Plasma Proprotein Convertase Subtilisin/Kexin Type 9: A Marker of LDL Apolipoprotein B-100 Catabolism?

Abstract Background: Experimental studies suggest that proprotein convertase subtilisin/kexin type 9 (PCSK9) is an important regulator of LDL metabolism because of its ability to facilitate degradation of the LDL receptor. We investigated the association between plasma PCSK9 concentration and LDL apolipoprotein B-100 (apo B-100) metabolism in men with a wide range of body mass index values. Methods: We used GC-MS to study the kinetics of LDL apo B-100 after intravenous administration of deuterated leucine and analyzed the data by compartmental modeling. The plasma PCSK9 concentration was measured by ELISA. Results: Univariate regression analysis revealed the plasma PCSK9 concentration to be significantly and positively correlated with cholesterol (r = 0.543; P = 0.011), LDL cholesterol (r = 0.543; P = 0.011), apo B-100 (r = 0.548; P = 0.010), and LDL apo B-100 concentrations (r = 0.514; P = 0.023), and inversely correlated with the LDL apo B-100 fractional catabolic rate (FCR) (r = −0.456; P = 0.038). The association between plasma PCSK9 concentration and the LDL apo B-100 FCR remained statistically significant after adjusting for age, obesity, plasma insulin, homeostasis model assessment score, and dietary energy; however, this association had borderline significance after adjusting for plasma lathosterol. Conclusions: In men, variation in plasma PCSK9 concentration influences the catabolism of LDL apo B-100. This finding appears to be independent of obesity, insulin resistance, energy intake, and age.

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Compound Heterozygous Familial Hypercholesterolemia and Familial Defective Apolipoprotein B-100 Produce Exaggerated Hypercholesterolemia

Clinical Chemistry ◽

10.1093/clinchem/47.3.438 ◽

2001 ◽

Vol 47 (3) ◽

pp. 438-443 ◽

Cited By ~ 10

Author(s):

E Shyong Tai ◽

Evelyn S C Koay ◽

Edmund Chan ◽

Tzer Jing Seng ◽

Lih Ming Loh ◽

...

Keyword(s):

Cell Proliferation ◽

Genetic Analysis ◽

Familial Hypercholesterolemia ◽

Apolipoprotein B ◽

Ldl Cholesterol ◽

Index Case ◽

Ldl Receptor ◽

Cholesterol Concentration ◽

Apo B ◽

First Degree Relatives

Abstract Background: Familial hypercholesterolemia (FH) and familial defective apolipoprotein B-100 (FDB) represent ligand-receptor disorders that are complementary. Individuals with both FH and FDB are unusual. We report a family with both disorders and the impact of the mutations on the phenotypes of the family members. Methods: We used single strand conformation polymorphism (SSCP) and denaturing gradient gel electrophoresis (DGGE) for genetic analysis of all 18 exons and the promoter region of the LDL receptor and DGGE for genetic analysis of the apolipoprotein B-100 (apo B-100) gene. The functional significance of the apo B-100 mutation was studied using a U937 cell proliferation assay. Fasting serum lipid profiles were determined for the index case and seven first-degree relatives. Results: One of the patient’s sisters had a missense mutation (Asp407→Lys) in exon 9 of the LDL receptor and a serum LDL-cholesterol concentration of 4.07 mmol/L. Four other first-degree relatives had hyperlipidemia but no LDL-receptor mutation. However, these subjects had a mutation of the apo B-100 gene (Arg3500→Trp). The cell proliferation rate of U937 cells fed with LDL from other subjects with the same mutation was fourfold less than that of controls. The index case had both FH- and FDB-related mutations. Her serum LDL-cholesterol (9.47 mmol/L) was higher than all other relatives tested. Conclusions: Existence of both FH and FDB should be considered in families with LDL-receptor mutations in some but not all individuals with hypercholesterolemia or when some individuals in families with FH exhibit exaggerated hypercholesterolemia.

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Effect of Low-Density Lipoprotein Apheresis on Kinetics of Apolipoprotein B in Heterozygous Familial Hypercholesterolemia1

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.86.4.7428 ◽

2001 ◽

Vol 86 (4) ◽

pp. 1679-1686

Author(s):

Cyrille Maugeais ◽

Khadija Ouguerram ◽

Regis Frénais ◽

Pascale Maugère ◽

Bernard Charbonnel ◽

...

