the variation in plasma PLTP specific activity. Analysis of the specific activity of PLTP complexes in nine plasma samples from healthy adults revealed two clusters of inactive PLTP complexes with mean molecular weights (MW) of 342kDa and 146kDa. The large and small inactive PLTP complexes represented 52±8% (range 39-63%) and 8±8% (range 1-28%) of the plasma PLTP, respectively. Active PLTP complexes had a mean MW of 207kDa and constituted 40±6% (range 33-50%) of the plasma PLTP. The specific activity of active PLTP varied from 16 to 32 μmol/μg/h. These data demonstrate for the first time the existence of small inactive plasma PLTP complexes. Variation in the amount of the two clusters of inactive PLTP complexes and the specific activity of the active PLTP contribute to the variation in plasma PLTP specific activity.
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](Journal of Lipid Research
Amino acid analysis was performed on four Lp[a] preparations to evaluate whether or not the amino... more Amino acid analysis was performed on four Lp[a] preparations to evaluate whether or not the amino acid data was consistent with Lp[a] containing one molecule of apolipoprotein[a] [apofa)] l i e d to one molecule of apoB-100. Amino acid analysis was carried out in duplicate on a Beckman model 121 amino acid analyzer. Apo[a] size was determined by a high-resolution agarose gel electrophoretic method that provides an estimate of apo[a] kringle 4 repeats. When Lp[a] was assumed to contain one apo[a] and one apoB molecule per particle, the average absolute bias between the expected molar percentage of each amino acid, as based on the known sequence of apo[a] and apoB, and the obtained molar percentage ranged from 2 to 3.5%. In contrast, by assuming two molecules of apo[a] and one of apoB per Lp[a] particle, the bias between the expected and observed molar percentage ranged from 8.5% to lo%, and by assuming one apo[a] and two apoB the bias ranged from 8.8% to 11.4%. Comparison of Lp[a] concentrations, calculated from six stable amino acids and the Lp[a] composition predicted from the known sequence, was in excellent agreement (bias ranging from 0.3% to 0.9%) with the Lp[al concentration calculated from the sum of the amino acid concentrations, when Lp[a] was assumed to contain one molecule of apo[a] and one molecule of apoB. However, there was poor agreement (7.4% to 8.4% bias) when it was assumed that Lp[a] contains two molecules of apo[a] and one molecule of apoB. These results indicate that the evaluated Lp[a] preparations contain one apo[a] per Lp[a] particle. Evaluation of amino acid analysis data provides a relatively simple approach to determine the molar ratio of apoB to apo[a] in Lp[a] and provides evidence that Lp[a] contains one molecule of apo[a] and one molecule of apoB.-Albers, J. J., H. Kennedy, and S. M. Marcovina. Evidence that Lp[a] contains one molecule of apo[a] and one molecule of apoB: evaluation of amino acid analysis data.
Standardization of the Immunochemical Determination of Apolipoproteins A-I and B: A Report on the International Federation of Clinical Chemistry Meeting on Standardization of Apolipoprotein A-I and B Measurements (Basis for Future Consensus), Vienna, Austria, April 18-19, 1989
Clinical Chemistry
The central aim of standardization is to have accurate, reproducible apo A-I and B measurements f... more The central aim of standardization is to have accurate, reproducible apo A-I and B measurements for use in defining a person's risk for cardiovascular disease or in evaluating a therapeutic response. A common accuracy-based standardization program is indispensable in establishing international reference intervals for clinical use. It is therefore important that the standardization be implemented as soon as possible. Many problems of the standardization of apo A-I and B measurements have been presented and discussed in this meeting. Although immediate solutions to all the problems were not evident, following the recommendations from this meeting can significantly improve the standardization process. The next step is to determine uniform reference intervals, followed by a consensus conference on apolipoproteins to define the cutpoints (cutoff values) for clinical decisions.
