Plasma apoA-I Concentrations Research Articles

M2 Monocyte Polarization in Dialyzed Patients Is Associated with Increased Levels of M-CSF and Myeloperoxidase-Associated Oxidative Stress: Preliminary Results

Cardiovascular diseases represent a major issue in terms of morbidity and mortality for dialysis patients. This morbidity is due to the accelerated atherosclerosis observed in these patients. Atherosclerosis is a chronic inflammatory disease characterized by key players such as monocytes, macrophages, or oxidized LDLs. Monocytes-macrophages are classified into subsets of polarized cells, with M1 and M2 macrophages considered, respectively, as pro- and anti-inflammatory. (1) Methods: The monocyte subsets and phenotypes were analyzed by flow cytometry. These data were completed by the quantification of plasma M-CSF, IL-8, CRP, Mox-LDLs, Apo-B, Apo-AI, chloro-tyrosine, and homocitrulline concentrations. The statistical differences and associations between two continuous variables were assessed using the Mann–Whitney U test and Spearman’s correlation coefficient, respectively. (2) Results: Hemodialyzed patients showed a significant increase in their concentrations of CRP, M-CSF, and IL-8 (inflammation biomarkers), as well as chloro-tyrosine and homocitrulline (myeloperoxidase-associated oxidative stress biomarkers). Moreover, we observed a higher percentage of M2 monocytes in the plasma of hemodialysis patients as compared to the controls. (3) Conclusions: Our data suggest that oxidative stress and an inflammatory environment, which is amplified in hemodialysis patients, seems to favor an increase in the concentration of circulating M-CSF, therefore leading to an increase in M2 polarization among circulating monocytes.

활동적 저항성 운동이 비만유도 노화 흰쥐 심장근의 apolipoprotein A-1 및 염증발현에 미치는 영향

The purpose of this study was to analyze the changes of dysfunctional HDL structure and inflammatory factors caused by toll like receptor 4 (TLR4) protein expression in order to enhance heart function for cardiovascular disease prevention. The study groups were consisted of 40 Wistar old male rats at 50 weeks, and were divided into 4 groups as a control group (Con; n=10), control exercise group (Con+Ex; n=10), high fat diet group (HFD; n=10), and high fat diet exercise group (HFD+Ex; n=10). Dynamic resistance exercise training program included of ladder-climbing exercise and treadmill exercise, 3 days per week, for 12 weeks. The expression of aplipoprotein A-1 (ApoA-I) and TLR4 p rotein was analyzed by western blot. Also, plasma ApoA-I and C-reaction protein (CRP) concentration was analyzed by ELISA. The body weight before sampling of HFD-Ex group was significantly (p.05) lower than HFD group. ApoA-I protein expression and plasma ApoA-I concentration in heart muscle were not significantly different between all groups. However, TLR4 protein expression and plasma CRP levels in heart muscle were significantly (p.05) decreased in the HFD-Ex group compared to the HFD group. Therefore, dynamic resistance exercise increases heart muscle function and reduces inflammatory cytokine secretion. However, additional protein analysis related to the function of dysfunctional HDL is needed and further studies will be needed.

Studies in genetically modified mice implicate maternal HDL as a mediator of fetal growth.

Studies in humans have shown a direct association between maternal plasma cholesterol concentrations and infant birthweight. Similarly, previous studies in our laboratory have shown that chow-fed mice lacking apolipoprotein (apo) A-I, the major protein in HDL, have low HDL-cholesterol (HDL-C) concentrations and smaller fetuses in midgestation. In the current study, we measured fetal weights in mice with varying levels of apoA-I gene dose (knockout, wild-type, and transgenic) and examined metabolic pathways known to affect fetal growth. As expected, we found the differences in apoA-I expression led to changes in HDL particle size and protein cargo as well as plasma cholesterol concentrations. Fetal masses correlated directly with maternal plasma cholesterol and apoA-I concentrations, but placental masses and histology did not differ between groups of mice. There was no significant difference in glucose or amino acid transport to the fetus or in expression levels of the glucose (glucose transporter 1 and 2) or amino acid (sodium-coupled neutral amino acid transporter 1 and 2) transporters in whole placentas, although there was a trend for greater uptake of both nutrients in the whole fetal unit (fetus + placenta) of mice with greater apoA-I levels; significant differences in transport rates occurred when mice without apoA-I (knockout) vs. mice with apoA-I (wild-type and transgenic) were compared. Glucose tolerance tests were improved in the mice with the highest level of apoA-I, suggesting increased insulin-induced uptake of glucose by tissues of apoA-I transgenic mice. Thus, maternal HDL is associated with fetal growth, an effect that is likely mediated by plasma cholesterol or other HDL-cargo, including apolipoproteins or complement system proteins. A direct role of enhanced glucose and/or amino acid transport cannot be excluded.-Rebholz, S. L., Melchior, J. T., Davidson, W. S., Jones, H. N., Welge, J. A., Prentice, A. M., Moore, S. E., Woollett, L. A. Studies in genetically modified mice implicate maternal HDL as a mediator of fetal growth.

