Higher Apo Research Articles

The effect of PPARδ agonists (HS00098) on serum lipid profiles in diet-induced obese rhesus monkeys

Aim Activation of peroxisome proliferator-activated receptor δ (PPARδ) subtypes increases expression of genes involved in fatty acid transport and oxidation and alters adiposity in animal models of obesity and type-2 diabetes. We aim to explore the effects of peroxisome proliferator-activated receptor δ (PPARδ) subtypes on serum lipid profiles in obese rhesus monkey, especially evaluate the efficacy of investigational new drug (HS00098). Methods: First, a prototype of obese rhesus monkey was established by continuously feeding test animals a high fat diet for 2 months. Fifteen obese rhesus monkeys were randomly divided into 3 groups, and the 2 test groups were treated with GW 501516 and HS00098. The test groups were administered doses of 0.3 mg/kg for 1 month, then with 1 mg/kg for 1 month, and finally with 3 mg/kg for 1 month. The control group received placebo treatment. In each experiment, the body weight of each animal was measured and recorded initially and prior to changing the dose of the drug each month. The total cholesterol, blood glucose, triglyceride, high density lipoprotein cholesterol, low-density lipoprotein cholesterol, serum Apo-A1, Apo-B100 and insulin were tested. Results: The average body weight gain of the GW501516 and HS00098 groups was significantly lower than that of the control group. The group receiving the HS00098 treatment had a higher signifycant increase in high density lipoprotein and apo-A1 (P < 0.05) than the control monkeys, while the total cholesterol, triglycerides, low density lipoproteins, apo-B100, and insulin (P < 0.05 or P < 0.01) were significantly decreased. Compared with GW50-1516, the effects of HS00098 on serum lipid profiles in diet-induced obese rhesus monkeys are more obvious. Conclusion: These results suggested that the investigational drug (HS00098) can effectively reduce body weight, blood lipid and blood sugar levels of diet-induced obese rhesus monkeys.

Individuals at risk for Alzheimer's disease show differential patterns of ERP brain activation during odor identification.

BackgroundStudies suggest that older adults at risk of developing Alzheimer’s disease may show olfactory processing deficits before other signs of dementia appear.MethodsWe studied 60 healthy non-demented individuals, half of whom were positive for the genetic risk factor the Apolipoprotein E ɛ4 allele, in three different age groups. Event-related potentials to visual and olfactory identification tasks were recorded and analyzed for latency and amplitude differences, and plotted via topographical maps.ResultsVarying patterns of brain activation were observed over the post-stimulus epoch for ɛ4- versus ɛ4+ individuals on topographical maps. Individuals with the ɛ4 allele demonstrated different ERP peak latencies during identification of olfactory but not visual stimuli. High correct ApoE classification rates were obtained utilizing the olfactory ERP.ConclusionsOlfactory ERPs demonstrate functional decline in individuals at risk for Alzheimer’s disease at much earlier ages than previously observed, suggesting the potential for pre-clinical detection of AD at very early stages.

Inflammation predicts changes in high-density lipoprotein particles and apolipoprotein A1 following initiation of antiretroviral therapy

The effects of HIV infection and antiretroviral therapy (ART) on usual lipid levels have been reported. The effects of initiating versus deferring ART on high-density and low-density lipoprotein particle (HDL-P and LDL-P, respectively) concentrations and apolipoprotein (Apo) levels are not well described. In a subgroup of participants not taking ART at study entry who were randomized in the Strategies for Management of Antiretroviral Therapy (SMART) trial to immediately initiate ART ('viral suppression group') or to defer it ('drug conservation group'), lipoprotein particle concentrations and ApoA1 and ApoB levels were measured at baseline and at 2 and 6 months following randomization. Compared with drug conservation group (n = 126), HDL-P and ApoA1 levels increased among viral suppression participants (n = 128) after starting ART. At 6 months, viral suppression participants had 13% higher total HDL-P (P < 0.001) and 9% higher ApoA1 (P < 0.001). LDL-P, very low density lipoprotein particle, and ApoB did not differ significantly between the viral suppression and drug conservation groups. Among viral suppression participants, predictors of HDL-P and ApoA1 increases included baseline levels of high-sensitivity C-reactive protein (hsCRP) and interleukin 6 (IL-6), but not HIV RNA level, CD4 cell count, or traditional cardiovascular disease risk factors. The effect of starting ART on changes in HDL-P and ApoA1 was greater for those with higher versus lower baseline levels of IL-6 (P = 0.001 and 0.08, respectively, for interaction) or hsCRP (P = 0.01 and 0.04, respectively, for interaction). HDL-P and ApoA1 increase following ART initiation, to a degree that depends on the degree of inflammation present at entry. These findings suggest that activation of inflammatory pathways contribute to HIV-associated changes in HDL.