Keyword(s):

Apolipoprotein B ◽

Low Density Lipoprotein ◽

Ldl Receptor ◽

Lipoprotein Metabolism ◽

Density Lipoprotein ◽

Low Density ◽

Fractional Catabolic Rate ◽

Ldl Apheresis ◽

Catabolic Rate ◽

High Level

The acute reduction of low-density lipoprotein (LDL) cholesterol obtained by LDL-apheresis allows the role of the high level of circulating LDL on lipoprotein metabolism in heterozygous familial hypercholesterolemia (heterozygous FH) to be addressed. We studied apolipoprotein B (apoB) kinetics in five heterozygous FH patients before and the day after an apheresis treatment using endogenous labeling with [2H3]leucine. Compared with younger control subjects, heterozygous FH patients before apheresis showed a significant decrease in the fractional catabolic rate of LDL (0.24 ± 0.08 vs. 0.65 ± 0.22 day−1; P < 0.01), and LDL production was increased in heterozygous FH patients (18.9 ± 7.0 vs. 9.9 ± 4.2 mg/kg·day; P< 0.05). The modeling of postapheresis apoB kinetics was performed using a nonsteady state condition, taking into account the changing pool size of very low density lipoprotein (VLDL), intermediate density lipoprotein, and LDL apoB. The postapheresis kinetic parameters did not show statistical differences compared with preapheresis parameters in heterozygous FH patients; however, a trend for increases in fractional catabolic rate of LDL (0.24 ± 0.08 vs. 0.35± 0.09 day−1; P = 0.067) and the production of VLDL (13.7 ± 8.3 vs. 21.9 ± 1.6 mg/kg·day; P = 0.076) was observed. These results suggested that the marked decrease in plasma LDL obtained a short time after LDL-apheresis is able to stimulate LDL receptor activity and VLDL production in heterozygous FH.

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Comparison the effects of aqueous and ethanolic extracts of Rheum ribes on insulin resistance and apolipoprotein AI (ApoA1), apolipoprotein B (ApoB) and Apo B to ApoA1 ratio in patients with type 2 diabetes mellitus: A Randomized, Double-Blind, and Placebo-Controlled Clinical Trial

10.21203/rs.2.24417/v1 ◽

2020 ◽

Author(s):

Atieh Ghafouri ◽

Sahar Jafari Karegar ◽

Ghazaleh Hajiluian ◽

Sharieh Hosseini ◽

Shahrzad Shidfar ◽

...

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Apolipoprotein B ◽

Serum Levels ◽

Diabetic Patients ◽

Model Assessment ◽

Apo B

Abstract Background: This study was conducted to determine the effect of Rheum ribes supplementation on glycemic indices and apolipoproteins in patients with type 2 diabetes mellitus (DMT2).Methods: In this randomized controlled trial, sixty type 2 diabetic patients, aged 30-60 years with body mass index (BMI) of 20-30 kg/m 2 , and hemoglobin A1c (HbA1c) of 6-8% were included. The patients were randomly assigned to receive 450 mg of Rheum ribes aqueous extract (AG), 450 mg of Rheum ribes ethanolic extract (EG) or placebo (PG), three times daily for 6 weeks. Then glucose, the homeostatic model assessment (HOMA-IR and HOMA-B) and apolipoprotein A-I (ApoA1) and apolipoprotein B (ApoB) were measured.Results: According to these findings, in the AG and EG intervention groups, we observed a significant reduction in serum levels of insulin (P=0.003 and P=0.001, respectively), HOMA-IR (P=0.01 and P=0.001, respectively) and HOMA-B (P=0.002 and P=0.001, respectively) indices, without no significant changes in glucose. There was also a significant reduction in serum levels of ApoB (P=0.006 and P=0.03, respectively) and ApoB/ApoA1 ratio (P=0.016 and P=0.04, respectively) in both AG and EG. Intervention in both AG and EG had increasing effects on ApoA1 (P=0.08 and P=0.05, respectively). None of these variables had a significant change in PG. At the end of study, there were significant differences in insulin (P=0.04), HOMA-IR (P=0.03), HOMA-B (P=0.01), ApoB (P=0.02), and ApoB/ApoA1 (P=0.03) ratio among groups.Conclusions: Rheum ribes intake may have favorable effects on insulin resistance and apolipoproteins in diabetic patients.Trial registration: The study was recorded in Iranian Registry of Clinical Trials under the registration number of IRCT201410142709N31 (Registration date: 2014-12-11, https://en.irct.ir/trial/2543 ).