Journal of Lipid Research
The Association of Sleep Disturbances with Glycemia and Obesity in Youth at Risk for or with Recently Diagnosed Type 2 Diabetes
Pediatric Diabetes
Biochimica et biophysica acta, Sep 5, 2018
Human phospholipid transfer protein (PLTP) mediates the transfer of phospholipids among atheropro... more Human phospholipid transfer protein (PLTP) mediates the transfer of phospholipids among atheroprotective high-density lipoproteins (HDL) and atherogenic low-density lipoproteins (LDL) by an unknown mechanism. Delineating this mechanism would represent the first step towards understanding PLTP-mediated lipid transfers, which may be important for treating lipoprotein abnormalities and cardiovascular disease. Here, using various electron microscopy techniques, PLTP is revealed to have a banana-shaped structure similar to cholesteryl ester transfer protein (CETP). We provide evidence that PLTP penetrates into the HDL and LDL surfaces, respectively, and then forms a ternary complex with HDL and LDL.. Insights into the interaction of PLTP with lipoproteins at the molecular level provide a basis to understand the PLTP-dependent lipid transfer mechanisms for dyslipidemia treatment.
Acta Biochimica et Biophysica Sinica
Glioma is one of the common tumors in brain. The expression level of lipoprotein lipase (LPL) or ... more Glioma is one of the common tumors in brain. The expression level of lipoprotein lipase (LPL) or phospholipid transfer protein (PLTP) may influence glioma progression and its relationship with clinical and pathological parameters. The clinical significance of LPL or PLTP expression in glioma has not been established. In the present study, the LPL and PLTP levels in glioma tumors were investigated and the relationship between the LPL and PLTP level and the grade of malignant glioma was analyzed, with the aim to provide new ideas for the diagnosis and treatment of gliomas in clinical and basic research settings. LPL and PLTP mRNA and protein levels were significantly higher in Grade IV glioma than those in the lower grade tumors (P < 0.01). Double immunofluorescent staining showed that the levels of LPL and PLTP were significantly associated with the pathological grade of glioma (P = 0.005). The levels of LPL and PLTP were increased with the shortened survival of glioma patients (P < 0.001). Knockdown of LPL and PLTP led to decreased cell growth and migration but increased apoptosis in vitro. Additionally, cell cycle-related cyclins and their partners were found to be down-regulated while cyclin-dependent kinase inhibitors p16, p21, and Rb were up-regulated. Furthermore, knockdown of LPL or PLTP resulted in the up-regulation of pro-apoptotic molecules and the down-regulation of anti-apoptotic molecules. Ablation of LPL or PLTP in U251 cells resulted in the down-regulation of epithelial mesenchymal transition markers and invasion molecules matrix metalloproteinases. LPL and PLTP appear to be novel gliomaassociated proteins and play a role in the progression of human glioma.
It has been estimated that 37% of the US population judged to be at high risk for developing coro... more It has been estimated that 37% of the US population judged to be at high risk for developing coronary artery disease (CAD), based on the National Cholesterol Edu- cation Program guidelines, have increased plasma li- poprotein(a) (Lp(a)), whereas Lp(a) is increased in only 14% of those judged to be at low risk. Therefore, the importance of establishing a better understanding
Apolipoprotein Assays: Standardization and Quality Control
A correct approach to standardization, accuracy-based methods, and well-defined quality assurance... more A correct approach to standardization, accuracy-based methods, and well-defined quality assurance programs is indispensable for the definition of international reference intervals of apo A-I and apo B. Variability in the immunochemical determination of apo A-I and apo B can be due to both preanalytical and analytical variations, and standardized laboratories should evaluate and minimize each source of error in determining the reference intervals. A key requirement to reduce the variation between measurement techniques is the use of a common protocol for the calibration of the different methods. The basis of a calibration system is the primary standard with the absolute mass accurately determined. The primary standard is indispensable in assigning an accurate target value to reference materials with a reference method in which the primary standard immunochemically reacts the same as the protein in plasma. The reference material, which must behave immunochemically the same as the patient's sample in all methods, is then used to assign a target value to the calibrator in each method and system. Following this procedure, all assay results can be traced back to the primary standard via the serum reference material. The development and distribution of reference and quality control materials, which do not exhibit matrix effects between methods, is fundamental for the standardization process.
