Background The capacity of high‐density lipoprotein cholesterol (HDL) to acquire free cholesterol (FC) from triglyceride‐rich lipoproteins during lipoprotein lipase–dependent lipolysis in a process of reverse remnant cholesterol transport, has been proposed as a key biological function of HDL particles that underlies the U‐shaped relationship between HDLcholesterol and cardiovascular diseases. Although reverse remnant cholesterol transport has been evaluated in a fasting state, it has never been explored under nonfasting conditions. Methods and Results FC transfer was evaluated in healthy men (n=78) before and throughout the postprandial phase up to 8 hours after consumption of a test meal. Postprandially, the capacity of HDL to acquire FC increased progressively, reaching a maximal mean value of 98.5%±22.5% 6 hours after meal intake ( P <0.05). Analysis of the study population according to tertiles of postprandial variation of FC transfer identified subjects exhibiting reduced capacity of HDL to acquire FC (tertile 1), those for whom the capacity of HDL to acquire FC remained unchanged (tertile 2), and subjects characterized by an enhanced FC transfer during the postprandial phase (tertile 3). Across the tertiles, we found an inverse relationship between the maximal postprandial change in FC transfer to HDL and the degree of postprandial triglyceride response. Conclusions Healthy individuals exhibiting exacerbated postprandial triglyceride response and reduced HDL cholesterol levels feature reduced FC transfer to HDL during the postprandial state. These data suggest that to normalize postprandial triglyceride response, 2 conditions need to be fulfilled: notably elevated FC transfer to HDL in the postprandial phase and increased levels of acceptor HDL particles.

While low concentrations of high-density lipoprotein-cholesterol (HDL-C) are widely accepted as an independent cardiovascular risk factor, HDL-C-rising therapies largely failed, suggesting the importance of both HDL functions and individual subspecies. Indeed HDL particles are highly heterogeneous, with small, dense pre-beta-HDLs being considered highly biologically active but remaining poorly studied, largely reflecting difficulties for their purification. We developed an original experimental approach allowing the isolation of sufficient amounts of human pre-beta-HDLs and revealing the specificity of their proteomic and lipidomic profiles and biological activities. Pre-beta-HDLs were enriched in highly poly-unsaturated species of phosphatidic acid and phosphatidylserine, and in an unexpectedly high number of proteins implicated in the inflammatory response, including serum paraoxonase/arylesterase-1, vitronectin and clusterin, as well as in complement regulation and immunity, including haptoglobin-related protein, complement proteins and those of the immunoglobulin class. Interestingly, amongst proteins associated with lipid metabolism, phospholipid transfer protein, cholesteryl ester transfer protein and lecithin:cholesterol acyltransferase were strongly enriched in, or restricted to, pre-beta-HDL. Furthermore, pre-beta-HDL potently mediated cellular cholesterol efflux and displayed strong anti-inflammatory activities. A correlational network analysis between lipidome, proteome and biological activities highlighted 15 individual lipid and protein components of pre-beta-HDL relevant to cardiovascular disease, which may constitute novel diagnostic targets in a pathological context of altered lipoprotein metabolism.