PS16 - 82. GLP-1 receptor agonism inhibits VLDL production and reverses hepatic steatosis by decreasing hepatic lipogenesis in high fat diet-fed APOE*3-Leiden mice

Glucagon-like peptide 1 (GLP-1) receptor agonism has been demonstrated to improve glucose intolerance and exendin-4, a GLP-1 receptor agonist, is currently being used for the treatment of type 2 diabetes mellitus. Recent studies suggest that GLP-1 may also ameliorate plasma triglyceride (TG) metabolism. In our previous study, we found exendin- 4 inhibited VLDL production by using APOE*3-Leiden (E3L) mouse, however, the mechanism underlying is still unclear. Therefore, the aim of this study was to evaluate the potential mechanism behind the inhibition of VLDL biosynthesis and secretion of exendin-4 in high fat diet-fed E3L mice.

A comparative study of serum and synovial fluid lipoprotein levels in patients with various arthritides

The aim of this study was to investigate apolipoprotein (apo) A-I, apo B, lipoprotein (Lp) (a), HDL-cholesterol (C), LDL-C, triglycerides (TG) and total cholesterol (TC) values in the serum and synovial fluid (SF) of untreated rheumatoid arthritis (RA), psoriatic arthritis (PsA), and osteoarthritis (OA) patients. MethodsPaired SF and serum samples were collected simultaneously from 14 patients with RA, 14 with PsA, and 16 with OA and tested for apo A-I, apo B, HDL-C, LDL-C, Lp(a), TC and TG. Serum C reactive protein (CRP) and amyloid A (SAA) levels were also determined. ResultsThe inflammatory arthritis patients had higher SF lipid levels with the exception of HDL. Reflecting increased synovial permeability, the lipid SF/serum ratio was always higher in RA and PsA with respect to OA patients. The positive correlation between serum and SF apo A-I, apo B, HDL-C, TG, and Lp(a) levels confirmed that there is lipoprotein diffusion into the SF.RA and PsA patients had lower concentrations of all serum lipids except for Lp(a) with respect to OA patients. The levels in the RA patients were similar to those in healthy matched controls, while the PsA patients had significantly lower apo A-I and HDL levels and higher apo B and LDL values. ConclusionsLipid diffusion into the joint cavity, which largely depends on the degree of inflammation, may contribute to modulating local inflammatory processes.

Relationship between lipid profiles and plasma total homocysteine, cysteine and the risk of coronary artery disease in coronary angiographic subjects