Proyecto de estandarización para la medición de apolipoproteínas A-I y B: II evaluación y selección de candidatos a materiales de referencia
Acta Bioquim Clin Latinoam, Mar 1, 1993
Mortality reduction in patients treated with long-term intensive lipid therapy: 25-year follow-up of the Familial Atherosclerosis Treatment Study - Observational Study
Journal of Clinical Lipidology, 2016
Cardiovascular disease (CVD) begins early in life and is associated with both the number of risk ... more Cardiovascular disease (CVD) begins early in life and is associated with both the number of risk factors present and length of exposure to these risk factors including hyperlipidemia. The clinical benefit of intensive lipid therapy over 25 years was investigated in the Familial Atherosclerosis Treatment Study-Observational Study. Of 175 coronary artery disease subjects with mean low-density lipoprotein cholesterol (LDL-C) of 191 mg/dL and mean age of 50 years, who completed the randomized and placebo-controlled Familial Atherosclerosis Treatment Study, 100 chose receiving lipid management by their physicians (usual care [UC]) and 75 elected to receive an intensive treatment [IT] for lipid management with lovastatin (40 mg/d), niacin (2.5 g/d), and colestipol (20 g/d) from 1989 to 2004, followed by double therapy with simvastatin (40-80 mg/d) and niacin from 2005 to 2006 and by triple therapy of ezetimibe 10 mg and simvastatin 40 to 80 mg/d plus niacin during 2007 to 2012. Deaths from CVD, non-CVD, and any cause were compared between UC and IT using Cox proportional hazards model. UC and IT groups were similar in risk factors with the exception that IT had more severe coronary artery disease. Mean LDL-C levels were 167 mg/dL from 1988 to 2004, 97 from 2005 to 2006, and 96 from 2007 to 2012 in surviving subjects receiving UC. IT lowered LDL-C to 119, 97, and 83 mg/dL in the 3 periods, respectively. Compared with UC, IT significantly reduced total mortality (11.1 vs 26.3 per 1000 person years [PY], hazard ratio [HR] = 0.45, 95% confidence interval [CI]: 0.26-0.77, P = .003) and CVD mortality (10.6 vs 27.7 per 1000 PY, HR = 0.34, 95% CI: 0.15-0.80, P = .009). The non-CVD mortality was also reduced but was not of statistical significance (6.8 vs 12.7 per 1000 PY, HR = 0.55, 95% CI: 0.27-1.14, P = .11). Long-term intensive lipid therapy significantly reduced total and cardiovascular mortality in Familial Atherosclerosis Treatment Study-Observational Study. These results support the importance of lifetime risk management to improve long-term outcome.
Activation of Lecithin:Cholesterol Acyltransferase by a Synthetic Model Lipid-Associating Peptide
Proceedings of the National Academy of Sciences, Jun 1, 1980
We have synthesized a model lipid-associating peptide of 20 residues (LAP-20) and studied its ass... more We have synthesized a model lipid-associating peptide of 20 residues (LAP-20) and studied its association with the phospholipid dimyristoyl phosphatidylcholine (DMPC) and its activation of the plasma enzyme lecithin:cholesterol acyl-transferase (EC 2.3.1.43). The lipid-associating behavior of LAP-20 is similar to that of well-characterized native plasma apolipoproteins after which it was modeled. Upon forming an isolated complex with DMPC, LAP-20 exhibits a large blue-shift in its intrinsic fluorescence, converts from a random coil to an alpha -helix, and changes turbid multilamellar structures of DMPC into small complexes that are optically clear. Addition of 2 mol % cholesterol does not detectably alter the structure or properties of the complex. The cholesterol-containing complexes of LAP-20 and DMPC are substrates for LCAT, having an activity 65% of that of complexes composed of DMPC, cholesterol, and the natural activator, apolipoprotein A-I. These findings suggest that the LCAT-activating regions of apoA-I may be confined to relatively short sequences that contain a lipid-binding determinant.
Biochemical and Biophysical Research Communications, Dec 26, 1995
Methods of detecting phospholipid transfer activity and kits therefor
Lipoprotein(a) quantification: comparison of methods and strategies for standardization
Curr Opin Lipidol, 1994
Despite an exponential increase in the number of published papers reporting the clinical signific... more Despite an exponential increase in the number of published papers reporting the clinical significance of lipoprotein(a), it is very difficult to relate the lipoprotein(a) data obtained from different studies because of wide dissimilarities in the reported values. Methodological aspects such as differences in assay design, degree of optimization, antibody source, calibration, and the expression of lipoprotein(a) values are the main contributors to the observed lack of comparability. A major effort in the evaluation and standardization of lipoprotein(a) assays is required to fully evaluate the clinical potential of lipoprotein(a) measurements.