Bioinformatic Analysis of Plasma Apolipoproteins A-I and A-II Revealed Unique Features of A-I/A-II HDL Particles in Human Plasma.

Plasma concentration of apoA-I, apoA-II and apoA-II-unassociated apoA-I was analyzed in 314 Japanese subjects (177 males and 137 females), including one (male) homozygote and 37 (20 males and 17 females) heterozygotes of genetic CETP deficiency. ApoA-I unassociated with apoA-II markedly and linearly increased with HDL-cholesterol, while apoA-II increased only very slightly and the ratio of apoA-II-associated apoA-I to apoA-II stayed constant at 2 in molar ratio throughout the increase of HDL-cholesterol, among the wild type and heterozygous CETP deficiency. Thus, overall HDL concentration almost exclusively depends on HDL with apoA-I without apoA-II (LpAI) while concentration of HDL containing apoA-I and apoA-II (LpAI:AII) is constant having a fixed molar ratio of 2 : 1 regardless of total HDL and apoA-I concentration. Distribution of apoA-I between LpAI and LpAI:AII is consistent with a model of statistical partitioning regardless of sex and CETP genotype. The analysis also indicated that LpA-I accommodates on average 4 apoA-I molecules and has a clearance rate indistinguishable from LpAI:AII. Independent evidence indicated LpAI:A-II has a diameter 20% smaller than LpAI, consistent with a model having two apoA-I and one apoA-II. The functional contribution of these particles is to be investigated.

HDL mimetic CER-001 targets atherosclerotic plaques in patients

Background and aimsInfusion of high-density lipoprotein (HDL) mimetics aimed at reducing atherosclerotic burden has led to equivocal results, which may relate in part to the inability of HDL mimetics to adequately reach atherosclerotic lesions in humans. This study evaluated delivery of recombinant human apolipoprotein A-I (apoA-I) containing HDL mimetic CER-001 in carotid plaques in patients. MethodsCER-001 was radiolabeled with the long-lived positron emitter zirconium-89 (89Zr) to enable positron emission tomography with computed tomography (PET/CT) imaging. Eight patients with atherosclerotic carotid artery disease (>50% stenosis) received a single infusion of unlabeled CER-001 (3 mg/kg), co-administered with 10 mg of 89Zr-labeled CER-001 (18 MBq). Serial PET/CT imaging and contrast enhanced-magnetic resonance imaging (CE-MRI) were performed to evaluate targeted delivery of CER-001. ResultsOne hour after infusion, mean plasma apoA-I levels increased by 9.9 mg/dL (p = 0.026), with a concomitant relative increase in the plasma cholesterol efflux capacity of 13.8% (p < 0.001). Using serial PET/CT imaging, we showed that arterial uptake of CER-001 expressed as target-to-background ratio (TBRmax) increased significantly 24 h after infusion, and remained increased up to 48 h (TBRmax t = 10 min: 0.98; t = 24 h: 1.14 (p = 0.001); t = 48 h: 1.12 (p = 0.007)). TBRmax was higher in plaque compared with non-plaque segments (1.18 vs. 1.05; p < 0.001). Plaque TBRmax correlated with local plaque contrast enhancement (r = 0.56; p = 0.019) as assessed by CE-MRI. ConclusionsInfusion of HDL mimetic CER-001 increases plasma apoA-I concentration and plasma cholesterol efflux capacity. Our data support the concept that CER-001 targets plaque regions in patients, which correlates with plaque contrast enhancement. These clinical findings may also guide future nanomedicine development using HDL particles for drug delivery in atherosclerosis. Clinical trial registrationNetherlands Trial Registry – NTR5178.http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=5178.