BackgroundHomocysteine and cysteine are considered as risk factors of cardiovascular disease. Homocysteine influences the liver expression of ApoA-I and decreases its blood level and HDL in genetic mice model. We aimed therefore to evaluate whether homocysteine and cysteine are associated with lipid parameters, and the joint effects of them on the risk of coronary artery disease (CAD). Plasma total homocysteine (tHcy), cysteine (tCys) and lipid markers were measured in 2058 consecutive coronary artery angiographic patients.ResultsPlasma tHcy but not tCys correlated negatively with ApoA-I (r = -0.153, P < 0.001) and with HDL cholesterol (r = -0.148, P < 0.001), and correlated positively with the risk of CAD (OR: 1.61; 95% confidence interval; 1.26 to 2.05). Combination of high tHcy and high tCys levels was associated with decreased ApoA-I and HDL cholesterol levels, and with increased risk of CAD (OR: 1.696, 95% CI (1.301-2.211)). Furthermore, low HDL cholesterol combined with low tHcy or high tHcy all had increased risk for CAD (OR: 1.254, 95% CI (1.114-1.565); OR: 1.332, 95% CI (1.093-1.624); respectively) whereas high HDL cholesterol counteracted the harmful effect of high tHcy on the risk of CAD. However, only the combination of high tHcy and high ApoA-I had an increased risk for CAD (OR: 1.438, 95% CI (1.170-1.768)).ConclusionsThe association of homocysteine and cysteine, ApoA-I or HDL cholesterol and their joint effects provide new insights on its role on CAD.

CD55 Deficiency Protects against Atherosclerosis in ApoE-Deficient Mice via C3a Modulation of Lipid Metabolism

Atherosclerosis, the leading cause of death in the Western world, is driven by chronic inflammation within the artery wall. Elements of the complement cascade are implicated in the pathogenesis, because complement proteins and their activation products are found in the atherosclerotic plaque. We examined the role of CD55, a membrane inhibitor of the complement component 3 (C3) convertase, which converts C3 into C3a and C3b, in atherosclerosis. CD55-deficient (CD55−/−) mice were crossed onto the atherosclerosis-prone apolipoprotein E (apoE)-deficient (apoE−/−) background. High fat–fed male apoE−/−/CD55−/− mice were strongly protected from developing atherosclerosis compared with apoE−/− controls. Lipid profiling showed significantly lower levels of triglycerides, nonesterified fatty acids, and cholesterol in apoE−/−/CD55−/− mice than that in controls after high-fat feeding, whereas body fat in apoE−/−/CD55−/− mice content was increased. Plasma levels of C3 fell, whereas concentrations of C3adesArg (alias acylation stimulating protein; ASP), produced by serum carboxypeptidase N–mediated desargination of C3a, increased in nonfasted high fat–fed apoE−/−/CD55−/− mice, indicating complement activation. Thus, complement dysregulation in the absence of CD55 provoked increased C3adesArg production that, in turn, caused altered lipid handling, resulting in atheroprotection and increased adiposity. Interventions that target complement activation in adipose tissue should be explored as lipid-decreasing strategies.

Granzyme B contributes to extracellular matrix remodeling and skin aging in apolipoprotein E knockout mice

Apolipoprotein E knockout (apoE-KO) mice have been utilized for decades as a model of atherosclerosis. However, in addition to atherosclerosis, apoE-KO mice develop extensive cutaneous xanthomatosis, accelerated skin aging and frailty when fed a high fat diet. Granzyme B (GrB) is a pro-apoptotic serine protease that has recently been shown to exhibit extracellular proteolytic activity in certain pathologies. In the present study, the role of GrB in skin aging and pathology was assessed using the apoE-KO model of skin aging. Male C57BL/6 wild type and apoE-KO mice were grown for 0, 5, 15 or 30 weeks on either a high fat (21.2% fat, 0.2% cholesterol) or regular chow diet (7% fat). ApoE/GrB double knockout (DKO) mice were also generated and assessed after being fed either diet for 30 weeks. Skin was removed from the mid to lower back and examined for age-related changes such as hair loss, skin thinning and collagen remodeling and disorganization. ApoE-KO mice exhibited signs of frailty, hair graying, hair loss, skin thinning, loss of collagen density and increased skin pathologies featuring collagen remodeling and reduced decorin compared to wild type controls. These phenotypes occurred earlier and were more severe when fed a high fat diet. In addition, we also observed increased GrB expression in proximity to areas of decorin degradation and reduced collagen density in the skin of apoE-KO mice. DKO mice exhibited protection against skin thinning, ECM degradation and loss of dermal collagen density. In summary, our results provide novel insights into the effects of a high fat diet and apoE deficiency on skin aging and pathology and suggest a role for GrB in age-related skin thinning and frailty.

