共查询到20条相似文献，搜索用时 0 毫秒
1.
Moerland M Samyn H van Gent T Jauhiainen M Metso J van Haperen R Grosveld F van Tol A de Crom R 《Journal of lipid research》2007,48(12):2622-2631
In low density lipoprotein receptor (LDLR)-deficient mice, overexpression of human plasma phospholipid transfer protein (PLTP) results in increased atherosclerosis. PLTP strongly decreases HDL levels and might alter the antiatherogenic properties of HDL particles. To study the potential interaction between human PLTP and apolipoprotein A-I (apoA-I), double transgenic animals (hPLTPtg/hApoAItg) were compared with hApoAItg mice. PLTP activity was increased 4.5-fold. Plasma total cholesterol and phospholipid were decreased. Average HDL size (analyzed by gel filtration) increased strongly, hPLTPtg/hApoAItg mice having very large, LDL-sized, HDL particles. Also, after density gradient ultracentrifugation, a substantial part of the apoA-I-containing lipoproteins in hPLTPtg/hApoAItg mice was found in the LDL density range. In cholesterol efflux studies from macrophages, HDL isolated from hPLTPtg/hApoAItg mice was less efficient than HDL isolated from hApoAItg mice. Furthermore, it was found that the largest subfraction of the HDL particles present in hPLTPtg/hApoAItg mice was markedly inferior as a cholesterol acceptor, as no labeled cholesterol was transferred to this fraction. In an LDLR-deficient background, the human PLTP-expressing mouse line showed a 2.2-fold increased atherosclerotic lesion area. These data demonstrate that the action of human PLTP in the presence of human apoA-I results in the formation of a dysfunctional HDL subfraction, which is less efficient in the uptake of cholesterol from cholesterol-laden macrophages. 相似文献
2.
A fraction of plasma transthyretin (TTR) circulates in HDL through binding to apolipoprotein A-I (apoA-I). Moreover, TTR is able to cleave the C terminus of lipid-free apoA-I. In this study, we addressed the relevance of apoA-I cleavage by TTR in lipoprotein metabolism and in the formation of apoA-I amyloid fibrils. We determined that TTR may also cleave lipidated apoA-I, with cleavage being more effective in the lipid-poor prebeta-HDL subpopulation. Upon TTR cleavage, discoidal HDL particles displayed a reduced capacity to promote cholesterol efflux from cholesterol-loaded THP-1 macrophages. In similar assays, TTR-containing HDL from mice expressing human TTR in a TTR knockout background had a decreased ability to perform reverse cholesterol transport compared with similar particles from TTR knockout mice, reinforcing the notion that cleavage by TTR reduces the ability of apoA-I to promote cholesterol efflux. As amyloid deposits composed of N-terminal apoA-I fragments are common in the atherosclerotic intima, we assessed the impact of TTR cleavage on apoA-I aggregation and fibrillar growth. We determined that TTR-cleaved apoA-I has a high propensity to form aggregated particles and that it formed fibrils faster than full-length apoA-I, as assessed by electron microscopy. Our results show that apoA-I cleavage by TTR may affect HDL biology and the development of atherosclerosis by reducing cholesterol efflux and increasing the apoA-I amyloidogenic potential. 相似文献
3.
Meriwether D Imaizumi S Grijalva V Hough G Vakili L Anantharamaiah GM Farias-Eisner R Navab M Fogelman AM Reddy ST Shechter I 《Journal of lipid research》2011,52(10):1795-1809
The apoA-I mimetic peptide L-4F [(Ac-D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F-NH2) synthesized from all L-amino acids] has shown potential for the treatment of a variety of diseases. Here, we demonstrate that LDL promotes association between L-4F and HDL. A 2- to 3-fold greater association of L-4F with human HDL was observed in the presence of human LDL as compared with HDL by itself. This association further increased when LDL was supplemented with the oxidized lipid 15S-hydroxy-5Z, 8Z, 11Z, 13E-eicosatetraenoic acid (15HETE). Additionally, L-4F significantly (P = 0.02) promoted the transfer of 15HETE from LDL to HDL. The transfer of L-4F from LDL to HDL was demonstrated both in vitro and in C57BL/6J mice. L-4F, injected into C57BL/6J mice, associated rapidly with HDL and was then cleared quickly from the circulation. Similarly, L-4F loaded onto human HDL and injected into C57BL/6J mice was cleared quickly with T(1/2) = 23.6 min. This was accompanied by a decline in human apoA-I with little or no effect on the mouse apoA-I. Based on these results, we propose that i) LDL promotes the association of L-4F with HDL and ii) in the presence of L-4F, oxidized lipids in LDL are rapidly transferred to HDL allowing these oxidized lipids to be acted upon by HDL-associated enzymes and/or cleared from the circulation. 相似文献
4.