Background and aims: While low concentrations of high-density lipoprotein-cholesterol (HDL-C) represent a wellestablished cardiovascular risk factor, extremely high HDL-C is paradoxically associated with elevated cardiovascular risk, resulting in the U-shape relationship with cardiovascular disease. Free cholesterol transfer to HDL upon lipolysis of triglyceride-rich lipoproteins (TGRL) was recently reported to underlie this relationship, linking HDL-C to triglyceride metabolism and atherosclerosis. In addition to free cholesterol, other surface components of TGRL, primarily phospholipids, are transferred to HDL during lipolysis. It remains indeterminate as to whether such transfer is linked to HDL-C and cardiovascular disease. Methods and results: When TGRL was labelled with fluorescent phospholipid 1,1?-dioctadecyl-3,3,3?,3?-tetramethylindocarbocyanine perchlorate (DiI), time- and dose-dependent transfer of DiI to HDL was observed upon incubations with lipoprotein lipase (LPL). The capacity of HDL to acquire DiI was decreased by -36% (p<0.001) in low HDL-C patients with acute myocardial infarction (n = 22) and by -95% (p<0.001) in low HDL-C subjects with Tangier disease (n = 7), unchanged in low HDL-C patients with Type 2 diabetes (n = 17) and in subjects with high HDL-C (n = 20), and elevated in subjects with extremely high HDL-C (+11%, p<0.05) relative to healthy normolipidemic controls. Across all the populations combined, HDL capacity to acquire DiI was directly correlated with HDL-C (r = 0.58, p<0.001). No relationship of HDL capacity to acquire DiI with both overall and cardiovascular mortality obtained from epidemiological studies for the mean HDL-C levels observed in the studied populations was obtained. Conclusions: These data indicate that the capacity of HDL to acquire phospholipid from TGRL upon LPL-mediated lipolysis is proportional to HDL-C and does not reflect cardiovascular risk in subjects widely differing in HDL-C levels.

In the Results section of this article (paragraph 6 in page 5), the values of DiI transfer to HDL of 3.0 ± 0.9 and 8.0 ± 5.7% (p < 0.001 vs. controls) observed in homo- (n = 4) and heterozygous (n = 3) Tangier subjects, respectively, were erroneously reported without normalization to the values of DiI transfer to reference HDL. Following such normalization, the values of DiI transfer were 10.0 ± 2.9% and 26.3 ± 18.7%, respectively (p < 0.001 vs. controls). This correction does not influence the statement of the paragraph as the p-values of the between-group differences were not modified by the correction. Overall conclusions of the manuscript are not affected either. The paragraph in question should read as follows: To verify that the reduction in DiI transfer to HDL observed in AMI patients was unrelated to their acute phase state, we recruited another group of low HDL-C subjects with Tangier disease (n = 7). Both HDL-C levels (2.2 ± 0.5 and 39 ± 11 mg/dL, p < 0.001 and p < 0.05, respectively, vs. controls) and DiI transfer to HDL (10.0 ± 2.9% and 26.3 ± 18.7%, p < 0.001 vs. controls) were significantly reduced in both homo- (n = 4) and heterozygous (n = 3) Tangier subjects, respectively. The authors sincerely apologize for this inaccuracy. Phospholipid transfer to high-density lipoprotein (HDL) upon triglyceride lipolysis is directly correlated with HDL-cholesterol levels and is not associated with cardiovascular riskAtherosclerosisVol. 324PreviewWhile low concentrations of high-density lipoprotein-cholesterol (HDL-C) represent a well-established cardiovascular risk factor, extremely high HDL-C is paradoxically associated with elevated cardiovascular risk, resulting in the U-shape relationship with cardiovascular disease. Free cholesterol transfer to HDL upon lipolysis of triglyceride-rich lipoproteins (TGRL) was recently reported to underlie this relationship, linking HDL-C to triglyceride metabolism and atherosclerosis. In addition to free cholesterol, other surface components of TGRL, primarily phospholipids, are transferred to HDL during lipolysis. Full-Text PDF