Apolipoprotein E mRNA expression in mononuclear cells from normolipidemic and hypercholesterolemic individuals treated with atorvastatin

BackgroundApolipoprotein E (apoE) is a key component of the lipid metabolism. Polymorphisms at the apoE gene (APOE) have been associated with cardiovascular disease, lipid levels and lipid-lowering response to statins. We evaluated the effects on APOE expression of hypercholesterolemia, APOE ε2/ε3/ε4 genotypes and atorvastatin treatment in Brazilian individuals. The relationship of APOE genotypes and plasma lipids and atorvastatin response was also tested in this population.MethodsAPOE ε2/ε3/ε4 and plasma lipids were evaluated in 181 normolipidemic (NL) and 181 hypercholesterolemic (HC) subjects. HC individuals with indication for lowering-cholesterol treatment (n = 141) were treated with atorvastatin (10 mg/day/4-weeks). APOE genotypes and APOE mRNA in peripheral blood mononuclear cells (PBMC) were analyzed by TaqMan real time PCR.ResultsHC had lower APOE expression than NL group (p < 0.05) and individuals with low APOE expression showed higher plasma total and LDL cholesterol and apoB, as well as higher apoAI (p < 0.05). Individuals carrying ε2 allele have reduced risk for hypercholesterolemia (OR: 0.27, 95% I.C.: 0.08-0.85, p < 0.05) and NL ε2 carriers had lower total and LDL cholesterol and apoB levels, and higher HDL cholesterol than non-carriers (p < 0.05). APOE genotypes did not affect APOE expression and atorvastatin response. Atorvastatin treatment do not modify APOE expression, however those individuals without LDL cholesterol goal achievement after atorvastatin treatment according to the IV Brazilian Guidelines for Dyslipidemia and Atherosclerosis Prevention had lower APOE expression than patients with desirable response after the treatment (p < 0.05).ConclusionsAPOE expression in PBMC is modulated by hypercholesterolemia and the APOE mRNA level regulates the plasma lipid profile. Moreover the expression profile is not modulated neither by atorvastatin nor APOE genotypes. In our population, APOE ε2 allele confers protection against hypercholesterolemia and a less atherogenic lipid profile. Moreover, low APOE expression after treatment of patients with poor response suggests a possible role of APOE level in atorvastatin response.

E0301 The relationship between apolipoprotein E gene polymorphisms and coronary atherosclerosis disease in the Northern Chinese

BackgroundPrevious studies on the attribution of apolipoprotein (apo) E polymorphisms on the occurrence of coronary atherosclerosis disease (CAD) showed inconsistent results. Apo E is a constituent of lipoproteins with considerable...

Differential levels of apolipoprotein E and butyrylcholinesterase show strong association with pathological signs of Alzheimer's disease in the brain in vivo

Recently, we reported that 3 of the known risk factors of Alzheimer's disease (AD), i.e., advanced age, apolipoprotein E (ApoE) ε4, and female gender, are associated with differential levels of ApoE proteins and butyrylcholinesterase (BuChE) in the cerebrospinal fluid (CSF) of AD patients. The ApoE ε4 allele and certain BuChE polymorphisms synergistically affect the conversion rate of mild cognitive impairment (MCI) to AD. Here, we investigated interrelationships between ApoE and BuChE levels, and pathological markers of AD in vivo. CSF from patients with probable AD, assessed for cerebral glucose metabolism (CMRglc; n = 50) and Pittsburgh compound B (PIB) retention (β-amyloid [Aβ] load, n = 29) by positron emission tomography (PET), was used for measurement of BuChE, ApoE, Aβ, tau, phosphorylated tau (P-tau) and interleukin-1β (IL-1β) levels. Levels of ApoE and BuChE strongly correlated with CMRglc (fluorodeoxyglucose [FDG]-PET, r = 0.54, p < 0.0001, n = 50), cerebral Aβ load (PIB retention, r = 0.73, p < 0.0001, n = 29), and CSF P-tau (r = 0.73, p < 0.0001, n = 33). High ApoE protein was tied to low CMRglc and high PIB retention and P-tau. BuChE levels had opposite relationships. Other CSF covariates were levels of interleukin-1β and Aβ(42) peptide. The pattern of the patients' cognitive Z-scores strongly supported these observations. High ApoE protein was also linked to changes in 3 of the biodynamic properties of BuChE. In vitro analysis indicated that high ApoE protein levels were related to an increased pool of dormant BuChE molecules with an abnormally high intrinsic catalytic rate in CSF, which was "turned on" by excess Aβ peptides. The findings suggest that abnormally high levels of ApoE may play a causative role in the pathological events of AD, particularly those involving the early cholinergic deficit in the AD brain, through modulation of cholinesterases activities, hence disturbing the acetylcholine-dependent activity of neurons and nonexcitable cells such as glial cells.