Francone OL Ishida BY de la Llera-Moya M Royer L Happe C Zhu J Chalkey RJ Schaefer P Cox C Burlingame A Kane JP Rothblat GH 《Journal of lipid research》2011,52(11):1974-1983
Given the increased prevalence of cardiovascular disease in the world, the search for genetic variations that impact risk factors associated with the development of this disease continues. Multiple genetic association studies demonstrate that procollagen C-proteinase enhancer 2 (PCPE2) modulates HDL levels. Recent studies revealed an unexpected role for this protein in the proteolytic processing of pro-apolipoprotein (apo) A-I by enhancing the cleavage of the hexapeptide extension present at the N-terminus of apoA-I. To investigate the role of the PCPE2 protein in an in vivo model, PCPE2-deficient (PCPE2 KO) mice were examined, and a detailed characterization of plasma lipid profiles, apoA-I, HDL speciation, and function was done. Results of isoelectric focusing (IEF) electrophoresis together with the identification of the amino terminal peptides DEPQSQWDK and WHVWQQDEPQSQWDVK, representing mature apoA-I and pro-apoA-I, respectively, in serum from PCPE2 KO mice confirmed that PCPE2 has a role in apoA-I maturation. Lipid profiles showed a marked increase in plasma apoA-I and HDL-cholesterol (HDL-C) levels in PCPE2 KO mice compared with wild-type littermates, regardless of gender or diet. Changes in HDL particle size and electrophoretic mobility observed in PCPE2 KO mice suggest that the presence of pro-apoA-I impairs the maturation of HDL. ABCA1-dependent cholesterol efflux is defective in PCPE2 KO mice, suggesting that the functionality of HDL is altered. 相似文献
5.
Paraoxonase-1 (PON1) and HDL are tightly associated in plasma, and this is generally assumed to reflect the need for the enzyme to associate with a hydrophobic complex. The association has been examined in coronary cases and age-matched controls. Highly significant (P < 0.0001), positive associations were observed between PON1 activities and concentrations and HDL-cholesterol and apolipoprotein A-I (apoA-I) concentrations in cases and controls. Corrected slopes were significantly different in cases (cases vs. controls: arylesterase, r = 0.19 vs. 0.38, P < 0.02 for apoA-I and r = 0.15 vs. 0.34, P < 0.02 for HDL-cholesterol) such that if PON1 should influence serum HDL, it would be less effective in coronary cases. When examined as a function of the PON1 gene promoter polymorphism C-107 T, highly significant differences (P < 0.001) in HDL-cholesterol and apoA-I were observed between genotypes for controls, with high expresser alleles having the highest HDL concentrations. This relationship was lost in cases with coronary disease. The coding region polymorphisms Q192R and L55M of the PON1 gene showed no association with HDL. The promoter polymorphism was an independent determinant of HDL concentrations in multivariate analyses. These data are consistent with an impact of PON1 on plasma concentrations of HDL, with detrimental modifications to the relationship in coronary cases. 相似文献
6.