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Abstract 394: Ldl-cholesterol, ApoB100 Kinetics and Atherosclerosis in Ldlr-deficient Yucatan Minipigs: A New Model for Familial Hypercholesterolemia

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.37.suppl_1.394 ◽

2017 ◽

Vol 37 (suppl_1) ◽

Author(s):

Dawn E Telford ◽

Amy C Burke ◽

Brian G Sutherland ◽

Cynthia G Sawyez ◽

Jane Y Edwards ◽

...

Keyword(s):

Translational Research ◽

Familial Hypercholesterolemia ◽

Ldl Receptor ◽

Lipoprotein Metabolism ◽

Lesion Area ◽

Apo B ◽

Miniature Pigs ◽

Lipoprotein Response ◽

Kinetics Of ◽

Pool Sizes

Lack of animal models with human-like lipoprotein metabolism and pathology has hampered translational research in atherosclerosis. Recently, a model of familial hypercholesterolemia was developed in Yucatan miniature pigs, in which the LDL receptor (LDLR) was deleted through gene targeting of exon 4. The objective of the present study was to determine the plasma lipoprotein response to a high fat diet and the kinetics of apolipoprotein (apo) B metabolism in LDLR-deficient miniature pigs. LDLR+/+ (n=5), LDLR+/- pigs (n=6) and LDLR-/- pigs (n=5) were fed a diet containing 34% kcal from fat and 0.2% cholesterol (C). At 6 weeks, the kinetics of plasma apoB100 (fasting) were measured using stable isotopic techniques and multi-compartmental modeling. In chow-fed pigs, LDL-C was 0.8mM, 1.3mM and 14mM in LDLR+/+, LDLR+/- and LDLR-/- pigs, respectively. On diet for 6 weeks, LDL-C increased 1.3-fold (to 1.09mM), 1.7-fold (to 2.3mM) and 1.2-fold (to 15.8mM) in LDLR+/+, LDLR+/- and LDLR-/- pigs, respectively. The effect of genotype or diet on plasma TG and HDL-C was modest. Compared to LDLR+/+ pigs, VLDL apoB100 pool sizes increased 1.4-fold in LDLR+/- and 1.7-fold in LDLR-/- pigs, due primarily to a decrease in fractional catabolic rates (FCR) of 18% and 63%, respectively. Compared to LDL+/+ pigs, LDL apoB100 pool sizes increased 2.2-fold and 14-fold in LDLR+/- and LDLR-/-, respectively, which was due to both 1.5-fold and 2-fold increases in production rates and 24% and 85% decreases in FCR, respectively. At 23 weeks, raised lesion area in the abdominal aorta was 3.3% in LDLR+/- pigs and 48.5% in LDLR-/- pigs. In the left anterior descending coronary artery, lesion area was 14.7x10 3 μm 2 in LDLR+/- pigs and 656x10 3 μm 2 in LDLR-/- pigs. This model should prove useful for translational research in lipoprotein metabolism and atherosclerosis.

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Screening for familial defective apolipoprotein B-100 with improved U937 monocyte proliferation assay

Clinical Chemistry ◽

10.1093/clinchem/40.3.395 ◽

1994 ◽

Vol 40 (3) ◽

pp. 395-399 ◽

Cited By ~ 8

Author(s):

A J Van den Broek ◽

L Hollaar ◽

H I Schaefer ◽

A Van der Laarse ◽

H Schuster ◽

...