Relationship between severity of coronary artery disease and apolipoprotein E gene polymorphism

To explore the possible contribution of the apolipoprotein (apo) E polymorphisms to the extent and severity of coronary artery disease (CAD) related to lipid metabolism. Overall, 53 Turkish patients, aged 54+/-11 years defined by coronary angiography were included in this cross-sectional study. Reardon's coronary artery scoring was used. Serum lipids were measured with enzymatic colorimetric methods. Apolipoproteins were measured with nephelometry. Apolipoprotein E gene polymorphisms were determined by the reverse hybridization method. Statistical analyses were performed using one-way ANOVA, Kruskal-Wallis and Chi- square tests. The genotype frequencies were 7.5% for E2/E3, 77.4% for E3/E3 and 15.1% for E3/E4. The E2 allele frequency was slightly lower than E4 allele. There were no significant differences between apo E2/E3, E3/E3 and E3/E4 genotypes for severity scorings (26, 41 and 32 respectively, p=0.30) and extent scorings (3.2, 5.5, 4.5, p=0.17). It was found that the most of patients who had E2/3 and E3/4 alleles had low severity scores. On the other hand, there were no significant score difference for patients who had E3/3 alleles. Lipids were not significantly different among the different genotypes. The E3 allele was associated with high apo B levels compared with E2 and E4 genotypes. It was found that severity and extent of disease were not related with lipid metabolism. We concluded that there were no statistically significant differences between genotypes for extent and severity scorings, but the apo E3 allele is associated with more severe disease than E2 allele. These associations with severity were mediated not only by changes in lipid metabolism but may be also by other mechanisms in CAD patients.

Impact of Serum Apolipoprotein A‐IV as a Marker of Cardiovascular Disease in Maintenance Hemodialysis Patients

The aim of this study was to investigate the relationship between serum apolipoprotein (apo) A-IV levels and markers for atherosclerosis, including carotid intima-media thickness (CIMT) and the ankle-brachial index (ABI), in hemodialysis patients. We performed a cross-sectional study involving 116 maintenance hemodialysis patients (70 males; median age, 64 years), measuring CIMT, ABI, the usual laboratory examinations, and serum apo A-IV before the dialysis session. The apo A-IV concentration was measured by a noncompetitive ELISA. Serum apo A-IV concentrations were significantly lower in hemodialysis patients with cardiovascular disease and plaque in the carotid artery. The apo A-IV level was positively associated with urea nitrogen and creatinine, and negatively associated with age, interleukin-6, the neutrophil/lymphocyte ratio, and maximum CIMT. Moreover, serum apo A-IV concentrations were significantly lower in the low ABI group. On logistic analysis, patients with high apo A-IV levels had a lower odds ratio for atherosclerosis (maximum CIMT > 1.0) and cardiovascular disease compared to patients with low apo A-IV levels. On stepwise multivariate regression analysis, the serum apo A-IV level was independently associated with creatinine, the neutrophil/lymphocyte ratio, and the maximum CIMT. Serum apo A-IV is associated with atherosclerotic lesions in hemodialysis patients. Apo A-IV levels may be useful for estimating the risk of cardiovascular disease in dialysis patients.

