Low Density Lipoprotein Phospholipids Research Articles

Exploration of plasma biomarkers for Alzheimer's disease by targeted lipid metabolomics based on nuclear magnetic resonance (NMR) spectroscopy.

Alzheimer's disease (AD) is the most common cause of dementia, but the disease lacks convenient and cost-effective alternative biomarkers currently. We utilized targeted lipid metabolomics based on nuclear magnetic resonance (NMR) spectroscopy to identify plasma biomarkers in AD patients. Our study was a cross-sectional study that enrolled 58 AD patients and 40 matched health controls (HCs). Firstly, we identified plasma lipid metabolites that were significantly different between the two groups based on P < 0.05 and variable importance in the projection (VIP) > 1. Then we examined the correlation between the lipid metabolites and cognitive function using partial correlation analysis and assessed the diagnostic ability of the lipid metabolites using receiver operating characteristic (ROC) curves. Seventeen lipoproteins showed significant differences between AD patients and HCs among 114 lipid metabolites. All 17 lipoproteins were subtypes of low-density lipoprotein (LDL). Among them, LDL-3 particle number, LDL-3 apolipoprotein-B, LDL-3 phospholipids, LDL free cholesterol and LDL phospholipids were significantly correlated with cognitive function. The ROC curves showed that LDL-2 triglycerides (TG) and LDL-3 TG could significantly distinguish AD patients from HCs, with the area under the curve (AUC) above 0.7. In addition, we explored a strategy of combined diagnosis that significantly improved the diagnostic efficacy for AD (AUC = 0.879). Our study provides insight into the lipoprotein alterations associated with AD and potential biomarkers for its diagnosis and cognitive function assessment.

Serum Levels of Adiponectin Are Strongly Associated with Lipoprotein Subclasses in Healthy Volunteers but Not in Patients with Metabolic Syndrome.

Metabolic syndrome (MS) is a widespread disease in developed countries, accompanied, among others, by decreased adiponectin serum levels and perturbed lipoprotein metabolism. The associations between the serum levels of adiponectin and lipoproteins have been extensively studied in the past under healthy conditions, yet it remains unexplored whether the observed associations also exist in patients with MS. Therefore, in the present study, we analyzed the serum levels of lipoprotein subclasses using nuclear magnetic resonance spectroscopy and examined their associations with the serum levels of adiponectin in patients with MS in comparison with healthy volunteers (HVs). In the HVs, the serum levels of adiponectin were significantly negatively correlated with the serum levels of large buoyant-, very-low-density lipoprotein, and intermediate-density lipoprotein, as well as small dense low-density lipoprotein (LDL) and significantly positively correlated with large buoyant high-density lipoprotein (HDL). In patients with MS, however, adiponectin was only significantly correlated with the serum levels of phospholipids in total HDL and large buoyant LDL. As revealed through logistic regression and orthogonal partial least-squares discriminant analyses, high adiponectin serum levels were associated with low levels of small dense LDL and high levels of large buoyant HDL in the HVs as well as high levels of large buoyant LDL and total HDL in patients with MS. We conclude that the presence of MS weakens or abolishes the strong associations between adiponectin and the lipoprotein parameters observed in HVs and disturbs the complex interplay between adiponectin and lipoprotein metabolism.

Causal relationship between metabolites and embolic stroke: based on Mendelian randomization and metabolomics.

This research employed Mendelian randomization (MR) methods to explore whether metabolites are causally associated with embolic stroke of undetermined source (ESUS). Genome-Wide Association Study (GWAS) data regarding metabolites and ESUS were downloaded from the database. Metabolites were employed as exposure factors, ESUS served as the outcome variable, and single nucleotide polymorphisms (SNPs) exhibiting significant association with ESUS were chosen as instrumental variables. The causal association between exposure factor metabolites and the outcome variable ESUS was assessed using two methods: MR-Egger regression and inverse variance-weighted (IVW) analysis. A causal relationship was observed between X-11593--O-methylascorbate* and ESUS, indicating a protective factor. Moreover, a causal relationship was identified between cholesterol esters in large very-low-density lipoprotein (VLDL), cholesterol esters in medium low-density lipoprotein (LDL), concentration of medium LDL particles, phospholipids in medium LDL, phenylalanine, total cholesterol in small LDL, total lipids in medium LDL and ESUS, representing risk factor. Funnel plots exhibited a symmetrical distribution of SNPs, while pleiotropic tests (p > 0.05) and leave-one-out tests indicated that the results were relatively stable. Metabolites are causally associated with ESUS. LDL and VLDL-related metabolites are identified as risk factors for ESUS.