High-sensitivity C-reactive protein, apolipoproteins, and residual diuresis in chronic kidney disease patients undergoing hemodialysis.

Residual diuresis (RD) is the simplest method for measuring renal residual function in patients with chronic kidney disease (CKD). A reduction in RD is associated with intensification of the inflammatory process caused by uremia. However, little is known regarding the relation between RD and inflammatory markers in these patients. We verify possible associations among the hs-CRP, atherogenic factors, and RD, in patients with CKD undergoing hemodialysis. This study enrolled 80 patients with CKD undergoing hemodialysis. Patients were stratified according to RD in anuric (RD-) group (n=47) and non-anuric (RD+) group (n=33). Urine volumes were collected in a 24h period during the interdialytic period. Serum high-sensitivity C-reactive protein (hs-CRP), and apolipoprotein (Apo) A1 and B levels were measured after fasting for 12h. Serum hs-CRP levels were higher in the RD- group than in the RD+ group (P=0.015). In the total group, hs-CRP was significantly correlated with RD (r=-0.25, P=0.025) and Apo AI (r=-0.25, P=0.024). A greater proportion of patients had reduced plasma concentrations of Apo AI in the RD- group (31.9%) compared with the RD+ group (9.1%) (P=0.014). This study shows a relationship between RD and the hs-CRP in patients undergoing hemodialysis. Although the inflammatory state was verified in a large part of the CKD population, patients without RD had more elevated hs-CRP serum levels than those with RD.

Marked antioxidant effect of orange juice intake and its phytomicronutrients in a preliminary randomized cross-over trial on mild hypercholesterolemic men

Blond orange juice is the most consumed fruit juice in the world. It is a source of hesperidin, a bioavailable flavonoid reported to exhibit potential vascular protective actions. However, the specific impact on vascular function of Citrus phytomicronutrients, is unknown. For the first time, we investigated the effects of blond orange juice compared with a control beverage mimicking the composition of orange juice (including Vitamin C but no phytomicronutrients), on antioxidant markers, cardiovascular risk factors and endothelial function. Twenty five male volunteers with two cardiovascular risk factors (age over 50 years and LDL-cholesterol between 130 and 190mg/L) were enrolled in a randomized cross-over study. They received 3 times daily 200mL of either blond orange juice or control beverage for 4 weeks, spaced by a 5-week wash-out. Endothelial function (flow mediated dilatation and plasma markers), oxidative status, lipid profile and inflammatory markers were assessed. Daily intakes of orange juice significantly led to a marked antioxidant effect which was correlated to hesperetin plasma levels and related with a decrease in reactive oxygen species. A tendency towards reduction of endothelial dysfunction and modest increase in plasma apoA-I concentration were also observed. This allows further experiments demonstrating the specific effect of phytomicronutrients from orange juice. These findings suggest that daily intake of nutritionally relevant dose of blond orange juice may contribute for a significant antioxidant effect through the phytochemicals contained in. Orange juice may be associated to other healthy foods to achieve a significant effect on the vascular function. This study is recorded in ClinicalTrials.com as NCT00539916.

Short term resistance training enhanced plasma apoA-I and FABP4 levels in Streptozotocin-induced diabetic rats

BackgroundType 1 diabetes mellitus is associated with a high risk for early atherosclerotic complications. Altered lipids and lipoprotein metabolism in chronic diabetes mellitus is associated with pathogenesis of atherosclerosis and other cardiovascular diseases. The aim of this study was to investigate the effects of 4 weeks resistance training on plasma lipid profile, fatty acid binding protein (FABP) 4 and apolipoprotein (apo) A-I levels in type 1 diabetic rats.MethodsThirty two male Wister rats (12–14 weeks old) were randomly divided into four groups: non-diabetic control; non-diabetic trained; diabetic control; diabetic trained. The rats in training groups were subjected to a resistance training program (3 days/wk, for 4 wk) consisted of climbing a ladder carrying a load suspended from the tail.ResultsDiabetic inducing increased plasma apoA-I and decreased FABP4 levels compared with non-diabetic control group (respectively, P = 0.001 & P = 0.041). After 4 weeks’ resistance training, plasma levels of apoA-I and FABP4 in the diabetic trained rats were significantly higher compared with the diabetic control group (respectively, P = 0.003 & P = 0.017). Plasma HDL-C level in diabetic trained group was higher than diabetic control group (P = 0.048). Liver triglycerides concentrations were significantly lower in both trained (non-diabetic and diabetic) groups compared with their control groups (respectively, P = 0.041 and P = 0.002).ConclusionThese data indicated that resistance training may be an efficient intervention strategy to increase plasma apoA-I, HDL-C and FABP4 concentrations, along with decreases liver triglycerides in streptozotocin induced diabetic rats. Further research is needed to elucidate physiological significance of circulating FABP4 levels.