Xiaohu Mei Mingjing Liu Haya Herscovitz David Atkinson 《Journal of lipid research》2016,57(8):1507-1517
apoA-I plays important structural and functional roles in reverse cholesterol transport. We have described the molecular structure of the N-terminal domain, Δ(185-243) by X-ray crystallography. To understand the role of the C-terminal domain, constructs with sequential elongation of Δ(185-243), by increments of 11-residue sequence repeats were studied and compared with Δ(185-243) and WT apoA-I. Constructs up to residue 230 showed progressively decreased percent α-helix with similar numbers of helical residues, similar detergent and lipid binding affinity, and exposed hydrophobic surface. These observations suggest that the C-terminal domain is unstructured with the exception of the last 11-residue repeat (H10B). Similar monomer-dimer equilibrium suggests that the H10B region is responsible for nonspecific aggregation. Cholesterol efflux progressively increased with elongation up to ∼60% of full-length apoA-I in the absence of the H10B. In summary, the sequential repeats in the C-terminal domain are probably unstructured with the exception of H10B. This segment appears to be responsible for initiation of lipid binding and aggregation, as well as cholesterol efflux, and thus plays a vital role during HDL formation. Based on these observations and the Δ(185-243) crystal structure, we propose a lipid-free apoA-I structural model in solution and update the mechanism of HDL biogenesis. 相似文献
7.
A novel human apolipoprotein [apolipoprotein M (apoM)] was recently described and demonstrated to be a lipocalin. We have now examined apoM in wild-type mice and mice with genetically altered lipoprotein metabolism. Liver and kidney showed high mRNA expression, whereas spleen, heart, brain, and testis demonstrated low expression. ApoM gene expression was initiated on embryonic day 10. Western blot analysis of plasma suggested that mouse apoM, like its human counterpart, is secreted with a retained signal peptide, but unlike human apoM it is not glycosylated. Gel filtration of plasma showed apoM to be associated with HDL-sized particles in wild-type and apoA-I-deficient mice and with HDL- and LDL-sized particles in LDL receptor-deficient mice, whereas apoM was mainly found in VLDL-sized particles in high-fat, high-cholesterol-fed apoE-deficient mice. The plasma concentration of apoM was similar in wild-type, LDL receptor-deficient, and apoE-deficient mice but was reduced to 33% in apoA-I-deficient compared with wild-type mice (P = 0.007). These data suggest that apoM mainly associates with HDL in normal mice but also with the pathologically increased lipoprotein fraction in genetically modified mice. The substantially decreased apoM levels in apoA-I-deficient mice suggest a connection between apoM and apoA-I metabolism. 相似文献
8.
C. Roger White David W. Garber G. M. Anantharamaiah 《Journal of lipid research》2014,55(10):2007-2021
Reduced levels of HDL cholesterol (HDL-C) are a strong independent predictor of coronary artery disease (CAD) risk. The major anti-atherogenic function of HDL is to mediate reverse cholesterol transport. This response is highly dependent on apoA-I and apoE, protein components of HDL. Randomized clinical trials have assessed effects of several classes of drugs on plasma cholesterol levels in CAD patients. Agents including cholestyramine, fibrates, niacin, and statins significantly lower LDL cholesterol (LDL-C) and induce modest increases in HDL-C, but tolerance issues and undesirable side effects are common. Additionally, residual risk may be present in patients with persistently low HDL-C and other complications despite a reduction in LDL-C. These observations have fueled interest in the development of new pharmacotherapies that positively impact circulating lipoproteins. The goal of this review is to discuss the therapeutic potential of synthetic apolipoprotein mimetic peptides. These include apoA-I mimetic peptides that have undergone initial clinical assessment. We also discuss newer apoE mimetics that mediate the clearance of atherogenic lipids from the circulation and possess anti-inflammatory properties. One of these (AEM-28) has recently been given orphan drug status and is undergoing clinical trials. 相似文献
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10.
Kapil Gadkar James Lu Srikumar Sahasranaman John Davis Norman A. Mazer Saroja Ramanujan 《Journal of lipid research》2016,57(1):46-55
The recent failures of cholesteryl ester transport protein inhibitor drugs to decrease CVD risk, despite raising HDL cholesterol (HDL-C) levels, suggest that pharmacologic increases in HDL-C may not always reflect elevations in reverse cholesterol transport (RCT), the process by which HDL is believed to exert its beneficial effects. HDL-modulating therapies can affect HDL properties beyond total HDL-C, including particle numbers, size, and composition, and may contribute differently to RCT and CVD risk. The lack of validated easily measurable pharmacodynamic markers to link drug effects to RCT, and ultimately to CVD risk, complicates target and compound selection and evaluation. In this work, we use a systems pharmacology model to contextualize the roles of different HDL targets in cholesterol metabolism and provide quantitative links between HDL-related measurements and the associated changes in RCT rate to support target and compound evaluation in drug development. By quantifying the amount of cholesterol removed from the periphery over the short-term, our simulations show the potential for infused HDL to treat acute CVD. For the primary prevention of CVD, our analysis suggests that the induction of ApoA-I synthesis may be a more viable approach, due to the long-term increase in RCT rate. 相似文献
11.
