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Background: Fetal growth restriction (GR) is associated with perinatal mortality and subsequent metabolic disorders in adulthood. Until now, there is little information regarding changes in the properties of lipoproteins from growth-restricted fetuses and their maternal sera., Objective: To identify unique lipoprotein biomarkers for fetal GR in maternal and cord sera from small neonates, we analyzed lipoprotein compositions and functions., Methods: Lipoprotein compositions and functions were compared between cord blood and maternal blood among small for gestational age neonates (SGA; n = 15, 2589 ± 50 g) and appropriate for gestational age neonates (AGA; n = 15) in Korea., Results: Cord blood from the SGA group showed 2-fold higher triglyceride (TG) and TG/high-density lipoprotein cholesterol levels than the AGA group as well as significantly lower (up to 20%) paraoxonase activity and apolipoprotein (apo) A-I content. The SGA group showed the highest cholesteryl ester transfer protein activities in both cord and maternal sera. SGA neonates showed elevated apo-B content in very low-density lipoprotein, 52% reduction of apo A-I content in high-density lipoprotein, and 30% increased glycation (P < .001) compared with AGA neonates. Especially, low-density lipoprotein from the SGA group showed 1.9-fold higher sensitivity to oxidation as well as 3-fold greater uptake into macrophages, suggesting stronger proatherosclerotic properties. Lipoproteins from maternal serum of SGA neonates showed greater oxidation along with TG enrichment and loss of antioxidant ability. On microinjection of cord serum (50 nL) into zebrafish embryos, the SGA group showed the most severe embryonic damage., Conclusions: Lipoproteins from cord and maternal sera of SGA neonates resulted in severe impairment of functional and structural correlations accompanied by greater pro-oxidant and proatherosclerotic properties., (Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Abstract Background Heart failure (HF) courses with chronic inflammatory process and alterations in lipid metabolism may aggravate the disease. The aim was to test whether the severity of HF, using brain natriuretic peptide (BNP) as a marker, is associated with alterations in functional aspects of HDL, such as lipid transfer, cholesterol ester transfer protein (CETP) and lecithin-cholesterol acyltransferase (LCAT) concentration. Methods Twenty-five HF patients in NYHA class I/II and 23 in class III/IV were enrolled. Plasma lipids, apolipoproteins, CETP, LCAT, oxidized-LDL (oxLDL) and paraoxonase-1 (PON-1) activity were determined. Lipid transfer from a donor artificial nanoparticle to HDL was measured by in vitro assay. Results Total cholesterol (p = 0.049), LDL-C (p = 0.023), non-HDL-C (p = 0.029) and CETP, that promotes lipid transfer among lipoproteins (p = 0.013), were lower in III/IV than in I/II group. Triglycerides, HDL-C, apo A-I, apo B, oxLDL, LCAT, enzyme that catalyzes serum cholesterol esterification, PON-1 activity, and in vitro transfers of cholesterol, triglycerides and phospholipids to HDL, important steps in HDL metabolism, were equal. IL-8 was higher in III/IV (p = 0.025), but TNFα, IL-1β, IL-6 and MCP-1 were equal. BNP was negatively correlated with CETP (r = − 0.294; p = 0.042) and positively correlated with IL-8 (r = 0.299; p = 0.039). Conclusions Our results disclosed the relationship between CETP levels and HF severity, by comparing two HF groups and by correlation analysis. Lower CETP levels may be a marker of HF aggravation and possibly of worse prognosis. Practical applications of this initial finding, as the issue whether CETP could be protective against HF aggravation, should be explored in larger experimental and clinical studies.