Dietary fatty acids were not independently associated with lipoprotein subclasses in elderly women

Dietary fatty acids are known to affect serum lipoproteins; however, little is known about the associations between consumption of dietary fatty acids and lipoprotein subclasses. In this study, we hypothesized that there is an association between dietary fatty acids and lipoprotein subclasses and investigated the cross-sectional association of dietary fat intake with subclasses of lipoproteins in elderly women. Altogether, 547 women (aged ≥65 years) who were part of OSTPRE cohort participated. Dietary intake was assessed by 3-day food records, lifestyle, and health information obtained through self-administrated questionnaires, and lipoprotein subclasses were determined by nuclear magnetic resonance spectroscopy. To analyze the associations between fatty acids and lipoprotein subclasses, we used Pearson and Spearman correlation coefficients and the analysis of covariance (ANCOVA) test with, adjustment for physical activity, body mass index, age, smoking status, and intake of lipid-lowering drugs. There were significant correlations between saturated fatty acids (SFA; % of energy) and concentrations of large, medium, and small low-density lipoproteins (LDL); total cholesterol in large, medium, and small LDL; and phospholipids in large, medium, and small LDL, after correction for multiple testing. After adjustment for covariates, the higher intake of SFA was associated with smaller size of LDL particles (P = .04, ANCOVA) and lower amount of triglycerides in small very low-density lipoproteins (P = .046, ANCOVA). However, these associations did not remain significant after correction for multiple testing. In conclusion, high intake of SFA may be associated with the size of LDL particles, but the results do not support significant, independent associations between dietary fatty acids and lipoprotein subclasses.

Identification of a novel series of anti-inflammatory and anti-oxidative phospholipid oxidation products containing the cyclopentenone moiety in vitro and in vivo: Implication in atherosclerosis

Oxidative stress and inflammation are two major contributing factors to atherosclerosis, a leading cause of cardiovascular disease. Oxidation of phospholipids on the surface of low density lipoprotein (LDL) particles generated under oxidative stress has been associated with the progression of atherosclerosis, but the underlying molecular mechanisms remain poorly defined. We identified a novel series of oxidation products containing the cyclopentenone moiety, termed deoxy-A2/J2-isoprostanes-phosphocholine, from 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine in vivo using mass spectrometry and by comparison to a chemically synthesized standard. Transcriptomic analysis (RNA-seq) demonstrated that these compounds affected >200 genes in bone marrow-derived macrophages, and genes associated with inflammatory and anti-oxidative responses are among the top 5 differentially expressed. To further investigate the biological relevance of these novel oxidized phospholipids in atherosclerosis, we chemically synthesized a representative compound 1-palmitoyl-2-15-deoxy-δ-12,14-prostaglandin J2-sn-glycero-3-phosphocholine (15d-PGJ2-PC) and found that it induced anti-inflammatory and anti-oxidant responses in macrophages through modulation of NF-κB, peroxisome proliferator-activated receptor γ (PPARγ), and Nrf2 pathways; this compound also showed potent anti-inflammatory properties in a mice model of LPS-induced systematic inflammatory response syndrome. Additionally, 15d-PGJ2-PC inhibited macrophage foam cell formation, suggesting a beneficial role against atherosclerosis. These properties were consistent with decreased levels of these compounds in the plasma of patients with coronary heart disease compared with control subjects. Our findings uncovered a novel molecular mechanism for the negative regulation of inflammation and positive enhancement of anti-oxidative responses in macrophages by these oxidized phospholipids in LDL in the context of atherosclerosis.