Antiobesity and Vasoprotective Effects of Resveratrol in ApoE-Deficient Mice

This study was performed to investigate the hypolipidemic, antiobese, and antiatherogenic effects of resveratrol in apoE-deficient mice fed an atherogenic diet (20% fat and 1% cholesterol). These animals were fed an atherogenic diet containing 0.02% lovastatin (w/w) or 0.02% resveratrol (w/w) for 12 weeks. Resveratrol and lovastatin supplementation significantly reduced either the body weight or epididymal fat weight without altering the food intake and food efficiency ratio. Resveratrol significantly decreased the plasma total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C) concentrations, apoB/apoA-I ratio, hepatic cholesterol, and triglyceride (TG) contents, whereas significantly it increased the plasma HDL-C concentration compared with the control and lovastatin groups. Plasma and hepatic TG and plasma apoB levels were significantly lower in both the lovastatin and resveratrol groups than in the control group without altering the plasma apoA-I concentration. Both resveratrol and lovastatin significantly decreased hepatic fatty acid and TG synthesis, whereas they increased fatty acid oxidation (β-oxidation) except for the carnitine palmitoyltransferase activity compared with the control group. However, there was no difference in hepatic 3-hydroxyl-3-methylglutaryl-CoA reductase activity among the groups, although hepatic acyl-CoA: cholesterol acyltransferase activity was significantly lower in the lovastatin groups than in the control group. In epididymal adipose tissue, resveratrol supplementation led to an increase in β-oxidation and decrease in TG synthesis, compared with the control group. Tissue morphology revealed that there were dramatic decreases in hepatic lipid droplets and aortic fatty streaks by resveratrol and lovastatin supplementation. This study demonstrates that resveratrol exerts not only antiobesity and hypolipidemic effects, but also protective effects for the liver and aorta through the modulation of lipid metabolism in both the liver and white adipose tissues.

A multiple ascending dose study of CSL112, an infused formulation of ApoA‐I

CSL112 is apoA-I purified from human plasma and reconstituted with phosphatidylcholine (PC) to form high-density lipoprotein (HDL)-particles suitable for infusion. CSL112 is in development for the potential treatment of acute coronary syndromes (ACS) by optimizing cholesterol efflux. This study assesses the pharmacokinetics (PK), safety and tolerability of CSL112. Repeat doses of CSL112 or placebo were administered intravenously once- (3.4 g or 6.8 g) or twice-weekly (3.4 g) to healthy subjects in a placebo-controlled, randomized (3 CSL112: 1 placebo), ascending-dose study (NCT01281774). Twenty-seven subjects received CSL112 and nine received placebo. Study endpoints included plasma apoA-I and PC concentrations and specific PK parameters. CSL112 infusions immediately produced robust increases in apoA-I concentration in a dose-proportional manner, reaching levels higher than observed with currently available or investigational HDL products. After infusion of CSL112, apoA-I levels remained above baseline for approximately 3 days. Multiple infusions of CSL112 were safe and well tolerated with no evidence of major organ toxicity or immunogenicity. CSL112 may provide a novel option to rapidly transport cholesterol from atherosclerotic plaque to the liver and reduce early recurrent events following ACS. The data presented here support continued clinical development of CSL112 in patient populations.