The Journal of Lipid Research, Feb 1, 2002
Due to conflicting reports concerning the relationship between phospholipid transfer protein (PLT... more Due to conflicting reports concerning the relationship between phospholipid transfer protein (PLTP) activity and mass in plasma, the protein concentration and activity of PLTP were assessed in fractions isolated by fast protein liquid chromatography from the plasma of healthy normolipidemic individuals. Using both polyclonal and monoclonal antibodies, PLTP was identified by Western blot analysis after both SDS and non-denaturing gradient gel electrophoresis, and quantitated by dot blot. PLTP activity was determined using a labeled vesicle/HDL assay. PLTP mass corresponded substantially with the activity distribution using the polyclonal antibody on dot blot with some inactive PLTP being present. However, the monoclonal antibody preferentially reacted with inactive PLTP, primarily associated with LDL and large HDL, overestimating inactive PLTP. Western blot analysis of non-denaturing gradient gels, using the polyclonal antibody, indicated that active PLTP was associated with numerous discrete HDL subpopulations (7.6-12.0 nm) with the major portion being 9-12 nm. Inactive PLTP was associated with particles of 12 to Ͼ 17 nm. The monoclonal antibody demonstrated a different pattern of reactivity on gradient gels, showing strong reactivity with the inactive PLTP in particles of 12 to Ͼ 17 nm, but less reactivity with particles of 7.6-12 nm. The differences in reactivities of antibodies for active versus inactive PLTP can account for some of the discrepancies reported in the literature regarding the relationship between PLTP mass and activity.
Journal of Lipid Research, Jul 1, 2015
Supplementary key words phospholipid transfer protein • coronary artery disease • paraoxonase 1 C... more Supplementary key words phospholipid transfer protein • coronary artery disease • paraoxonase 1 Cholesterol carried on HDL (HDL-C) has long been believed to be cardioprotective, based on consistent epidemiologic fi ndings of an inverse relationship between incident CVD and HDL-C levels in subjects healthy at baseline (1, 2). Estimates from the Framingham Heart Study found that risk of myocardial infarction (MI) increased by 25% for each 5 mg/dl decrease in HDL-C below median values of HDL-C for both healthy men and women (2). Similar fi ndings of the cardioprotective effects of HDL-C have also been reported in subjects with CVD at baseline (3). In confl ict with these epidemiologic fi ndings, recent attempts to establish a causal relationship between HDL-C Abstract Recent studies have failed to demonstrate a causal cardioprotective effect of HDL cholesterol levels, shifting focus to the functional aspects of HDL. Phospholipid transfer protein (PLTP) is an HDL-associated protein involved in reverse cholesterol transport. This study sought to determine the genetic and nongenetic predictors of plasma PLTP activity (PLTPa), and separately, to determine whether PLTPa predicted carotid artery disease (CAAD). PLTPa was measured in 1,115 European ancestry participants from a casecontrol study of CAAD. A multivariate logistic regression model was used to elucidate the relationship between PLTPa and CAAD. Separately, a stepwise linear regression determined the nongenetic clinical and laboratory characteristics that best predicted PLTPa. A fi nal stepwise regression considering both nongenetic and genetic variables identifi ed the combination of covariates that explained maximal PLTPa variance. PLTPa was signifi cantly associated with CAAD (7.90 × 10 ؊ 9), with a 9% decrease in odds of CAAD per 1 unit increase in PLTPa (odds ratio = 0.91). Triglyceride levels (P = 0.0042), diabetes (P = 7.28 × 10 ؊ 5), paraoxonase 1 (PON1) activity (P = 0.019), statin use (P = 0.026), PLTP SNP rs4810479 (P = 6.38 × 10 ؊ 7), and PCIF1 SNP rs181914932 (P = 0.041) were all signifi cantly associated with PLTPa. PLTPa is signifi cantly inversely correlated with CAAD. Furthermore, we report a novel association between PLTPa and PON1 activity, a known predictor of CAAD.