102 - Modulation of Macrophage Function by Oxidized Phospholipids in Low Density Lipoproteins in the Context of Atherogenesis

102 - Modulation of Macrophage Function by Oxidized Phospholipids in Low Density Lipoproteins in the Context of Atherogenesis

Analysis of in vitro oxidized human LDL phospholipids by solid‐phase extraction and micellar electrokinetic capillary chromatography

Phospholipids of in vitro oxidized human low-density lipoproteins (LDL) were separated by two different solid-phase extraction (SPE) methods. One of the two methods was designed to test the effects of gradient elution. This SPE method isolated more phospholipids from in vitro oxidized LDL than the other one according to the results of liquid chromatography and electrospray ionization mass spectrometry (LC ESI-MS) analysis. A micellar electrokinetic capillary chromatography (MEKC) method was also used to analyze phospholipids separated by SPE. The results of MEKC and LC ESI-MS were consistent for the major phospholipid classes, including PC, lysoPC, PE, PI and PS. The MEKC profiles showed significant differences for native and oxidized LDL phospholipids. Therefore, the unique combination of SPE and MEKC methods showed dramatic distinctions between native and in vitro oxidized human LDL phospholipids. The combination also shows great potential for rapid analysis of in vivo oxidized human LDL phospholipids in the future.

Antioxidant activity of the volatile oils of Zingiber officinale (ginger)

AIM: The present study aimed to investigate the effects of Zingiber officinale Roscoe (ginger) extract on diminish hypercholesterolemic atherosclerosis and it had antioxidant activity. METHODS: Lipid profile (cholesterol, triglycerides and lipoproteins levels of cholesterol and triglycerides (low density lipoprotein (LDL) and very low density lipoprotein (VLDL) levels in the homogenate aorta and in serum of hypercholesterolemic animals were estimated. The development of atherosclerosis in aortic tissues and anti-oxidant effect of ginger extract by using 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay were evaluated in albino mice. RESULTS: The present results revealed a significant reduction in the levels of cholesterol, triglycerides, phospholipids and both levels of VLDL and LDL cholesterol and triglycerides in serum and tissue of aorta with high levels dose of ginger extract (P < 0.01). Moreover, the antioxidant effect of ginger extract was studied by measuring its radical scavenging activity (RSA), using rapid 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay showed strong antioxidative activity with high levels dose of ginger extract (P < 0.01). CONCLUSION: The ginger extract has reduced in serum LDL cholesterol, total cholesterol, triglycerides and phospholipids levels, as well as cellular cholesterol accumulation , reduce DPPH absorption , scavenge free radicals and it has potential to improve the histopathological lesion occurring in different layers of the arterial tissue. In the other word it is effective in attenuating of atherosclerosis development.

Serum paraoxonase 1 (PON1) lactonase activity is lower in end-stage renal disease patients than in healthy control subjects and increases after hemodialysis

The mechanism of paraoxonase 1 (PON1) atheroprotective remains elusive. The lactonizing/lactonase activity of PON1 is gaining favor as the most significant in physiology. We studied 42 end-stage renal disease (ESRD) patients undergoing hemodialysis (HD) and 49 control subjects. We measured PON1 lactonase, arylesterase and triesterase activities by kinetic methods. Serum lactonase activity was 11% lower in ESRD patients (p<0.0001) and did not correlate with high-density lipoprotein (HDL) cholesterol when controlling for confounders. Lactonase activity was significantly higher after dialysis. Using a repeated measure-ANOVA adjusted for the confounders (age, gender, total cholesterol, triglyceride and HDL cholesterol) we show that the changes in lactonase after dialysis were significant (p<0.0001). HD increases lactonase activity to levels indistinguishable from those of control subjects. In simple linear regression analyses we showed a significant inverse correlation between changes in lactonase and those of creatinine by dialysis (r=-0.339, p=0.028). ESRD patients maybe more susceptible to lipid peroxidation and to protein homocysteinylation than healthy subjects due to the decreased activity of lactonase. A lower serum lactonase activity would be coupled with delayed catabolism of oxidized phospholipids in low-density lipoprotein and oxidized macrophages, and with greater protein homocysteinylation, accelerating atherogenesis. One mechanism for lower lactonase activity in ESRD patients may be inhibition by uremic toxins and oxidative stress. The pathophysiology of reduced lactonase activity in uremia and the beneficial effects of HD need further investigation.