Endothelial lipase (EL) plays an important physiological role in modulating HDL metabolism. Data suggest that plasma contains an inhibitor of EL, and previous studies have suggested that apolipoprotein A-II (apoA-II) inhibits the activity of several enzymes involved in HDL metabolism. Therefore, we hypothesized that apoA-II may reduce the ability of EL to influence HDL metabolism. To test this hypothesis, we determined the effect of EL expression on plasma phospholipase activity and HDL metabolism in human apoA-I and human apoA-I/A-II transgenic mice. Expression of EL in vivo resulted in lower plasma phospholipase activity and significantly less reduction of HDL-cholesterol, phospholipid, and apoA-I levels in apoA-I/A-II double transgenic mice compared with apoA-I single transgenic mice. We conclude that the presence of apoA-II on HDL particles inhibits the ability of EL to influence the metabolism of HDL in vivo. 相似文献
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13.
Sebastian R. Freeman Xueting Jin Joshua J. Anzinger Qing Xu Sonya Purushothaman Michael B. Fessler Lia Addadi Howard S. Kruth 《Journal of lipid research》2014,55(1):115-127
Previous studies have demonstrated that the ATP-binding cassette transporters (ABC)A1 and ABCG1 function in many aspects of cholesterol efflux from macrophages. In this current study, we continued our investigation of extracellular cholesterol microdomains that form during enrichment of macrophages with cholesterol. Human monocyte-derived macrophages and mouse bone marrow-derived macrophages, differentiated with macrophage colony-stimulating factor (M-CSF) or granulocyte macrophage colony-stimulation factor (GM-CSF), were incubated with acetylated LDL (AcLDL) to allow for cholesterol enrichment and processing. We utilized an anti-cholesterol microdomain monoclonal antibody to reveal pools of unesterified cholesterol, which were found both in the extracellular matrix and associated with the cell surface, that we show function in reverse cholesterol transport. Coincubation of AcLDL with 50 μg/ml apoA-I eliminated all extracellular and cell surface-associated cholesterol microdomains, while coincubation with the same concentration of HDL only removed extracellular matrix-associated cholesterol microdomains. Only at an HDL concentration of 200 µg/ml did HDL eliminate the cholesterol microdomains that were cell-surface associated. The deposition of cholesterol microdomains was inhibited by probucol, but it was increased by the liver X receptor (LXR) agonist TO901317, which upregulates ABCA1 and ABCG1. Extracellular cholesterol microdomains did not develop when ABCG1-deficient mouse bone marrow-derived macrophages were enriched with cholesterol. Our findings show that generation of extracellular cholesterol microdomains is mediated by ABCG1 and that reverse cholesterol transport occurs not only at the cell surface but also within the extracellular space. 相似文献
14.
Wallace JM Schwarz M Coward P Houze J Sawyer JK Kelley KL Chai A Rudel LL 《Journal of lipid research》2005,46(5):1009-1016
The objective of this study was to demonstrate the efficacy of a novel peroxisome proliferator-activated receptor (PPAR) agonist and known PPARalpha and PPARdelta agonists to increase HDL-cholesterol (HDL-C) in the St. Kitts vervet, a nonhuman primate model of atherosclerosis. Four groups (n = 6) were studied and each group was assigned one of the following \"treatments\": a) vehicle only (vehicle); b) the PPARdelta selective agonist GW501516 (GW); c) the PPARalpha/delta agonist T913659 (T659); and d) the PPARalpha agonist TriCor (fenofibrate). No statistically significant changes were seen in body weight, total plasma cholesterol, plasma triglycerides, VLDL-C, LDL-C, or apolipoprotein B (apoB) concentrations. Each of the PPARalpha and PPARdelta agonists investigated in this study increased plasma HDL-C, apoA-I, and apoA-II concentrations and increased HDL particle size in St. Kitts vervets. The maximum percentage increase in HDL-C from baseline for each group was as follows: vehicle, 5%; GW, 43%; T659, 43%; and fenofibrate, 20%. Treatment with GW and T659 resulted in an increase in medium-sized HDL particles, whereas fenofibrate showed increases in large HDL particles. These data provide additional evidence that PPARalpha and PPARdelta agonists (both mixed and selective) have beneficial effects on HDL-C in these experimental primates. 相似文献
15.