Apolipoprotein E Highly Correlates with AβPP- and Tau-Related Markers in Human Cerebrospinal Fluid
Journal of Alzheimer's Disease, 2008
Journal of Lipid Research, 1990
Two types of A-I-containing lipoproteins are found in human high density lipoproteins (HDL): part... more Two types of A-I-containing lipoproteins are found in human high density lipoproteins (HDL): particles with A-I1 (Lp(A-I with A-11)) and particles without A-I1 (Lp(A-I without A-11)). We have studied the distribution of 1ecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer (CET) activities in these particles. Lp(A-I with A-11) and Lp(A-I without A-11) particles were isolated from ten normolipidemic subjects by anti-A-I and anti-A-I1 immunosorbents. Most plasma LCAT mass (70 k 15%), LCAT (69 f 16%), and CET (81 2 15%) activites were detected in Lp(A-I without A-11). Some LCAT (mass: 16 k 776, activity: 17 f 8%) and CET activities (7 f 8%) were detected in Lp(A-I with A-11). To determine the size subspecies that contain LCAT and CET activities, isolated Lp(A-I with All) and Lp(A-I without A-11) particles of six subjects were further fractionated by gel filtration column chromatography. In Lp(A-I without All), most LCAT and CET activities were associated with different size particles, with the majority of the LCAT and CET activities located in particles with hydrated Stokes diameters of 11.6 f 0.4 nm and 10.0 f 0.6 nm, respectively. In Lp(A-I with A-Il), most of the LCAT and CET activities were located in particles similar in size: 11.1 f 0.4 nm and 10.6 2 0.3 nm, respectively. Ultracentrifugation of A-I-containing lipoproteins resulted in dissociation of both LCAT and CET activities from the particles. Furthermore, essentially all CET and LCAT activities were recovered in the non-B-containing plasma obtained by anti-LDL immunoaffinity chromatography. I This report, therefore, provides direct evidence for the association of LCAT and CET protein with A-I-containing lipoproteins. Our conclusions pertain to fasting normolipidemic subjects and may not be applicable to hyperlipidemic or nonfasting subjects.-Cheung,
Atherosclerosis, Aug 11, 2016
Previous results of the AIM-HIGH trial showed that baseline levels of the conventional lipid para... more Previous results of the AIM-HIGH trial showed that baseline levels of the conventional lipid parameters were not predictive of future cardiovascular (CV) outcomes. The aims of this secondary analysis were to examine the levels of cholesterol in high density lipoprotein (HDL) subclasses (HDL2-C and HDL3-C), small dense low density lipoprotein (sdLDL-C), and LDL triglyceride (LDL-TG) at baseline, as well as the relationship between these levels and CV outcomes. Individuals with CV disease and low baseline HDL-C levels were randomized to simvastatin plus placebo or simvastatin plus extended release niacin (ERN), 1500 to 2000 mg/day, with ezetimibe added as needed in both groups to maintain an on-treatment LDL-C in the range of 40-80 mg/dL. The primary composite endpoint was death from coronary disease, nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome, or symptom-driven coronary or cerebrovascular revascularization. HDL-C, HDL3-C, sdLDL-C and ...
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2011
Phospholipid transfer protein (PLTP) facilitates the transfer of phospholipids among lipoproteins... more Phospholipid transfer protein (PLTP) facilitates the transfer of phospholipids among lipoproteins. Over half of the PLTP in human plasma has been found to have little phospholipid transfer activity (inactive PLTP). We recently observed that plasma PLTP specific activity is inversely correlated with high-density lipoprotein (HDL) level and particle size in healthy adults. The purpose of this study was to evaluate the factors that contribute to the variation in plasma PLTP specific activity. Analysis of the specific activity of PLTP complexes in nine plasma samples from healthy adults revealed two clusters of inactive PLTP complexes with mean molecular weights (MW) of 342kDa and 146kDa. The large and small inactive PLTP complexes represented 52±8% (range 39-63%) and 8±8% (range 1-28%) of the plasma PLTP, respectively. Active PLTP complexes had a mean MW of 207kDa and constituted 40±6% (range 33-50%) of the plasma PLTP. The specific activity of active PLTP varied from 16 to 32 μmol/μg/h. These data demonstrate for the first time the existence of small inactive plasma PLTP complexes. Variation in the amount of the two clusters of inactive PLTP complexes and the specific activity of the active PLTP contribute to the variation in plasma PLTP specific activity.