Keyword(s):

Apolipoprotein B ◽

Ldl Cholesterol ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Human Monocyte ◽

Cell Number ◽

Cholesterol Concentration ◽

U937 Cells ◽

Proliferation Assay ◽

Apo B

Abstract Frostegård et al. (J Lipid Res 1990;31:37-44) demonstrated that the proliferation of the human monocyte cell line U937 is critically dependent on the uptake of low-density lipoprotein (LDL) via the apo B, E (LDL) receptor, a characteristic that was used to detect patients with familial defective apolipoprotein B-100 (FDB). Here we applied this principle to develop a simple and reproducible assay for the detection of patients with functionally defective LDL. We added serum to U937 cells in cholesterol-free incubation medium and determined the increase in cell number after a 72-h incubation at 37 degrees C by using an electronic cell counter. Sera from 10 normolipidemic individuals and from 34 patients with type IIa hyperlipoproteinemia stimulated the growth of U937 cells in proportion to the exogenous cholesterol concentration (r = 0.83, P < 0.001) and the LDL-cholesterol concentration (r = 0.81, P < 0.001). However, sera from 16 patients with FDB stimulated less cell proliferation than did sera from patients with type IIa hyperlipoproteinemia with equal LDL-cholesterol concentrations. With a 15% reduction in growth as the cutoff value, this test had a sensitivity and specificity for diagnosis of FDB of 87.5% and 100%, respectively. The improved U937 monocyte proliferation assay can be used for screening hypercholesterolemic patients to detect individuals with functionally defective LDL.

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Scintigraphic studies in rats. Kinetics of insulin analogues covering wide range of receptor affinities

Diabetes ◽

10.2337/diabetes.40.5.628 ◽

1991 ◽

Vol 40 (5) ◽

pp. 628-632 ◽

Cited By ~ 3

Author(s):

I. Jensen ◽

V. Kruse ◽

U. D. Larsen

Keyword(s):

Insulin Analogues ◽

Wide Range ◽

Kinetics Of

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Structure and Function of Proprotein Convertase Subtilisin/kexin Type 9 (PCSK9) in Hyperlipidemia and Atherosclerosis

Current Drug Targets ◽

10.2174/1389450120666190214141626 ◽

2019 ◽

Vol 20 (10) ◽

pp. 1029-1040 ◽

Cited By ~ 1

Author(s):

Xinjie Lu

Keyword(s):

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Structure And Function ◽

Lipid Lowering ◽

Lipid Lowering Therapy ◽

Proprotein Convertase ◽

Novel Target ◽

New Treatments ◽

And Function

Background:One of the important factors in Low-Density Lipoprotein (LDL) metabolism is the LDL receptor (LDLR) by its capacity to bind and subsequently clear cholesterol derived from LDL (LDL-C) in the circulation. Proprotein Convertase Subtilisin-like Kexin type 9 (PCSK9) is a newly discovered serine protease that destroys LDLR in the liver and thereby controls the levels of LDL in plasma. Inhibition of PCSK9-mediated degradation of LDLR has, therefore, become a novel target for lipid-lowering therapy.Methods:We review the current understanding of the structure and function of PCSK9 as well as its implications for the treatment of hyperlipidemia and atherosclerosis.Results:New treatments such as monoclonal antibodies against PCSK9 may be useful agents to lower plasma levels of LDL and hence prevent atherosclerosis.Conclusion:PCSK9's mechanism of action is not yet fully clarified. However, treatments that target PCSK9 have shown striking early efficacy and promise to improve the lives of countless patients with hyperlipidemia and atherosclerosis.

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Interaction of 4-hydroxynonenal-modified low-density lipoproteins with the fibroblast apolipoprotein B/E receptor

Biochemical Journal ◽

10.1042/bj2340245 ◽

1986 ◽

Vol 234 (1) ◽

pp. 245-248 ◽

Cited By ~ 31

Author(s):

W Jessup ◽

G Jurgens ◽

J Lang ◽

H Esterbauer ◽

R T Dean

Keyword(s):

Apolipoprotein B ◽

Negative Charge ◽

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Low Density ◽

Lipid Peroxidation Product ◽

Modified Low Density Lipoproteins ◽

Peroxidation Product

The incorporation of the lipid peroxidation product 4-hydroxynonenal into low-density lipoprotein (LDL) increases the negative charge of the particle, and decreases its affinity for the fibroblast LDL receptor. It is suggested that this modification may occur in vivo, and might promote atherogenesis.