Phosphatidylethanolamine is an important inner-leaflet phospholipid, and CTP:phosphoethanolamine cytidylyltransferase-Pcyt2 acts as the main regulator of the de novo phosphatidylethanolamine synthesis from ethanolamine and diacylglycerol. Complete deletion of the mouse Pcyt2 gene is embryonic lethal, and the single-allele deficiency leads to development of the metabolic syndrome phenotype, including liver steatosis, hypertriglyceridemia, obesity, and insulin resistance. This study aimed to specifically elucidate the mechanisms of hypertriglyceridemia in Pcyt2 heterozygous mice (Pcyt2(+/-)). Evidence here shows that unlike 8 week-old mice, 32 week- and 42 week-old Pcyt2(+/-) mice experience increased VLDL secretion and liver microsomal triglyceride transfer protein activity. Older Pcyt2(+/-) mice also demonstrate increased levels of postprandial plasma TAGs, increased stimulation of genes responsible for intestinal lipid absorption, transport and chylomicron secretion, and dramatically elevated plasma Angptl4, apoB-100, and apoB-48 content. In addition, plasma HL and LPL activities and TAG clearance following a lipid challenge were significantly reduced in Pcyt2(+/-) mice relative to control littermates. Collectively, these results establish that the hypertriglyceridemia that accompanies Pcyt2 deficiency is the result of multiple metabolic adaptations, including elevated hepatic and intestinal lipoprotein secretion and stimulated expression and/or activity of genes involved in lipid absorption and transport and lipoprotein assembly, together with reduced plasma TAG clearance and utilization with peripheral tissues. 相似文献
16.
Abdominal obesity is associated with a decreased plasma concentration of HDL cholesterol and with qualitative modifications of HDL, such as triglyceride enrichment. Our aim was to determine, in isolated aorta rings, whether HDL from obese subjects can counteract the inhibitory effect of oxidized low density lipoprotein (OxLDL) on endothelium-dependent vasodilation as efficiently as HDL from normolipidemic, lean subjects. Plasma triglycerides were 74% higher (P < 0.005) in obese subjects compared with controls, and apolipoprotein A-I (apoA-I) and HDL cholesterol concentrations were 12% and 17% lower (P < 0.05), respectively. HDL from control subjects significantly reduced the inhibitory effect of OxLDL on vasodilation [maximal relaxation (E(max)) = 82.1 +/- 8.6% vs. 54.1 +/- 8.1%; P < 0.0001], but HDL from obese subjects had no effect (E(max) = 47.2 +/- 12.5% vs. 54.1 +/- 8.1%; NS). In HDL from abdominally obese subjects compared with HDL from controls, the apoA-I content was 12% lower (P < 0.05) and the triglyceride-to-cholesteryl ester ratio was 36% higher (P = 0.08)). E(max)(OxLDL + HDL) was correlated with HDL apoA-I content and triglyceride-to-cholesteryl ester ratio (r = 0.36 and r = -0.38, respectively; P < 0.05). We conclude that in abdominally obese subjects, the ability of HDL to counteract the inhibitory effect of OxLDL on vascular relaxation is impaired. This could contribute to the increased cardiovascular risk observed in these subjects. 相似文献
17.