Journal of Lipid Research
Amino acid analysis was performed on four Lp[a] preparations to evaluate whether or not the amino... more Amino acid analysis was performed on four Lp[a] preparations to evaluate whether or not the amino acid data was consistent with Lp[a] containing one molecule of apolipoprotein[a] [apofa)] l i e d to one molecule of apoB-100. Amino acid analysis was carried out in duplicate on a Beckman model 121 amino acid analyzer. Apo[a] size was determined by a high-resolution agarose gel electrophoretic method that provides an estimate of apo[a] kringle 4 repeats. When Lp[a] was assumed to contain one apo[a] and one apoB molecule per particle, the average absolute bias between the expected molar percentage of each amino acid, as based on the known sequence of apo[a] and apoB, and the obtained molar percentage ranged from 2 to 3.5%. In contrast, by assuming two molecules of apo[a] and one of apoB per Lp[a] particle, the bias between the expected and observed molar percentage ranged from 8.5% to lo%, and by assuming one apo[a] and two apoB the bias ranged from 8.8% to 11.4%. Comparison of Lp[a] concentrations, calculated from six stable amino acids and the Lp[a] composition predicted from the known sequence, was in excellent agreement (bias ranging from 0.3% to 0.9%) with the Lp[al concentration calculated from the sum of the amino acid concentrations, when Lp[a] was assumed to contain one molecule of apo[a] and one molecule of apoB. However, there was poor agreement (7.4% to 8.4% bias) when it was assumed that Lp[a] contains two molecules of apo[a] and one molecule of apoB. These results indicate that the evaluated Lp[a] preparations contain one apo[a] per Lp[a] particle. Evaluation of amino acid analysis data provides a relatively simple approach to determine the molar ratio of apoB to apo[a] in Lp[a] and provides evidence that Lp[a] contains one molecule of apo[a] and one molecule of apoB.-Albers, J. J., H. Kennedy, and S. M. Marcovina. Evidence that Lp[a] contains one molecule of apo[a] and one molecule of apoB: evaluation of amino acid analysis data.
Standardization of the Immunochemical Determination of Apolipoproteins A-I and B: A Report on the International Federation of Clinical Chemistry Meeting on Standardization of Apolipoprotein A-I and B Measurements (Basis for Future Consensus), Vienna, Austria, April 18-19, 1989
Clinical Chemistry
The central aim of standardization is to have accurate, reproducible apo A-I and B measurements f... more The central aim of standardization is to have accurate, reproducible apo A-I and B measurements for use in defining a person's risk for cardiovascular disease or in evaluating a therapeutic response. A common accuracy-based standardization program is indispensable in establishing international reference intervals for clinical use. It is therefore important that the standardization be implemented as soon as possible. Many problems of the standardization of apo A-I and B measurements have been presented and discussed in this meeting. Although immediate solutions to all the problems were not evident, following the recommendations from this meeting can significantly improve the standardization process. The next step is to determine uniform reference intervals, followed by a consensus conference on apolipoproteins to define the cutpoints (cutoff values) for clinical decisions.
Journal of Lipid Research
The Association of Sleep Disturbances with Glycemia and Obesity in Youth at Risk for or with Recently Diagnosed Type 2 Diabetes
Pediatric Diabetes
Biochimica et biophysica acta, Sep 5, 2018
Human phospholipid transfer protein (PLTP) mediates the transfer of phospholipids among atheropro... more Human phospholipid transfer protein (PLTP) mediates the transfer of phospholipids among atheroprotective high-density lipoproteins (HDL) and atherogenic low-density lipoproteins (LDL) by an unknown mechanism. Delineating this mechanism would represent the first step towards understanding PLTP-mediated lipid transfers, which may be important for treating lipoprotein abnormalities and cardiovascular disease. Here, using various electron microscopy techniques, PLTP is revealed to have a banana-shaped structure similar to cholesteryl ester transfer protein (CETP). We provide evidence that PLTP penetrates into the HDL and LDL surfaces, respectively, and then forms a ternary complex with HDL and LDL.. Insights into the interaction of PLTP with lipoproteins at the molecular level provide a basis to understand the PLTP-dependent lipid transfer mechanisms for dyslipidemia treatment.