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Image Statistics Preserving Encrypt-then-Compress Scheme Dedicated for JPEG Compression Standard

Entropy ◽

10.3390/e23040421 ◽

2021 ◽

Vol 23 (4) ◽

pp. 421

Author(s):

Dariusz Puchala ◽

Kamil Stokfiszewski ◽

Mykhaylo Yatsymirskyy

Keyword(s):

Statistical Analysis ◽

Image Encryption ◽

Experimental Studies ◽

Quality Measures ◽

Input Image ◽

Jpeg Compression ◽

Image Statistics ◽

Compression Stage ◽

Wide Range ◽

The Impact

In this paper, the authors analyze in more details an image encryption scheme, proposed by the authors in their earlier work, which preserves input image statistics and can be used in connection with the JPEG compression standard. The image encryption process takes advantage of fast linear transforms parametrized with private keys and is carried out prior to the compression stage in a way that does not alter those statistical characteristics of the input image that are crucial from the point of view of the subsequent compression. This feature makes the encryption process transparent to the compression stage and enables the JPEG algorithm to maintain its full compression capabilities even though it operates on the encrypted image data. The main advantage of the considered approach is the fact that the JPEG algorithm can be used without any modifications as a part of the encrypt-then-compress image processing framework. The paper includes a detailed mathematical model of the examined scheme allowing for theoretical analysis of the impact of the image encryption step on the effectiveness of the compression process. The combinatorial and statistical analysis of the encryption process is also included and it allows to evaluate its cryptographic strength. In addition, the paper considers several practical use-case scenarios with different characteristics of the compression and encryption stages. The final part of the paper contains the additional results of the experimental studies regarding general effectiveness of the presented scheme. The results show that for a wide range of compression ratios the considered scheme performs comparably to the JPEG algorithm alone, that is, without the encryption stage, in terms of the quality measures of reconstructed images. Moreover, the results of statistical analysis as well as those obtained with generally approved quality measures of image cryptographic systems, prove high strength and efficiency of the scheme’s encryption stage.

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Familial hypertriglyceridemia: an entity with distinguishable features from other causes of hypertriglyceridemia

Lipids in Health and Disease ◽

10.1186/s12944-021-01436-6 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Ivette Cruz-Bautista ◽

Alicia Huerta-Chagoya ◽

Hortensia Moreno-Macías ◽

Rosario Rodríguez-Guillén ◽

María Luisa Ordóñez-Sánchez ◽

...

Keyword(s):

Apolipoprotein B ◽

Rare Variants ◽

Regulatory Proteins ◽

Fibroblast Growth Factor 21 ◽

Fibroblast Growth ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Apo B ◽

Independent Components ◽

Apolipoprotein A

Abstract Background Familial hypertriglyceridemia (FHTG) is a partially characterized primary dyslipidemia which is frequently confused with other forms hypertriglyceridemia. The aim of this work is to search for specific features that can help physicians recognize this disease. Methods This study included 84 FHTG cases, 728 subjects with common mild-to-moderate hypertriglyceridemia (CHTG) and 609 normotriglyceridemic controls. All subjects underwent genetic, clinical and biochemical assessments. A set of 53 single nucleotide polymorphisms (SNPs) previously associated with triglycerides levels, as well as 37 rare variants within the five main genes associated with hypertriglyceridemia (i.e. LPL, APOC2, APOA5, LMF1 and GPIHBP1) were analyzed. A panel of endocrine regulatory proteins associated with triglycerides homeostasis were compared between the FHTG and CHTG groups. Results Apolipoprotein B, fibroblast growth factor 21(FGF-21), angiopoietin-like proteins 3 (ANGPTL3) and apolipoprotein A-II concentrations, were independent components of a model to detect FHTG compared with CHTG (AUC 0.948, 95%CI 0.901–0.970, 98.5% sensitivity, 92.2% specificity, P < 0.001). The polygenic set of SNPs, accounted for 1.78% of the variance in triglyceride levels in FHTG and 6.73% in CHTG. Conclusions The clinical and genetic differences observed between FHTG and CHTG supports the notion that FHTG is a unique entity, distinguishable from other causes of hypertriglyceridemia by the higher concentrations of insulin, FGF-21, ANGPTL3, apo A-II and lower levels of apo B. We propose the inclusion of these parameters as useful markers for differentiating FHTG from other causes of hypertriglyceridemia.

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