Alteraciones en el contenido proteico y disfunción de lipoproteínas de alta densidad en ratones hiperhomocisteinémicos

AimThe aim of this study was to evaluate the proteic changes in high-density lipoproteins (HDL) induced by methionine-induced hyperhomocysteinemia in mice and its relationship with two of their main antiatherogenic properties. Methods and resultsThe oral administration of methionine resulted in an elevation (∼8times) in the plasma concentration of homocysteine. Hyperhomocysteinemia was inversely correlated with the plasma concentration of HDL cholesterol and its main protein component of HDL, apolipoprotein (apo) A-I, respectively. The cholesterol efflux in vivo from macrophages to HDL was decreased in hyperhomocysteinemic mice compared with the control mice. However, the reverse cholesterol transport from macrophages to feces remained unchanged. On the other hand, the ability of HDL from hyperhomocysteinemic mice to prevent the oxidative modification of low-density lipoproteins (LDL) was found decreased and associated with a concomitant reduction in the plasma activity of paraoxonase-1 (PON1) and the plasma concentration of apoA-I, and with a relative reduction in the apoA-IV content (∼1.5times) in the hyperhomocysteinemic HDL, respectively. ConclusionThe decrease in the ability of HDL from hyperhomocysteinemic mice to prevent LDL from oxidation was associated with a decrease in the apoA-I, PON1 and apoA-IV.

Effect of an isoenergetic traditional Mediterranean diet on apolipoprotein A-I kinetic in men with metabolic syndrome

BackgroundThe impact of the Mediterranean diet (MedDiet) on high-density lipoprotein (HDL) kinetics has not been studied to date. The objective of this study was therefore to investigate the effect of the MedDiet in the absence of changes in body weight on apolipoprotein (apo) A-I kinetic in men with metabolic syndrome (MetS).MethodsTwenty-six men with MetS (NCEP-ATP III) were recruited from the general community. In this fixed sequence study, participants’ diet was first standardized to a control diet reflecting current averages in macronutrient intake in North American men, with all foods and beverages provided under isoenergetic conditions for 5 weeks. Participants were then fed an isoenergetic MedDiet over a subsequent period of 5 weeks to maintain their weight constant. During the last week of each diet, participants received a single bolus dose of [5,5,5-2H3] L-leucine and fasting blood samples were collected at predetermined time points. ApoA-I kinetic was determined by multicompartmental modeling using isotopic enrichment data over time. Data were analyses using MIXED models.ResultsThe response of HDL-cholesterol (C) to MedDiet was heterogeneous, such that there was no mean change compared with the control diet. Plasma apoA-I concentration (−3.9%) and pool size (−5.3%, both P < 0.05) were significantly lower after MedDiet and apoA-I production rate tended to be reduced (−5.7%, P = 0.07) with no change in apoA-I fractional catabolic rate (FCR, -1.6%, P = 0.64). Participants among whom HDL-C concentrations were increased with MedDiet (responders: mean ∆HDL-C: +9.9 ± 3.2%, N = 11) showed significantly greater reductions in apoA-I FCR and in apoB and very-low-density lipoprotein-triglycerides (VLDL-TG) concentrations (all P < 0.04) than those among whom HDL-C levels were reduced after the MedDiet (non-responders: mean ∆HDL-C: -12.0 ± 3.9%, N = 8). Correlation analysis revealed that only variations in apoA-I FCR (r = -0.48, P = 0.01) and in plasma VLDL-TG (r = −0.45, P = 0.03) concentrations were correlated with the individual HDL-C response to the MedDiet.ConclusionsData from this controlled feeding study suggest that the heterogeneous response of HDL-C to MedDiet, in the absence of important weight loss, is primarily related to individual variations in apoA-I FCR and in plasma VLDL-TG concentrations.Trial registrationClinicalTrial.gov registration number: NCT00988650

Abstract 125: Weight Loss Selectively Increases High-density Lipoprotein without apoC-III, a Subfraction with Protective Association Against Coronary Heart Disease.