Acta Biochimica et Biophysica Sinica
Glioma is one of the common tumors in brain. The expression level of lipoprotein lipase (LPL) or ... more Glioma is one of the common tumors in brain. The expression level of lipoprotein lipase (LPL) or phospholipid transfer protein (PLTP) may influence glioma progression and its relationship with clinical and pathological parameters. The clinical significance of LPL or PLTP expression in glioma has not been established. In the present study, the LPL and PLTP levels in glioma tumors were investigated and the relationship between the LPL and PLTP level and the grade of malignant glioma was analyzed, with the aim to provide new ideas for the diagnosis and treatment of gliomas in clinical and basic research settings. LPL and PLTP mRNA and protein levels were significantly higher in Grade IV glioma than those in the lower grade tumors (P < 0.01). Double immunofluorescent staining showed that the levels of LPL and PLTP were significantly associated with the pathological grade of glioma (P = 0.005). The levels of LPL and PLTP were increased with the shortened survival of glioma patients (P < 0.001). Knockdown of LPL and PLTP led to decreased cell growth and migration but increased apoptosis in vitro. Additionally, cell cycle-related cyclins and their partners were found to be down-regulated while cyclin-dependent kinase inhibitors p16, p21, and Rb were up-regulated. Furthermore, knockdown of LPL or PLTP resulted in the up-regulation of pro-apoptotic molecules and the down-regulation of anti-apoptotic molecules. Ablation of LPL or PLTP in U251 cells resulted in the down-regulation of epithelial mesenchymal transition markers and invasion molecules matrix metalloproteinases. LPL and PLTP appear to be novel gliomaassociated proteins and play a role in the progression of human glioma.
It has been estimated that 37% of the US population judged to be at high risk for developing coro... more It has been estimated that 37% of the US population judged to be at high risk for developing coronary artery disease (CAD), based on the National Cholesterol Edu- cation Program guidelines, have increased plasma li- poprotein(a) (Lp(a)), whereas Lp(a) is increased in only 14% of those judged to be at low risk. Therefore, the importance of establishing a better understanding
Apolipoprotein Assays: Standardization and Quality Control
A correct approach to standardization, accuracy-based methods, and well-defined quality assurance... more A correct approach to standardization, accuracy-based methods, and well-defined quality assurance programs is indispensable for the definition of international reference intervals of apo A-I and apo B. Variability in the immunochemical determination of apo A-I and apo B can be due to both preanalytical and analytical variations, and standardized laboratories should evaluate and minimize each source of error in determining the reference intervals. A key requirement to reduce the variation between measurement techniques is the use of a common protocol for the calibration of the different methods. The basis of a calibration system is the primary standard with the absolute mass accurately determined. The primary standard is indispensable in assigning an accurate target value to reference materials with a reference method in which the primary standard immunochemically reacts the same as the protein in plasma. The reference material, which must behave immunochemically the same as the patient's sample in all methods, is then used to assign a target value to the calibrator in each method and system. Following this procedure, all assay results can be traced back to the primary standard via the serum reference material. The development and distribution of reference and quality control materials, which do not exhibit matrix effects between methods, is fundamental for the standardization process.
Proyecto de estandarización para la medición de apolipoproteínas A-I y B: II evaluación y selección de candidatos a materiales de referencia
Acta Bioquim Clin Latinoam, Mar 1, 1993
Mortality reduction in patients treated with long-term intensive lipid therapy: 25-year follow-up of the Familial Atherosclerosis Treatment Study - Observational Study
Journal of Clinical Lipidology, 2016
Cardiovascular disease (CVD) begins early in life and is associated with both the number of risk ... more Cardiovascular disease (CVD) begins early in life and is associated with both the number of risk factors present and length of exposure to these risk factors including hyperlipidemia. The clinical benefit of intensive lipid therapy over 25 years was investigated in the Familial Atherosclerosis Treatment Study-Observational Study. Of 175 coronary artery disease subjects with mean low-density lipoprotein cholesterol (LDL-C) of 191 mg/dL and mean age of 50 years, who completed the randomized and placebo-controlled Familial Atherosclerosis Treatment Study, 100 chose receiving lipid management by their physicians (usual care [UC]) and 75 elected to receive an intensive treatment [IT] for lipid management with lovastatin (40 mg/d), niacin (2.5 g/d), and colestipol (20 g/d) from 1989 to 2004, followed by double therapy with simvastatin (40-80 mg/d) and niacin from 2005 to 2006 and by triple therapy of ezetimibe 10 mg and simvastatin 40 to 80 mg/d plus niacin during 2007 to 2012. Deaths from CVD, non-CVD, and any cause were compared between UC and IT using Cox proportional hazards model. UC and IT groups were similar in risk factors with the exception that IT had more severe coronary artery disease. Mean LDL-C levels were 167 mg/dL from 1988 to 2004, 97 from 2005 to 2006, and 96 from 2007 to 2012 in surviving subjects receiving UC. IT lowered LDL-C to 119, 97, and 83 mg/dL in the 3 periods, respectively. Compared with UC, IT significantly reduced total mortality (11.1 vs 26.3 per 1000 person years [PY], hazard ratio [HR] = 0.45, 95% confidence interval [CI]: 0.26-0.77, P = .003) and CVD mortality (10.6 vs 27.7 per 1000 PY, HR = 0.34, 95% CI: 0.15-0.80, P = .009). The non-CVD mortality was also reduced but was not of statistical significance (6.8 vs 12.7 per 1000 PY, HR = 0.55, 95% CI: 0.27-1.14, P = .11). Long-term intensive lipid therapy significantly reduced total and cardiovascular mortality in Familial Atherosclerosis Treatment Study-Observational Study. These results support the importance of lifetime risk management to improve long-term outcome.