Size-selective uptake of colloidal low density lipoprotein aggregates by cultured white blood cells

This paper illustrates how principles of colloid science are useful in studying atherosclerosis. Accumulation of foam cells in the arterial intima is a key step in atherogenesis. The extent of foam cell formation is enhanced by low density lipoprotein (LDL) aggregates, and we have previously shown that the size of sphingomyelinase (Smase)-hydrolysis-induced aggregates depends directly on the concentration of ceramide generated in the LDL phospholipid monolayer, mediated by the hydrophobic effect. Here, we focus on the effect of LDL aggregate particle sizes on their subsequent uptake by macrophages. Our data show the first direct measurement of uptake as a function of aggregate size and the first direct comparison of uptake after Smase-catalyzed and vortex-mixing-mediated aggregation. Vortex-mixed aggregates with radii 20–77 nm showed maximal uptake ∼118 μg sterol/mg protein at a 53 nm intermediate size, consistent with a mathematical model describing competition between aggregate surface area and volume. Smase-treated aggregates with radii 25–211 nm also showed maximal uptake at an intermediate size, ∼58 μg sterol/mg protein for 132 nm particles, and fit a modified model that incorporated ceramide concentration expressed as aggregate size. This study shows that particle size is significant and composition may also be a factor in LDL uptake.

Subgram daily supplementation with docosahexaenoic acid protects low-density lipoproteins from oxidation in healthy men

ObjectiveTo determine the effect of supplementation with increasing doses of docosahexaenoic acid (DHA), as the only n-3 polyunsaturated fatty acid (PUFA), on low-density lipoprotein (LDL) redox status and oxidizability. MethodsTwelve healthy men aged 53–65 years ingested consecutive doses of DHA (200, 400, 800 and 1600mg/day), each dose for two weeks. ResultsThe proportions of DHA increased dose-dependently in LDL phospholipids and cholesteryl esters, even after two weeks of supplementation with 200mg/day DHA. The daily intake of 200, 400 and 800mg DHA resulted in increased alpha-tocopherol concentrations, decreased MDA concentrations, and a longer lag time for copper-induced LDL oxidation. Supplementation with 1600mg/day DHA had no effect on the above parameters. In plasma, concentrations of 4-hydroxy-hexenal, specifically derived from the peroxidation of n-3 fatty acids, significanty increased after 800 and 1600mg DHA, representing 0.01% of plasma n-3 PUFAs, while 4-hydroxy-nonenal concentrations, derived from the peroxidation of n-6 fatty acids, did not change. ConclusionOur results clearly show that an intake of 200–800mg/day DHA may have protective and antioxidant effects on LDL and could represent optimal doses for cardiovascular disease prevention in a healthy population.

Abstract 3605: Lipoprotein-Associated Phospholipase A 2 and Myocardial Infarction in Women

Lipoprotein-Associated Phospholipase A 2 (Lp-PLA 2 ) is an enzyme that hydrolyzes oxidized phospholipids in low-density lipoprotein, creating pro-inflammatory molecules that are hypothesized to play a role in the development of coronary heart disease. Many of the previous studies that have shown Lp-PLA 2 activity to be associated with a moderate increase in risk for CHD have been conducted mostly among men. The one previous study among women was small and reported a modest nonsignificant increase in risk. Thus, the association of Lp-PLA 2 with CHD risk in women warrants exploration. We conducted a nested case-control study among participants in the Nurses’ Health Study who provided a blood sample in 1989 –1990. With approximately 15 years of follow-up through 2004 we identified 438 incident cases of fatal and non-fatal MI and used incidence density sampling to match controls to cases (2:1) based on age, smoking status, date of blood draw, and fasting status at the time of blood draw. Lp-PLA 2 activity was measured using a colorimetric activity assay. We used conditional logistic regression in multivariate models. Compared to women in the lowest tertile, the relative risk of CHD for women in the second and third tertiles of Lp-PLA 2 activity were 1.75 (95% CI 1.26 –2.44) and 2.67 (1.94 – 3.69), respectively (p for trend = 0.002). After further adjustment for LDL cholesterol, c-reactive protein,body mass index, alcohol intake, aspirin use, physical activity, and post-menopausal hormone use, and histories of hypercholesterolemia, diabetes, and hypertension, the relative risks were similar: 1.81 (1.26 – 2.60) comparing the second to the first tertile, and 2.26 (1.54 – 3.30) comparing the third to the first tertile (p trend &lt; 0.001). Further adjustment for HDL cholesterol modestly attenuated the relative risks to 1.62 (1.13 – 2.35) and 1.81 (1.20 – 2.71) (p trend = 0.007). The significantly elevated relative risks were not appreciably modified by HDL or LDL. In conclusion, we found that Lp-PLA 2 activity was associated with increased risk for MI among women. Adjustment for standard risk factors modestly attenuated this relationship, but Lp-PLA 2 remained a strong independent predictor of MI in this population of women healthy at baseline.