Increased apolipoprotein E level and reduced high-density lipoprotein mean particle size associate with low high-density lipoprotein cholesterol and features of metabolic syndrome

The metabolic syndrome (MetS) pandemic predisposes patients to low high-density lipoprotein cholesterol (HDL-C). To successfully treat low HDL-C, there is an urgent need for a better understanding of the changes in HDL particles in the low–HDL-C state. Especially, apolipoprotein (apo) E metabolism in HDL particles is an emerging and important issue. Therefore, we determined HDL subspecies, apo E distribution, and the impact of the MetS in subjects with low and high HDL-C. We studied 246 subjects derived from the Finnish Health 2000 Health Examination Survey. The 2 groups included 113 low–HDL-C (≤10th percentile) and 133 high–HDL-C (≥90th percentile) subjects. The low–HDL-C subjects had higher apo E concentration (39.4 ± 19.4 vs 25.6 ± 8.0 μg/mL, P < .001) and smaller HDL mean particle size (9.0 ± 0.2 vs 9.8 ± 0.3 nm, P < .001). The distribution of apo E genetic isoforms could not explain the difference. Apolipoprotein E content of very low-density lipoprotein particles was comparable between the study groups. In the low–HDL-C subjects, apo E level in large HDL particles was lower ( P < .001) compared with that in the high–HDL-C subjects. The subjects with MetS had smaller HDL mean particle size and higher serum apo E concentration. Serum apo E concentration associated positively with different MetS markers (waist circumference, triglycerides, and glucose), whereas HDL mean particle size associated with those negatively. Our results highlight that, in the low–HDL-C state, there are changes in the size and composition of HDL particles associating with MetS. Apolipoprotein E, although generally considered antiatherogenic, associates with MetS and low HDL-C. Our results emphasize the need for a better understanding of apo E metabolism in HDL particles.

TaqIB polymorphism in the CETP gene modulates the impact of HC/LF diet on the HDL profile in healthy Chinese young adults

The aim of this study was to investigate the interactions of genetic variants in the genes of cholesterol ester transfer protein ( CETP) and low-density lipoprotein receptor ( LDLR) with high carbohydrate and low fat (HC/LF) diet on lipid profiles in a young and healthy Chinese Han population. Fifty-six healthy subjects (22.89±1.80 years) were given washout diets of 31% fat and 54% carbohydrate for 7 days, followed by HC/LF diets of 15% fat and 70% carbohydrate for 6 days, with no total energy restriction. Serum lipid profiles at baseline, after washout and following HC/LF diets, as well as CETP and LDLR polymorphisms were analyzed. Carriers of B2 allele of CETP TaqIB polymorphism had significantly higher levels of high density lipoprotein cholesterol (HDL-C) and apo A-I in the whole study population after the diet intervention. Notably, males with CETP TaqIB B1B1 experienced significantly increased HDL-C and apo A-I after HC/LF diet. Regarding the LDLR Pvu II polymorphism, both P1P1 subjects and P2 carriers experienced decreased total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels after HC/LF diet with no statistically significant differences between the genotypes. Our results demonstrate that the elevated HDL-C levels after HC/LF diet in healthy Chinese Han youth are associated with CETP TaqI B2 allele while males with B1B1 genotype are more susceptible to the influence of HC/LF diet on their HDL-C levels. The decreased TC and LDL-C levels after HC/LF diet are not associated with LDLR Pvu II polymorphism.