BackgroundLow concentrations of high-density lipoprotein cholesterol (HDL-C) represent a well-established cardiovascular risk factor. Paradoxically, extremely high HDL-C levels are equally associated with elevated cardiovascular risk, resulting in the U-shape relationship of HDL-C with cardiovascular disease. Mechanisms underlying this association are presently unknown. We hypothesised that the capacity of high-density lipoprotein (HDL) to acquire free cholesterol upon triglyceride-rich lipoprotein (TGRL) lipolysis by lipoprotein lipase underlies the non-linear relationship between HDL-C and cardiovascular risk.MethodsTo assess our hypothesis, we developed a novel assay to evaluate the capacity of HDL to acquire free cholesterol (as fluorescent TopFluor® cholesterol) from TGRL upon in vitro lipolysis by lipoprotein lipase.ResultsWhen the assay was applied to several populations markedly differing in plasma HDL-C levels, transfer of free cholesterol was significantly decreased in low HDL-C patients with acute myocardial infarction (−45%) and type 2 diabetes (–25%), and in subjects with extremely high HDL-C of >2.59 mmol/L (>100 mg/dL) (−20%) versus healthy normolipidaemic controls. When these data were combined and plotted against HDL-C concentrations, an inverse U-shape relationship was observed. Consistent with these findings, animal studies revealed that the capacity of HDL to acquire cholesterol upon lipolysis was reduced in low HDL-C apolipoprotein A-I knock-out mice and was negatively correlated with aortic accumulation of [3H]-cholesterol after oral gavage, attesting this functional characteristic as a negative metric of postprandial atherosclerosis.ConclusionsFree cholesterol transfer to HDL upon TGRL lipolysis may underlie the U-shape relationship between HDL-C and cardiovascular disease, linking HDL-C to triglyceride metabolism and atherosclerosis.

Apolipoprotein B-containing lipoproteins and low-density lipoprotein play a key role in atherosclerotic vascular disease. Modified forms of low-density lipoprotein drive inflammation, an integral aspect of plaque progression. High-density lipoprotein particles are equipped to protect low-density lipoprotein from enzymatic and nonenzymatic modification. Under normal conditions, high-density lipoproteins facilitate cholesterol efflux from tissues, preventing its accumulation with deleterious consequences. However, the high-density lipoprotein particles characteristic of dyslipidemic states associated with premature atherosclerosis are typically dysfunctional as a result of alteration in their metabolism and consequently their structure and composition. Such an effect indirectly enhances low-density lipoprotein atherogenicity.

Large-scale epidemiological studies firmly established the association between low plasma levels of high-density lipoprotein-cholesterol (HDL-C) and elevated risk of cardiovascular disease. This relationship is thought to reflect the key biological function of HDL, which involves reverse cholesterol transport from the arterial wall to the liver for further excretion from the body. Other aspects of the cardioprotective HDL functionality include antioxidative, anti-inflammatory, anti-apoptotic, anti-thrombotic, vasodilatory, anti-infectious and antidiabetic activities. Over the last decades, wide interest in HDL as an athero- and cardioprotective particle has resulted in the development of HDL-C raising as a therapeutic approach to reduce cardiovascular risk. Several strategies to increase circulating HDL-C concentrations were developed that primarily included use of niacin and fibrates as potent HDL-C raising agents. In the statin era, inhibition of cholesteryl ester transfer protein, infusion of artificially reconstituted HDL and administration of apolipoprotein A-I mimetics were established as novel approaches to raise HDL-C. More recently, other strategies targeting HDL metabolism, such as upregulation of apolipoprotein A-I production by the liver, were added to the list of HDL therapeutics. This review summarises current knowledge of novel HDL-targeting therapies and discusses perspectives of their use.

以甲基乙烯基硅橡胶为基体材料,植入钛钉,一次设计成型胰肠吻合器.通过红外光谱(FT-IR)对其结构进行表征;通过力学性能实验对其拉伸强度和断裂伸长率进行测试;通过耐介质性测试观察其接触到水、酒精及双氧水的性能变化;通过环氧乙烷灭菌测试其灭菌前后力学性能的变化.结果表明:吻合器断裂伸长率和拉伸强度达282.6％和2.17MPa,经过蒸馏水、75％酒精、3％双氧水,NaOH(pH=9)和HCl(pH=0.8)浸泡的吻合器袁观无变化,质量损失最大值仅为5.63％;且可经受环氧乙烷灭菌测试.硅橡胶因其生理无毒性可以用来制作吻合器,并能满足各指标要求.