Human high-density lipoprotein (HDL) particles are highly heterogeneous in composition, and in relation to coronary heart disease (CHD). Specifically, HDL containing apoC-III predicts increased incidence of CHD, whereas HDL that does not contain apoC-III predicts decreased CHD incidence. Recently, we found that obese subjects had a higher concentration of HDL with apoC-III and a lower concentration of HDL without apoC-III than normal weight controls. However, the effects of weight loss on HDL with or without apoC-III are not known. We studied 39 obese participants (mean BMI of 34) in a weight-loss trial assigned to a high fat 40%/high protein 25%/low carbohydrate 35% diet for 2 years. We chose this diet group because HDL-cholesterol (-C) levels increased the most compared to the other diet groups with more carbohydrate and less fat. Participants with at least 8% loss of initial body weight at 2 years were assigned to the weight loss group (n=21), while those without a change in weight comprised the no-weight loss group (n=18). Subjects were matched by age (mean 51 years), gender, and race. HDL without apoC-III and HDL with apoC-III were separated from plasma by sequentially using anti-apoA-I and anti-apoC-III immunoaffinity chromatography. For both groups, the mean baseline HDL-C and total plasma apoA-I concentrations were 48 and 119mg/dL, respectively. Weight loss increased HDL-C concentration by an average of 25% (p&lt;0.01 for changes between groups), and total apoA-I by 9% (p&lt;0.02). In the weight-loss group, mean apoA-I concentrations of HDL without apoC-III increased by12% (from 99 to 111 mg/dL) compared to a decrease of 6% in the no-weight loss group (from 107 to 101mg/dL) (p&lt;0.02). The apoA-I concentration of HDL with apoC-III, 15 mg/dL, remained unchanged. In conclusion , moderate weight loss selectively increased the concentration of HDL without apoC-III, the predominant HDL type that predicts reduced incidence of CHD. In contrast, weight loss did not affect HDL with apoC-III, an HDL type associated with increased CHD risk. This represents a partial normalization of HDL subtypes by moderate weight loss. This effect on HDL subpopulations defined by absence of apoC-III suggests a novel mechanism by which weight loss may reduce cardiovascular disease risk.

Abstract 18904: High-denisty Lipoprotein Distribution in Obesity Favors Apolipoprotein E and C-III-containing Subfractions Associated with Risk for Future Coronary Heart Disease

Human high-density lipoprotein (HDL) particles are highly heterogeneous in composition. Both the plasma concentration of HDL with apoC-III and the concentration of apoE in HDL predict higher incidence of coronary heart disease (CHD). Little is known about the concentration of HDL apoA-I associated with apoE or apoC-III, whether apoE and apoC-III are present in smaller or larger cholesterol ester-rich HDL, and whether the distribution is affected in obesity. We studied 20 normal weight subjects (BMI 23-25) and 20 obese subjects (BMI 30-35) matched by age (mean age, 51 years). Sixteen distinct HDL subpopulations were separated from plasma samples by first using anti-apoAI, anti-apoE and anti-apoC-III immunoaffinity chromatography in sequence followed by size separation using nondenaturing electrophoresis. The mean HDL-cholesterol and plasma apoA-I concentrations in the normal weight group were 65 and 179mg/dL respectively, compared to 50 and 170mg/dL in the obese group. Mean apoA-I concentrations of HDL fractions without apoE or apoC-III was 160mg/dL in the normal weight group, compared to 136mg/dL in the obese; with apoE only 9 and 12mg/dL respectively; with apoC-III only 7.4 and 14.7 mg/dL; and with both apoE and apoC-III 2.6 and 7.5mg/dL (p&lt;0.01 for a difference in apoA-I concentration and distribution across HDL types). All told, about 10% of HDL apoA-I in normal weight subjects contained apoE, apoC-III or both, compared to 20% in obese subjects. The concentrations of apoE and apoC-III in HDL in the obese were about double that of the normal weight group (p&lt;0.01). In the obese group, the high concentration of HDL with apoE was distributed to small HDL. More so, obese had a higher percent of large HDL containing apoC-III and no apoE. In conclusion, despite similar plasma total apoA-I levels in obese and normal weight groups, the obese had higher concentrations of HDL containing apoE or apoC-III, subfractions which are associated with CHD, whereas the normal weight group had higher concentration of HDL without apoE or apoC-III, a subtraction with protective association against CHD. Mechanistically, the increased presence of apoC-III in large size HDL and apoE in small size HDL in obese may indicate a reduced capacity of HDL for RCT.

Effect of weight loss, independent of change in diet composition, on apolipoprotein AI kinetic in men with metabolic syndrome

We investigated the effect of weight loss, independent of change in diet composition, on HDL and apoAI metabolism in men with metabolic syndrome (MetS). Subjects (19 men with MetS [NCEP-ATPIII]) were fed an isoenergetic Mediterranean-style diet for 5 weeks (all foods provided). Participants then underwent a 20-week free-living period during which they were counseled to restrict energy intake, after which they were again fed an isoenergetic Mediterranean-style diet for 5 weeks. At the end of the two controlled diets, participants received a single bolus of [5,5,5-(2)H(3)] (L)-leucine, and fasting blood samples were collected over a 96 h period. ApoAI kinetic was assessed using multicompartmental modeling of the tracer enrichment data. Participants achieved a 9.1 ± 2.8% reduction in body weight (P < 0.001). Weight loss resulted in an increase in plasma HDL-cholesterol (HDL-C) concentrations of 6.0% (P = 0.059) and HDL(3)-C of 7.9% (P = 0.045), attributable to a reduction in apoAI fractional catabolic rate (-7.8%; P = 0.046) with no change in apoAI production rate (2.2%; P = 0.58). These data indicate that weight loss, independent of variation in diet composition, increases plasma HDL primarily by delaying the catabolism of apoAI.