Common Apolipoprotein E Gene Mutations Contribute to Lipoprotein Glomerulopathy in China

Background: Lipoprotein glomerulopathy (LPG) is a unique disease characterized by thrombus-like lipoprotein deposition in glomeruli and an increased serum apolipoprotein E level (ApoE protein or APOE gene). Several APOE mutations contribute to the occurring of LPG. Methods: We confirmed LPG in 7 individuals by renal biopsy, and investigated families of 2 patients with urinalysis, serum creatinine and serum lipid examination. Exons of APOE of all individuals as well as their relatives were amplified and sequenced directly. Results: Two types of APOE mutations were identified in the 7 patients and their relatives. APOE Maebashi (Arg142-Leu144→0) heterozygotes were found in 5 individuals who were from 4 different families. APOE Kyoto (Arg25-Cys) was confirmed heterogeneous in another 2 individuals. Both mutations present incomplete penetrance. Conclusion: Our research indicates that APOE Maebashi (Arg142-Leu144→0) is a common mutation in Chinese LPG. However, not all carriers of the 2 mutations have LPG, although hyperlipidemia and high serum ApoE level are tested. There are likely other reasons, such as a local mechanism in the glomeruli, which participated in the renal injury.

Relationship between PON1L55M and Q192R gene polymorphisms and high APO B/APO A-I ratios

Elevated Apolipoprotein B Apolipoprotein A-I ratio is a risk factor for predicting coronary artery disease (CAD). Paraoxonase 1 (PON1) is a high density lipoprotein (HDL) associated serum enzyme. PON1 protects lowdensity lipoproteins (LDLs) from oxidative modifications and thus has a protective effect against CAD progression. There are two common polymorphisms, Q192R and L55M, in PON1 gene. There may be a relationship between these polymorphisms and elevated ApoB/ApoA-I ratios. Therefore, we decided to evaluate effect of these polymorphisms on individuals with high and normal ApoB/ApoA-I ratios. To evaluate Q192R and L55M polymorphisms in Iranian case group (n=75) with high ApoB/ApoA-I ratio, and control group (n=75) with normal ApoB/ApoA-I ratio, we carried out PCR using specific primers. Then, we digested PCR products by RFLP. ApoB and ApoA-I levels were determined by immunoturbidimetry method. Genotype frequencies for Q192R were determined: 49.3%QQ, 44%QR, 6.7%RR in case group, and 53.3%QQ, 33.3%QR, 13.4%RR in controls (P= 0.236). Genotype frequencies for L55M were determined: 21.3%LL, 68%LM, 10.7%MM in case group and 42.7%LL, 52%LM, 5.3%MM in controls (P= 0.016). A significant relationship between L55M polymorphism and familial history of cardiovascular disease was found (P= 0.011). In our study PON1L55M polymorphism was associated with high ApoB/ApoA-I ratios in case group. Thus, L55M polymorphism may be an independent risk factor for cardiovascular disease. Since L55M polymorphism was associated with familial history of cardiovascular disease, it is better to evaluate L55M polymorphism in younger ages even in the absence of high ApoB/ApoA-I ratios.

The apolipoprotein E ε4 allele plays pathological roles in AD through high protein expression and interaction with butyrylcholinesterase

The apolipoprotein E (ApoE) ε4 allele has consistently been established as an Alzheimer's disease (AD) risk factor, but its pathological contribution to AD is obscure. Certain butyrylcholinesterase (BuChE) polymorphisms together with the ApoE ε4 allele synergistically increase the risk of AD. In addition, AD risk factors, i.e. advanced age, female gender and ApoE ε4 are associated with different levels of CSF BuChE in AD patients, and BuChE protein attenuates Aβ fibrillization in vitro. Here we investigated the roles of ApoE and BuChE gene products as modulators of pathological features of AD in vivo. We found that AD risk factors were associated with different levels of ApoE protein in the CSF of AD patients (n=115). Women and ApoE ε4 carriers had the highest levels of ApoE protein (up by 50-120%, p<0.01-0.0001), which were increased with age (r=0.30, p<0.0006). The CSF surrogate markers of pathological features of AD, i.e. high tau and P-tau, low Aβ(42) and high tau/Aβ(42) ratio, were associated with high levels of ApoE protein. Intriguingly, high ApoE protein levels were not only associated with low amounts of BuChE, but they also altered the aging and activity of this enzyme in concentration- and isoform-dependent manners, particularly in the presence of Aβ peptides. Both ApoE and BuChE levels were also differentially related to levels of the proinflammatory cytokine IL-1β. In conclusion, ApoE ε4 might impart its pathological role through high protein expression and interaction with BuChE, which in turn might modulate central cholinergic activity and Aβ load in the brain.