Simultaneous Quantitative Analysis for Phospholipids in Human HDL and LDL Using Two Internal Standards by Liquid Chromatography/Mass Spectrometry

A liquid chromatography/mass spectrometry method using two internal standards was developed for the simultaneous quantitative determination of phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidylethanolamine (PE), phosphatidylcholine (PC), sphingomyelin (SM), and lysophosphatidylcholine (LPC) in human high‐density lipoprotein (HDL) and low‐density lipoprotein (LDL). We evaluated this method by examining precision, accuracy, and recovery of phospholipid concentrations in several matrixes. We obtained the time course of phospholipid content in human HDL and LDL treated with sPLA2‐X and quantitatively observed the decrease of PC, PI, PE, and the increase of LPC. This method should be useful for examination of simultaneous change of endogenous phospholipids in various enzymatic assays.

Combining β-adrenergic and peroxisome proliferator–activated receptor γ stimulation improves lipoprotein composition in healthy moderately obese subjects

Current pharmacological regimens for hypertriglyceridemia and low high-density lipoprotein (HDL) are limited to the peroxisome proliferator–activated receptor (PPAR) α activating fibrates, niacin, and statins. This pilot study examined the impact of simultaneous stimulation of cyclic adenosine monophosphate with a β-adrenergic agonist and PPAR γ with pioglitazone (PIO) on lipoprotein composition in moderately obese, healthy subjects. Subjects were treated with PIO (45 mg) to stimulate PPAR γ or a combination of ephedrine (25 mg TID), a β-agonist, with caffeine (200 mg TID), a phosphodiesterase inhibitor (ephedrine plus caffeine), or both for 16 weeks. Lipoproteins were separated by gradient ultracentrifugation into very low-density lipoprotein (VLDL), intermediate-density lipoprotein, low-density lipoprotein (LDL), and 3 HDL (L, M, and D) subfractions. Apolipoproteins were measured by high-performance liquid chromatography. PIO alone reduced the core triglyceride (TG) content relative to cholesterol ester (CE) in VLDL (−40%), IDL (−25%), and HDL-M (−38%). Ephedrine plus caffeine alone reduced LDL CE (−13%), phospholipids (−9%), and apolipoprotein (apo) B (−13%); increased HDL-M LpA-I (HDL containing apoA-I without apoA-II, 28%), CE/TG (23%), and CE/apoA-I (8%) while reducing apoA-II (−10%); and increased HDL-L LpA-I (29%). Combination therapy reduced total plasma TG (−28%), LDL cholesterol (LDL-C, −10%), apoB (−16%), apoB/apoA-I ratio (−21%) while increasing HDL cholesterol (HDL-C, 21%), total plasma apoA-I (12%), LpA-I (43%), and apoC-I (26%). It also reduced VLDL total mass (−34%) and apoC-III (−39%), LDL CE (−13%), apoB (−13%), and total mass (−11%). Combination therapy increased HDL-L CE/TG (32%), apoC-I (30%), apoA-I (56%), and LpA-I (70%), as well as HDL-M CE (35%), phospholipids (24%), total mass (19%), apoC-I (25%), apoA-I (18%), and LpA-I (56%). In conclusion, simultaneous β-adrenergic and PPAR γ activation produced beneficial effects on VLDL, LDL, HDL-L, and HDL-M. Perhaps the most important impact of combination therapy was dramatic increases in LpA-I and apoC-I in HDL-L and HDL-M, which were much greater than the sum of the monotherapies. Because LpA-I appears to be the most efficient mediator of reverse-cholesterol transport and a major negative risk factor for cardiovascular disease, this combination therapy may provide very effective treatment of atherosclerosis.