Abstract 171: Impact of the Mediterranean Diet on Apolipoprotein AI Kinetic in Men with Metabolic Syndrome

The impact of the Mediterranean diet (MedDiet) on HDL metabolism has not been extensively studied to date. The objective of the study was to investigate the effect of the MedDiet consumed under controlled isoenergetic feeding conditions on HDL as well as on apolipoprotein (apo) AI kinetic in men with metabolic syndrome (MetS). The diet of 26 men aged between 24 to 62 years with the MetS (NCEP-ATP III) was first standardized to a North American control diet, which was consumed for 5 weeks. MedDiet was then consumed over a subsequent period of 5 weeks. Both diets were consumed under isoenergetic feeding conditions with all foods, including red wine, provided to participants. During the last week of each diet, participants received a single bolus of [5,5,5- 2 H 3 ] L -leucine and fasting blood samples were collected at predetermined time points over a period of 96 hours. Kinetic parameters were derived using multicompartmental modeling of the enrichment data over time. Although no change in plasma HDL-C concentrations was observed, consumption of the MedDiet led to a significant reduction in plasma apoAI concentration and pool size (both P &lt;0.05) compared with the control diet. The MedDiet was also associated with a trend towards a reduction in apoAI production rate (PR, P =0.07) but had no impact on apoAI fractional catabolic rate (FCR, P =0.64). However, only variations in apoAI FCR correlated with diet-induced variations in plasma HDL-C and in apoAI concentrations ( r = -0.50 and r = -0.49 respectively, P &lt;0.02). Based on the individual HDL-C response to MedDiet, responders and non-responders were identified. Participants among whom HDL-C concentrations were increased with MedDiet (mean ΔHDL-C: +9.9 ± 3.2 %) showed significantly greater reductions in apoAI FCR and in apoB and VLDL-TG concentrations (all P &lt;0.04) than those among whom HDL-C levels were reduced after the MedDiet (mean ΔHDL-C: -11.1 ± 4.5 %). Data from this controlled feeding study suggest that the heterogeneous response of HDL-C and apoAI to MedDiet is primarily determined by variations in apoAI FCR, which in turn may be due to concurrent changes in plasma TG concentrations.

Low Rate of Production of Apolipoproteins B100 and AI in 2 Patients With Anderson Disease (Chylomicron Retention Disease)

Anderson disease is a rare inherited lipid malabsorption syndrome associated with hypocholesterolemia and linked to SAR1B mutations. The aim of this article was to analyze the mechanisms responsible for the low plasma apolipoprotein Apo-B100 and Apo-AI in 2 patients with Anderson disease. A primed constant infusion of (13)C-leucine was administered for 14 hours to determine the kinetics of lipoproteins. In the 2 patients, total cholesterol (77 and 85 mg/dL versus 155±32 mg/dL), triglycerides (36 and 59 versus 82±24 mg/dL), Apo-B100 (48 and 43 versus 71±5 mg/dL), and Apo-AI (47 and 62 versus 130±7 mg/dL) were lower compared with 6 healthy individuals. Very-low-density lipoprotein-B100 production rate of the patients was lower (4.08 and 5.52 mg/kg/day versus 12.96±2.88 mg/kg/day) as was the fractional catabolic rate (5.04 and 4.32 day(-1) versus 12.24±3.84 day(-1)). No difference was observed in intermediate-density lipoprotein-B100 and LDL-B100 kinetic data. The production rate of high-density lipoprotein Apo-AI was lower in the patients (7.92 and 8.64 versus 11.96±1.92 mg/kg/day) and the fractional catabolic rate was higher (0.38 and 0.29 versus 0.22±0.01 day(-1)). The low plasma Apo-B100 and Apo-AI concentrations in the patients with Anderson disease were mainly related to low rates of production.