Decrease of Lp(a) during weight reduction in obese children is modified by the apo(a) kringle-IV copy number variation

Lipoprotein(a) [Lp(a)] is considered an independent risk factor for cardiovascular disease. Its concentration is mainly determined by the kringle-IV repeat copy number variation (CNV) at the apolipoprotein(a) [apo(a)] locus. We aimed to investigate the immediate effect of weight reduction on plasma Lp(a) levels and its dependency on the apo(a) CNV in obese children. We performed a prospective longitudinal intervention study of a low-fat hypocaloric diet conducted in a 3-week dietary camp for obese children. In all, 140 obese participants (54 boys and 86 girls) with a mean age of 12.5+/-1.6 years and a mean relative body mass index (BMI) before treatment of 165.6+/-24.7% were included. Body weight and plasma levels of Lp(a), lipids, apolipoproteins A-I and B, insulin, and C-reactive protein were determined before the onset and after the end of the intervention. In addition, the number of apo(a) kringle-IV repeats were determined using sodium dodecyl sulfate agarose gel electrophoresis. The mean loss of body weight was 5.0+/-1.3 kg (-6.6%), resulting in a mean decrease of the relative BMI of 6.6%. Blood chemistry revealed significant changes in all parameters, especially in Lp(a), with a decrease from 24.4+/-30.6 to 17.9+/-22.6 mg per 100 ml or -19% (P<0.001). The decrease of Lp(a) levels was higher in the group with low compared with high molecular weight apo(a) phenotypes (-23.9 vs -16.6%). Weight reduction in obese children is associated with significant changes in Lp(a) levels, especially in subjects with high pre-treatment Lp(a) concentrations. This effect is markedly influenced by the molecular phenotype at the copy-number variable apo(a) locus.

Fasting and postprandial apolipoprotein B-48 levels in healthy, obese, and hyperlipidemic subjects

Apolipoprotein (apo) B-48 is the only specific marker of intestinal lipoproteins. We evaluated a novel enzyme-linked immunosorbent assay (ELISA) standardized with recombinant apo B-48 to measure apo B-48 in plasma and triglyceride-rich lipoproteins (TRLs, density <1.006 g/mL). Coefficients of variation were less than 2.5%. Assay values correlated well ( r = 0.82, P < .001) with values obtained by gel scanning of TRLs (n = 75 samples); however, the gel scanning method yielded values that were about 50% lower than ELISA values. About 60% to 70% of apo B-48 was found in TRLs. In 12 healthy subjects, median fasting plasma apo B-48 levels were 0.51 mg/dL and were increased by 121% to 147% in the fed state. In 63 obese subjects, median fasting apo B-48 values were 0.82 mg/dL; and feeding resulted in almost no change in total cholesterol, non–high-density lipoprotein cholesterol, or total apo B values, whereas triglyceride, remnant lipoprotein cholesterol, and apo B-48 levels were significantly higher ( P < .05; by +73%, +58%, and +106%), and direct low-density lipoprotein cholesterol and direct high-density lipoprotein cholesterol were significantly lower ( P < .001, by −13% and −20%) than fasting values. Relative to controls, 270 hyperlipidemic subjects had significantly higher ( P < .001, +115%) fasting total apo B and higher apo B-48 values ( P = .06, +37%). Our data indicate that the apo B-48 ELISA tested provides highly reproducible results and is excellent for research studies. Median apo B-48 values in healthy subjects are about 0.5 mg/dL and increase more than 100% in the fed state. Elevated levels are observed in obese and hyperlipidemic subjects.