Role of Lipoprotein-Associated Phospholipase A 2 in Atherosclerosis

The development of atherosclerotic vascular disease is invariably linked to the formation of bioactive lipid mediators and accompanying vascular inflammation. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme that is produced by inflammatory cells, co-travels with circulating low-density lipoprotein (LDL), and hydrolyzes oxidized phospholipids in LDL. Its biological role has been controversial with initial reports purporting atheroprotective effects of Lp-PLA2 thought to be a consequence of degrading platelet-activating factor and removing polar phospholipids in modified LDL. Recent studies, however, focused on pro-inflammatory role of Lp-PLA2 mediated by products of the Lp-PLA2 reaction (lysophosphatidylcholine and oxidized nonesterified fatty acids). These bioactive lipid mediators, which are generated in lesion-prone vasculature and to a lesser extent in the circulation (eg, in electronegative LDL), are known to elicit several inflammatory responses. The proinflammatory action of Lp-PLA2 is also supported by a number of epidemiology studies suggesting that the circulating level of the enzyme is an independent predictor of cardiovascular events, despite some attenuation of the effect by inclusion of LDL, the primary carrier of Lp-PLA2, in the analysis. These observations provide a rationale to explore whether inhibiting Lp-PLA2 activity and consequent interference with the formation of bioactive lipid mediators will abrogate inflammation associated with atherosclerosis, produce favorable changes in intermediate cardiovascular end points (eg, biomarkers, imaging, and endothelial function), and ultimately reduce cardiovascular events in high-risk patients.

Effects of oils rich in eicosapentaenoic and docosahexaenoic acids on the oxidizability and thrombogenicity of low-density lipoprotein

Consumption of oily fish and fish oils is associated with protection against cardiovascular disease. Paradoxically, long-chain polyunsaturated fatty acids present in low-density lipoprotein (LDL) are suggested to be susceptible to oxidation. It is not clear whether eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have similar effects on the susceptibility of LDL to oxidation or whether they affect the thrombogenicity of oxidized LDL. This study examined the influence of highly purified preparations of EPA and DHA on LDL oxidizability and LDL-supported thrombin generation in healthy human volunteers. Forty-two healthy volunteers were randomly assigned to receive olive oil (placebo), an EPA-rich oil or a DHA-rich oil for 4 weeks at a dose of 9 g oil/day. EPA and DHA were incorporated into LDL phospholipids and cholesteryl esters during the supplementation period, but were progressively lost during ex vivo copper-mediated oxidation. Following supplementation, the EPA treatment significantly increased the formation of conjugated dienes during LDL oxidation compared with baseline, whereas the DHA treatment had no effect. Neither treatment significantly affected the lag time for oxidation, oxidation rate during the propagation phase or maximum diene production. Neither EPA nor DHA significantly affected the thrombotic tendency of oxidized LDL compared with the placebo, although DHA tended to decrease it. In conclusion, there are subtle differences in the effects of EPA and DHA on the oxidizability and thrombogenicity of LDL. DHA does not appear to increase the susceptibility of LDL to oxidation to the same degree as EPA and has a tendency to decrease LDL-supported thrombin generation.

Plasma lipoprotein lipase, hepatic lipase activities, VLDL, LDL compositions at different times of hemodialysis

The effects of hemodialysis duration (HD) on lipoprotein lipase (LPL) and hepatic lipase (HL) activities and very low density lipoprotein (VLDL), low density lipoproteins (LDL) amounts and compositions were investigated in 58 patients, divided according to HD: GI: under 1 year, GII: 1–5 years, GIII: 5–13 years. HL and LPL activities were reduced in GIII versus GI ( P<0.01) and 47% of GIII patients had negligible HL activity. LPL and HL activities were correlated with HD ( r=−0.80, P<0.001). Apo C-III concentrations were correlated with HD ( r=0.58, P<0.05). Compared with controls, triacylglycerols (TG) were increased in GI, GII ( P<0.01) and GIII ( P<0.001), and were correlated with HD ( r=0.75, P<0.05). VLDL amounts and VLDL–cholesteryl esters (CE) were enhanced in GIII versus GI and GII ( P<0.05). VLDL–TG and VLDL–phospholipids (PL) were correlated with HD ( r=0.60, P<0.05). LDL–apolipoproteins and unesterified cholesterol (UC) were increased in GII versus GI ( P<0.05) and in GIII versus GII and GI ( P<0.01). LDL–PLs were decreased in GIII versus GI ( P<0.05). Compared with controls, LDL–TGs were higher in GI and GII ( P<0.01) and in GIII ( P<0.05). Long-term treatment with acetate hemodialysis using cuprophane membrane does not improve lipolytic activity decrease and lipoprotein alterations generated by chronic renal failure (CRF).