Background: Heart failure (HF) courses with chronic inflammatory process and alterations in lipid metabolism may aggravate the disease. The aim was to test whether the severity of HF, using brain natriuretic peptide (BNP) as a marker, is associated with alterations in functional aspects of HDL, such as lipid transfer, cholesterol ester transfer protein (CETP) and lecithin-cholesterol acyltransferase (LCAT) concentration. Methods: Twenty-five HF patients in NYHA class I/II and 23 in class III/IV were enrolled. Plasma lipids, apolipoproteins, CETP, LCAT, oxidized-LDL (oxLDL) and paraoxonase-1 (PON-1) activity were determined. Lipid transfer from a donor artificial nanoparticle to HDL was measured by in vitro assay. Results: Total cholesterol (p = 0.049), LDL-C (p = 0.023), non-HDL-C (p = 0.029) and CETP, that promotes lipid transfer among lipoproteins (p = 0.013), were lower in III/IV than in I/II group. Triglycerides, HDL-C, apo A-I, apo B, oxLDL, LCAT, enzyme that catalyzes serum cholesterol esterification, PON-1 activity, and in vitro transfers of cholesterol, triglycerides and phospholipids to HDL, important steps in HDL metabolism, were equal. IL-8 was higher in III/IV (p = 0.025), but TNFα, IL-1β, IL-6 and MCP-1 were equal. BNP was negatively correlated with CETP (r = - 0.294; p = 0.042) and positively correlated with IL-8 (r = 0.299; p = 0.039). Conclusions: Our results disclosed the relationship between CETP levels and HF severity, by comparing two HF groups and by correlation analysis. Lower CETP levels may be a marker of HF aggravation and possibly of worse prognosis. Practical applications of this initial finding, as the issue whether CETP could be protective against HF aggravation, should be explored in larger experimental and clinical studies. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To verify whether the capacity of high-density lipoprotein (HDL) to simultaneously receive nonesterified cholesterol, triglycerides, cholesteryl esters, and phospholipids changes with aging and the presence of coronary artery disease. DESIGN: Cross-sectional study with biochemical analyses. SUBJECTS: Eleven elderly patients with coronary artery disease (74±5 years) were compared with the following groups of non-coronary artery disease subjects (referred to as "healthy"): 25 young (25±5 years), 25 middle-aged (42± years), and 25 elderly subjects (75±8 years). METHODS: Plasma samples were incubated with a nanoemulsion labeled with radioactive lipids; the transfer of the lipids from the nanoemulsion to the HDL was measured in chemically precipitated HDL. HDL size and paraoxonase-1 activity were also determined. RESULTS: The transfer of cholesteryl esters and phospholipids to high-density lipoprotein was significantly greater (p

Abstract: Lipidomics has developed rapidly over the past decade to the point where clinical application may soon be possible. Developments including high throughput technologies enable the simultaneous quantification of several hundred lipid species, thereby providing a global assessment of lipid metabolism. Given the key role of lipids in the pathophysiology of diabetes and cardiovascular disease, lipidomics has the potential to: [i)] Significantly improve prediction of future disease risk, [ii)] Inform on mechanisms of disease pathogenesis, [iii)] Identify patient groups responsive to particular therapies and [iv)] More closely monitor response to therapy. Lipidomic analyses of both whole plasma and lipoprotein subfractions are integral to the current initiative to understand the relationships between lipoprotein composition and function and how these are affected by disease and treatment. This approach will not only aid in appropriate targeting of existing lipid lowering therapies such as statins and fibrates, but will be important in unravelling the controversies surrounding HDL-based therapies which have failed in clinical trials to date. The ultimate utility of lipidomics to clinical practice will depend firstly on the ability of risk prediction models incorporating lipidomic parameters to significantly improve upon conventional clinical risk markers in predicting future disease risk. Secondly, for widespread application, lipidomic-based measurements must be practical and accessible through standard pathology laboratories. This review will cover developments in lipidomics including methodology, bioinformatics/statistics, insights into disease pathophysiology, the effect of therapeutic interventions, the role of large clinical outcome trials in validating lipidomic approaches to patient management and potential applications in clinical practice. [Copyright &y& Elsevier]

Eur J Clin Invest 2012; 42 (7): 709-716 Abstract Objective Accelerated cholesteryl ester transfer (CET) in patients with types 1 (T1D) and 2 diabetes enhances the atherogenicity of the apoB-containing CE acceptor lipoproteins. The study of lipoprotein density fractions cannot identify which of the five immunologically distinct apoB subclasses function as CE acceptors because they are heterogeneous and present in very low-, intermediate- and low density lipoproteins (VLDL, IDL and LDL, respectively). In order to design lipid-modifying therapies that specifically target these CE-enriched lipoprotein particles, it is necessary to first characterize their CE acceptor function. Methods and Results To identify the CE acceptors, we estimated CE net mass transfer to the apoB subclasses LpB:C, LpB:E + LpB:C:E, LpB and LpAII:B:C:D:E from changes in neutral lipids measured by gas chromatography following their separation by sequential immunoaffinity chromatography in the plasma of 12 patients with T1D and six control subjects. In both groups, CE was distributed equally to LpB:E + LpB:C:E and LpB:C. In the T1D CE acceptors, however, both the magnitude of the increase (18% vs. 10%; P < 0·01) and the per particle mass of CE transferred were significantly greater than in controls (T1D: 2·29 μmol ± 2·1 vs. control 0·43 ± 0·43/mg apoB; P < 0·047). Conclusion While LpB:E + LpB:C:E and LpB:C functioned as CE acceptors in both groups, these subclasses increased their CE content to a greater degree and accrued more CE per particle in the patients with T1D. As this disturbance in lipoprotein remodelling may increase the cholesterol burden and potential atherogenicity of these apoB subclasses, it may be a previously unrecognized factor that increases cardiovascular risk in patients with T1D. [ABSTRACT FROM AUTHOR]