Activation of Lecithin:Cholesterol Acyltransferase by a Synthetic Model Lipid-Associating Peptide
Proceedings of the National Academy of Sciences, Jun 1, 1980
We have synthesized a model lipid-associating peptide of 20 residues (LAP-20) and studied its ass... more We have synthesized a model lipid-associating peptide of 20 residues (LAP-20) and studied its association with the phospholipid dimyristoyl phosphatidylcholine (DMPC) and its activation of the plasma enzyme lecithin:cholesterol acyl-transferase (EC 2.3.1.43). The lipid-associating behavior of LAP-20 is similar to that of well-characterized native plasma apolipoproteins after which it was modeled. Upon forming an isolated complex with DMPC, LAP-20 exhibits a large blue-shift in its intrinsic fluorescence, converts from a random coil to an alpha -helix, and changes turbid multilamellar structures of DMPC into small complexes that are optically clear. Addition of 2 mol % cholesterol does not detectably alter the structure or properties of the complex. The cholesterol-containing complexes of LAP-20 and DMPC are substrates for LCAT, having an activity 65% of that of complexes composed of DMPC, cholesterol, and the natural activator, apolipoprotein A-I. These findings suggest that the LCAT-activating regions of apoA-I may be confined to relatively short sequences that contain a lipid-binding determinant.
Biochemical and Biophysical Research Communications, Dec 26, 1995
Methods of detecting phospholipid transfer activity and kits therefor
Lipoprotein(a) quantification: comparison of methods and strategies for standardization
Curr Opin Lipidol, 1994
Despite an exponential increase in the number of published papers reporting the clinical signific... more Despite an exponential increase in the number of published papers reporting the clinical significance of lipoprotein(a), it is very difficult to relate the lipoprotein(a) data obtained from different studies because of wide dissimilarities in the reported values. Methodological aspects such as differences in assay design, degree of optimization, antibody source, calibration, and the expression of lipoprotein(a) values are the main contributors to the observed lack of comparability. A major effort in the evaluation and standardization of lipoprotein(a) assays is required to fully evaluate the clinical potential of lipoprotein(a) measurements.
The Journal of Lipid Research, Feb 1, 2002
Due to conflicting reports concerning the relationship between phospholipid transfer protein (PLT... more Due to conflicting reports concerning the relationship between phospholipid transfer protein (PLTP) activity and mass in plasma, the protein concentration and activity of PLTP were assessed in fractions isolated by fast protein liquid chromatography from the plasma of healthy normolipidemic individuals. Using both polyclonal and monoclonal antibodies, PLTP was identified by Western blot analysis after both SDS and non-denaturing gradient gel electrophoresis, and quantitated by dot blot. PLTP activity was determined using a labeled vesicle/HDL assay. PLTP mass corresponded substantially with the activity distribution using the polyclonal antibody on dot blot with some inactive PLTP being present. However, the monoclonal antibody preferentially reacted with inactive PLTP, primarily associated with LDL and large HDL, overestimating inactive PLTP. Western blot analysis of non-denaturing gradient gels, using the polyclonal antibody, indicated that active PLTP was associated with numerous discrete HDL subpopulations (7.6-12.0 nm) with the major portion being 9-12 nm. Inactive PLTP was associated with particles of 12 to Ͼ 17 nm. The monoclonal antibody demonstrated a different pattern of reactivity on gradient gels, showing strong reactivity with the inactive PLTP in particles of 12 to Ͼ 17 nm, but less reactivity with particles of 7.6-12 nm. The differences in reactivities of antibodies for active versus inactive PLTP can account for some of the discrepancies reported in the literature regarding the relationship between PLTP mass and activity.