Role of phospholipids in drug–LDL bindings as studied by high-performance frontal analysis/capillary electrophoresis

The binding study between basic drugs (( S)-verapamil (VER) and ( S)-propranolol (PRO)) and phospholipid liposomes was performed by using high-performance frontal analysis/capillary electrophoresis (HPFA/CE) in order to investigate the effect of oxidative modification of low-density lipoprotein (LDL) upon drug-binding affinity from molecule-based viewpoint. 1-Palmitoyl-2-oleoyl-phosphatidylcholine (POPC, 16:0, 18:1), 1-palmitoyl-2-linoleoyl-phosphatidylcholine (PLPC, 16:0, 18:2), dilauloyl-phosphatidylcholine (DLaPC, 12:0, 12:0), 1-palmitoyl-2-oleoyl-phosphatidyl-glycerol (POPG, 16:0, 18:1), and 1-palmitoyl-sn-glycero-3-phosphocholine (monoPPC, 16:0) were used to prepare the model liposomes. At physiological pH (pH 7.4), the model liposome prepared from POPG+POPC had negative net charges, while the total net charge of the other model liposomes (POPC liposome, PLPC liposome, DLaPC liposome, and monoPPC+POPC liposome) was zero. The drug and the model liposome mixed solutions were subjected to HPFA/CE, and the total binding affinities (nK) were calculated. The nK values of VER and PRO to POPG+POPC liposome were more than six and 10 times higher than those of other liposomes, respectively. On the other hand, the nK values of the model drugs to POPC liposome, PLPC liposome, DLaPC liposome and monoPPC+POPC liposome showed small differences less than twice. These results indicate that the electrostatic interaction plays an important effect on drug–liposome binding, and suggest that the increase in the negative charge of LDL phospholipids gives more significant effect on the drug-binding affinity of the basic drugs than the acyl-chain structure.

Novel bioactive phospholipids: practical total syntheses of products from the oxidation of arachidonic and linoleic esters of 2-lysophosphatidylcholine(1).

Total syntheses of nine novel phospholipids were accomplished to facilitate the identification and biological testing of compounds that are generated upon oxidative cleavage of arachidonate and linoleate esters of 2-lysophosphatidylcholine, the two most abundant polyunsaturated phospholipids in low-density lipoprotein. An efficient general synthesis exploiting 2-lithiofuran as a 4-oxo-2-butenoyl carbanion equivalent provided phospholipids containing gamma-keto-alpha,beta-unsaturated carbonyl functional arrays. By exploiting facile cis-trans isomerizations, two commercially available cis alkenes, (2Z)-2-butene-1,4-diol and 2,5-dihydrofuran, could be employed as starting materials for preparing the Horner-Wadsworth-Emmons reagent 4-(diethoxyphosphoryl)-2E-butenal, a valuable building block for the synthesis of 2,4-dienals. The reagent was exploited in a total synthesis of 13-oxotridec-9E,11E-dienoic acid, confirming the identity of this product that is generated upon autoxidation of linoleic acid and by decomposition of 13-hydroperoxy-9,11-octadecadienoate (13-HPODE), especially in the presence of redox active transition metal ions, cytochrome p-450, or hydroperoxide lyase.

Dyslipidemia and a reversible decrease in insulin sensitivity induced by therapy with 13-cis-retinoic acid.

13-cis-Retinoic acid (Roaccutan) treatment is associated with disturbances in lipid and sometimes also in glucose metabolism. Thus, we investigated whether 13-cis-retinoic acid treatment decreases insulin sensitivity. We studied 11 men [aged 24+/-2 years (mean+/-SEM), body mass index (BMI) 22.1+/-0.9 kg/m(2)] who received Roaccutan treatment for acne for a period averaging 5 months but who were otherwise healthy. The insulin sensitivity of the subjects was measured before, during and 1-3 months after the end of treatment using the euglycaemic hyperinsulinaemic clamp technique. Treatment with 13-cis-retinoic acid reduced total (59+/-4 vs 55+/-4 micromol/kg/min, p<0.02), oxidative (25+/-1 vs 22+/-2 micromol/kg/min, p<0.05) and non-oxidative (36+/-3 vs 33+/-3 micromol/kg/min, p=0.05) glucose disposal rate, and there was a 4% increase in HbA(1c) (from 5.2+/-0.07 to 5.4+/-0.07%, p<0.02). After treatment cessation these values returned to baseline. 13-cis-Retinoic acid treatment also resulted in increased very low density lipoprotein (VLDL) and low density lipoprotein (LDL) cholesterol, increased VLDL triglyceride, and increased VLDL and LDL phospholipid concentrations. Treatment of acne with 13-cis-retinoic acid reduces insulin sensitivity and induces alterations in lipid metabolism resembling those of the insulin resistance syndrome.