Background. High-density lipoprotein cholesterol (HDL-C) and cholesteryl ester transfer protein (CETP) gene deficiency mutations that increase HDL-C levels have been associated with exceptional longevity. However, a recent clinical trial of a promising CETP inhibitor that markedly increases HDL-C was terminated due to increased mortality. In light of this controversy, we examined the relationship among HDL-C, CETP mutations, and longevity phenotypes in the long-lived Japanese-American men of the Honolulu Heart Program (HHP). Methods. Japanese-American men (n = 3562) were followed for up to 8 years, from average age 78 to average age 84 (maximum age 99), or until death. Total mortality, cause-specific mortality, and healthy survival were evaluated for associations with HDL-C level and CETP genetic variants common in the Japanese population (CD4420 and Int 14A). Results. HDL-C was negatively associated with cardiovascular disease (CVD) mortality (p = .002) but not related to non-CVD (p = .147) or total (p = .547) mortality after adjustment for common risk factors. There was a trend for lower mortality for the men with the Tnt 14A variant. These men also had higher HDL-C levels (p = .047) and were significantly more likely to be healthy survivors (absence of six major age-related diseases and high physical/cognitive function) beyond the age of 90 years (p = .005). Conclusions. Low HDL-C level is a risk factor for CVD mortality in elderly Japanese-American men. High HDL-C and the Int 14A variant of the CETP gene may increase odds for healthy aging. [ABSTRACT FROM AUTHOR]

We highlight the importance of the low-density lipoprotein (LDL) receptor family and its pharmaceutical implications in the field of drug delivery. The members of the LDL receptor family are a group of cell surface receptors that transport a number of macromolecules into cells through a process called receptor-mediated endocytosis. This process involves the receptor recognizing a ligand from the extracellular membrane (ECM), internalizing it through clathrin-coated pits and degrading it upon fusion with lysosomes. There are nine members of the receptor family, which include the LDL receptor, low-density lipoprotein-related protein (LRP), megalin, very low-density lipoprotein (VLDL) receptor, apoER2 and sorLA/LRP11, LRP1b, MEGF7, LRP5/6; the former six having been identified in humans. Each member is expressed in a number of different tissues and has a wide range of different ligands, not specific to the recognition of the LDL particle. Thus, rather than the original hypothesis that the receptor is only a mediator of cholesterol uptake, it may also be involved in a number of other physiological functions, including the progression of certain disease states and, potentially, cellular drug uptake. A number of studies have suggested that the LDL receptors are involved in endocytosis of drugs and drug formulations including aminoglycosides, anionic liposomes and cyclosporine A (CsA). This article reviews the importance of lipoproteins as a drug delivery system and how LDL receptors are relevant to the design and targeting of specific drugs. [Copyright &y& Elsevier]

The high-density lipoprotein (HDL) system offers an attractive target for novel therapeutic approaches to prevent or treat atherosclerosis. Clinical preventative studies with HDL modulators, both increasing HDL levels [peroxisome proliferator activator receptor (PPAR) α agonists] and stimulating turnover [cholesteryl ester transfer protein (CETP) activators] have led to favorable outcomes. Treatment of preexisting atherosclerosis with novel HDL mimetics, i.e., wild-type recombinant apo A-I, reconstituted HDL from human serum, large unilamellar phospholipid vesicles (LUV), and the recombinant apo A-IMilano dimer (AIM) offer exciting opportunities. Recent findings with AIM are consistent with the hypothesis that direct HDL administration can rapidly regress coronary plaques. [Copyright &y& Elsevier]