Plasma levels of sphingosine-1-phosphate and apolipoprotein M in patients with monogenic disorders of HDL metabolism

BackgroundApolipoprotein M (apoM) has been identified as a specific sphingosine-1-phosphate (S1P) binding protein of HDL. Objectives and methodsTo investigate the in vivo effects of disturbed apoM or HDL metabolism we quantified S1P and apoM in plasmas of wild-type, apoM-knock-out, and apoM transgenic mice as well as 50 patients with seven different monogenic disorders of HDL metabolism and their 51 unaffected relatives. ResultsCompared to wild type mice, S1P plasma levels in apoM knock-out and apoM transgenic mice were decreased by 30% and increased by 270%, respectively. Compared to family controls, S1P and apoM levels in apoB-depleted plasma were significantly decreased by in average 34% and 12%, respectively, in heterozygous carriers of mutations in APOA1, LCAT or ABCA1, and by 70% and 48%, respectively, in carriers of two defective alleles in LCAT or ABCA1. Heterozygous mutations in CETP, SCARB1, LIPC, or LIPG did not significantly affect S1P or apoM concentrations. Albumin-corrected molar S1P-to-apoM ratios varied from 0.12 to 0.8 (median 0.3) and were not affected by any mutation. S1P levels in apoB-depleted plasma correlated significantly with HDL-cholesterol and less so with apoM both if apoA-I plasma concentrations were below the median. ConclusionIn the context of previous data, our findings can be explained by the existence of a specific apoM and S1P containing HDL subclass which contains a considerable molar excess of apoM over S1P and is critically determined by apoA-I up to a threshold concentration around the median found in a Caucasian population.

Studies in mice, hamsters, and rats demonstrate that repression of hepatic apoA-I expression by taurocholic acid in mice is not mediated by the farnesoid-X-receptor

It is claimed that apoA-I expression is repressed in mice by cholic acid (CA) and its taurine conjugate, taurocholic acid (TCA) via farnesoid X receptor (FXR) activation. We measured apoA-I expression in mice, hamsters, and rats treated with highly potent and selective synthetic FXR agonists or with TCA. All of the synthetic agonists bound to FXR with high affinity in a scintillation proximity assay. However, TCA did not compete with the radioligand up to the highest concentration used (100 μM). The C-site regulatory region of apoA-I, through which FXR has been reported to regulate its expression, is completely conserved across the species investigated. In both male and female human apoA-I-transgenic mice, we reproduced the previously reported strong inhibition of human apoA-I expression upon treatment with the typical supraphysiological dose of TCA used in such studies. However, in contrast to some previous reports, TCA did not repress murine apoA-I expression in the same mice. Also, more-potent and -selective FXR agonists did not affect human or murine apoA-I expression in this model. In LDL receptor-deficient mice and Golden Syrian hamsters, selective FXR agonists did not affect apoA-I expression, whereas in Wistar rats, some even increased apoA-I expression. In conclusion, selective FXR agonists do not repress apoA-I expression in rodents. Repression of human apoA-I expression by TCA in transgenic mice is probably mediated through FXR-independent mechanisms.

Impact of serum amyloid A on high density lipoprotein composition and levels

Serum amyloid A (SAA) is an acute-phase protein mainly associated with HDL. To study the role of SAA in mediating changes in HDL composition and metabolism during inflammation, we generated mice in which the two major acute-phase SAA isoforms, SAA1.1 and SAA2.1, were deleted [SAA knockout (SAAKO) mice], and induced an acute phase to compare lipid and apolipoprotein parameters between wild-type (WT) and SAAKO mice. Our data indicate that SAA does not affect apolipoprotein A-I (apoA-I) levels or clearance under steady-state conditions. HDL and plasma triglyceride levels following lipopolysaccharide administration, as well as the decline in liver expression of apoA-I and apoA-II, did not differ between both groups of mice. The expected size increase of WT acute-phase HDL was surprisingly also seen in SAAKO acute-phase HDL despite the absence of SAA. HDLs from both mice showed increased phospholipid and unesterified cholesterol content during the acute phase. We therefore conclude that in the mouse, SAA does not impact HDL levels, apoA-I clearance, or HDL size during the acute phase and that the increased size of acute-phase HDL in mice is associated with an increased content of surface lipids, particularly phospholipids, and not surface proteins. These data need to be transferred to humans with caution due to differences in apoA-I structure and remodeling functions.