Zabalawi M Bharadwaj M Horton H Cline M Willingham M Thomas MJ Sorci-Thomas MG 《Journal of lipid research》2007,48(1):52-65
Diet-fed low density lipoprotein receptor-deficient/apolipoprotein A-I-deficient (LDLr-/-, apoA-I-/-) mice accumulate a 10-fold greater mass of cholesterol in their skin despite a 1.5- to 2-fold lower plasma cholesterol concentration compared with diet-fed LDLr-/- mice. The accumulation of cholesterol predominantly in the skin has been shown to occur in a growing number of other hypercholesterolemic double knockout mouse models sharing deficits in genes regulating cellular cholesterol homeostasis. Exploring the relationship between cholesterol balance and inflammation, we have examined the time course of cholesterol accumulation in a number of extrahepatic tissues and correlated with the onset of inflammation in diet-fed LDLr-/-, apoA-I-/- mice. After 4 weeks of diet, LDLr-/-, apoA-I-/- mice showed a significant increase in skin cholesterol mass compared with LDLr-/- mice. In addition, after 4 weeks on the diet, cholesterol accumulation in the skin was also found to be associated with macrophage infiltration and accompanied by increases in tumor necrosis factor-alpha, cyclooxygenase-2, and langerin mRNA, which were not seen in the liver. Overall, these data suggest that as early as 4 weeks after starting the diet, the accumulation of skin cholesterol and the onset of inflammation occur concurrently. In summary, the use of hypercholesterolemic LDLr-/-, apoA-I-/- mice may provide a useful tool to investigate the role that apoA-I plays in maintaining cholesterol homeostasis and its relationship to inflammation. 相似文献
18.
de Beer MC van der Westhuyzen DR Whitaker NL Webb NR de Beer FC 《Journal of lipid research》2005,46(10):2143-2150
The HDL receptor scavenger receptor class B type I (SR-BI) binds HDL and mediates the selective uptake of cholesteryl ester. We previously showed that remnants, produced when human HDL(2) is catabolized in mice overexpressing SR-BI, become incrementally smaller, ultimately consisting of small alpha-migrating particles, distinct from pre-beta HDL. When mixed with mouse plasma, some remnant particles rapidly increase in size by associating with HDL without the mediation of cholesteryl ester transfer protein, LCAT, or phospholipid transfer protein. Here, we show that processing of HDL(2) by SR-BI-overexpressing mice resulted in the preferential loss of apolipoprotein A-II (apoA-II). Short-term processing generated two distinct, small alpha-migrating particles. One particle (8.0 nm diameter) contained apoA-I and apoA-II; the other particle (7.7 nm diameter) contained only apoA-I. With extensive SR-BI processing, only the 7.7 nm particle remained. Only the 8.0 nm remnants were able to associate with HDL. Compared with HDL(2), this remnant was more readily taken up by the liver than by the kidney. We conclude that SR-BI-generated HDL remnants consist of particles with or without apoA-II and that only those containing apoA-II associate with HDL in an enzyme-independent manner. Extensive SR-BI processing generates small apoA-II-depleted particles unable to reassociate with HDL and readily taken up by the liver. This represents a pathway by which apoA-I and apoA-II catabolism are segregated. 相似文献
19.
Anna Schwendeman Denis O. Sviridov Wenmin Yuan Yanhong Guo Emily E. Morin Yue Yuan John Stonik Lita Freeman Alice Ossoli Seth Thacker Salena Killion Milton Pryor Y. Eugene Chen Scott Turner Alan T. Remaley 《Journal of lipid research》2015,56(9):1727-1737
The goal of this study was to understand how the reconstituted HDL (rHDL) phospholipid (PL) composition affects its cholesterol efflux and anti-inflammatory properties. An ApoA-I mimetic peptide, 5A, was combined with either SM or POPC. Both lipid formulations exhibited similar in vitro cholesterol efflux by ABCA1, but 5A-SM exhibited higher ABCG1- and SR-BI-mediated efflux relative to 5A-POPC (P < 0.05). Injection of both rHDLs in rats resulted in mobilization of plasma cholesterol, although the relative potency was 3-fold higher for the same doses of 5A-SM than for 5A-POPC. Formation of preβ HDL was observed following incubation of rHDLs with both human and rat plasma in vitro, with 5A-SM inducing a higher extent of preβ formation relative to 5A-POPC. Both rHDLs exhibited anti-inflammatory properties, but 5A-SM showed higher inhibition of TNF-α, IL-6, and IL-1β release than did 5A-POPC (P < 0.05). Both 5A-SM and 5A-POPC showed reduction in total plaque area in ApoE−/− mice, but only 5A-SM showed a statistically significant reduction over placebo control and baseline (P < 0.01). The type of PL used to reconstitute peptide has significant influence on rHDL’s anti-inflammatory and anti-atherosclerosis properties. 相似文献
20.