Background: During pregnancy, serum cholesterol (TC) and triglyceride (TG) concentrations are known to increase significantly, but whether remnant lipoprotein particles (RLP) increase has not been shown. Methods: We compared lipid profiles in 22 healthy pregnant women to 31 healthy nonpregnant women and 24 patients with diabetes mellitus (DM), by measuring cholesterol and TG concentrations in major lipoprotein classes after HPLC separation and immunoseparation of RLP. Results: Serum TG and TC concentrations were significantly higher in the pregnant group than in the healthy control or DM groups. Cholesterol and TG concentrations of all major lipoprotein classes were also significantly higher in the pregnant group than the control and DM groups, except for VLDL-TG in the DM group. RLP-C and RLP-TG concentrations were significantly higher in the pregnant group (8.7 mg/dl and 25.4 mg/dl on average) than the control group (2.4 mg/dl and 5.7 mg/dl), but not different from the DM group (8.8 mg/dl and 24.1 mg/dl). RLP-TG to RLP-C ratios were similar among the three groups and correlated with the VLDL-TG to VLDL-C ratio. The percentages of RLP-C in VLDL-C and RLP-TG in VLDL-TG in the pregnant group (15.9% and 15.7%) were significantly lower than those of the control (48.5% and 35.6%) and the DM (32.7% and 20.8%) groups. Conclusions: RLP increased moderately during gestation with the increase in VLDL and TG, but the percentage of RLP in VLDL was significantly lower in the pregnant women compared with the control and DM patients, suggesting that hypertriglyceridemia in pregnancy is not primarily due to an increase in the atherogenic RLP. [Copyright &y& Elsevier]

In mediating the transfer of cholesteryl esters (CE) from antiatherogenic high density lipoprotein (HDL) to proatherogenic apolipoprotein (apo)-B-containing lipoprotein particles (including very low density lipoprotein [VLDL], VLDL remnants, intermediate density lipoprotein [IDL], and low density lipoprotein [LDL]), the CE transfer protein (CETP) plays a critical role not only in the reverse cholesterol transport (RCT) pathway but also in the intravascular remodeling and recycling of HDL particles. Dyslipidemic states associated with premature atherosclerotic disease and high cardiovascular risk are characterized by a disequilibrium due to an excess of circulating concentrations of atherogenic lipoproteins relative to those of atheroprotective HDL, thereby favoring arterial cholesterol deposition and enhanced atherogenesis. In such states, CETP activity is elevated and contributes significantly to the cholesterol burden in atherogenic apoB-containing lipoproteins. In reducing the numbers of acceptor particles for HDL-derived CE, both statins (VLDL, VLDL remnants, IDL, and LDL) and fibrates (primarily VLDL and VLDL remnants) act to attenuate potentially proatherogenic CETP activity in dyslipidemic states; simultaneously, CE are preferentially retained in HDL and thereby contribute to elevation in HDL-cholesterol content.Mutations in the CETP gene associated with CETP deficiency are characterized by high HDL-cholesterol levels (>60 mg/dL) and reduced cardiovascular risk. Such findings are consistent with studies of pharmacologically mediated inhibition of CETP in the rabbit, which argue strongly in favor of CETP inhibition as a valid therapeutic approach to delay atherogenesis. Consequently, new organic inhibitors of CETP are under development and present a potent tool for elevation of HDL in dyslipidemias involving low HDL levels and premature coronary artery disease, such as the dyslipidemia of type II diabetes and the metabolic syndrome. The results of clinical trials to evaluate the impact of CETP inhibition on premature atherosclerosis are eagerly awaited. [Copyright &y& Elsevier]

Background: Estrogen administration is known to increase serum triglyceride concentrations. This study measured changes in lipoproteins of patients with prostate cancer treated with estrogen to determine whether the increased triglyceride concentrations are associated with atherogenic lipoprotein patterns. Methods: Fifteen patients (52–87 years) with histologically diagnosed prostate cancer received diethylstilbestrol diphosphate (250 mg/day). Serum samples were collected before and after 1 and 2 weeks of treatment. Cholesterol and triglyceride profiles of major lipoproteins were determined by HPLC, remnant-like particle cholesterol and triglyceride concentrations by an immunoseparation technique, and apolipoproteins by immunologic methods. Results: Estrogen treatment induced a 63.3% increase in total triglyceride concentrations, which occurred in all major lipoprotein classes with significant increases in HDL-triglycerides (130.4%), LDL-triglycerides (60.7%) and VLDL-triglycerides (56.2%). HDL-cholesterol increased significantly by 26.8%, while LDL-cholesterol decreased (15.6%). Remnant-like particle triglyceride concentrations also increased significantly by 77%, whereas remnant-like particle cholesterol concentrations remained unchanged. Apolipoproteins A-I and A-II increased; apolipoprotein E and Lp(a) decreased. Conclusions: The techniques used here conveniently demonstrated that short-term estrogen treatment in prostate cancer patients resulted in triglyceride enrichment of all major lipoprotein classes but did not induce changes in the lipoprotein profiles generally recognized as increasing risk for cardiovascular disease, except for the elevation of plasma triglyceride and remnant-like particle triglyceride. [Copyright &y& Elsevier]