Background Livestock that consume locoweed exhibit multiple neurological symptoms, including dispirited behavior, staggered gait, trembling, ataxia, impaired reproductive function and cellular vacuolar degeneration of multiple tissues due to toxicity from plant-derived alkaloids such as swainsonine. Results Swainsonine was administered to F 0 and F 1 mice by intraperitoneal injection before, during and after pregnancy at the following doses: 0.525 mg/kg BW(I), 0.2625 mg/kg BW(II), 0.175 mg/kg BW(III) and 0 mg/kg BW(IV). Hemosiderin deposits were observed the lamina propria of endometrium in uterus and the red pulp of spleen. Ovary corpus lutea counts in F 0 mice were higher in swainsonine-treated mice compared to control mice. Indirect bilirubin content and reticulocyte numbers were increased in swainsonine-treated F 0 and F 1 generation mice compared to control group ( P < 0.05). Lactate dehydrogenase, alkaline phosphatase, aspartate aminotransferase and alanine aminotransferase content in F 0 -I and F 0 -II mice were significantly increased compared with F 0 -IV group mice ( P < 0.05). Red blood cells, hemoglobin and mean corpuscular hemoglobin levels were significantly decreased in F 0 and F 1 mice compared with the control group ( P < 0.05). Conclusions Swainsonine exerts effects on estrus period and reproductive ability, and offspring of dams dosed with swainsonine were affected in-utero or from nursing. Damage to liver, uterus and spleen, as well as hematological changes, are observable before neurological symptoms present.

Locoweeds are perennial herbaceous plants included in Astragalus spp. and Oxytropis spp. that contain the toxic indolizidine alkaloid swainsonine. The livestock that consume locoweed feeding can suffer from a type of toxicity called "locoism." There are aliphatic nitro compounds, selenium, selenium compounds and alkaloids in locoweed. The toxic component in locoweeds has been identified as swainsonine, an indolizidine alkaloid. Swainsonine inhibits lysosomal α-mannosidase and mannosidase II, resulting in altered oligosaccharide degradation and incomplete glycoprotein processing. As a result, livestock that consume locoweeds exhibit several symptoms, including dispirited behavior, staggering gait, chromatopsia, trembling, ataxia, and cellular vacuolar degeneration of most tissues by pathological observation. Locoism results in significant annual economic losses. Recently, locoweed populations have increased domestically in China and abroad, resulting in an increase in the incidence of poisoning. Therefore, in this paper, we review the current research on locoweed, including on species variation, pathogenesis, damage and poisoning prevention measures.

Évaluation clinique de la fonction anti-athérogène de la lipoprotéine de haute densité Il a été bien établi chez l’Homme qu'il existe une forte association entre les faibles concentrations plasmatiques de cholestérol associé aux lipoprotéines de haute densité (HDL-C) et le risque accru de maladie cardiovasculaire (MCV). Augmenter le taux de HDL-C a donc été proposé comme stratégie thérapeutique visant à réduire le risque de MCV. En effet, les HDL présentent de multiples fonctions athéroprotectrices, notamment la capacité d’efflux du cholestérol, ainsi que des activités antioxydantes, anti-inflammatoires, vasodilatatrices, cytoprotectrices, anti-infectieuses et anti- thrombotiques. Cependant, des essais cliniques à grande échelle ont révélé que l'augmentation du HDL-C induite par un médicament ne réduisait pas nécessairement le risque CV. En outre, des études de randomisation mendélienne ont montré que des concentrations faibles de HDL-C déterminées génétiquement ne se traduisaient pas toujours par un risque accru de MCV. Récemment, plusieurs études épidémiologiques à grande échelle ont mis en évidence une dépendance en forme de U entre la maladie cardiovasculaire et les taux de HDL-C, établissant un lien entre un taux de HDL-C extrêmement élevé et un risque CV élevé. Afin de surmonter les limites du HDL-C en tant que facteur de risque CV, le concept de fonctionnalité des lipoprotéines HDL a été étudié, ce qui a permis de développer un test permettant la mesure de la capacité des HDL à faire de l’efflux de cholestérol comme approche de prédiction du risque. Cependant, ce concept révèle plusieurs faiblesses, telles que la préservation de l'efflux de cholestérol tissulaire chez les patients ayant un taux de HDL-C bas d'origine génétique. Dans la circulation, le métabolisme des HDL est intimement lié à celui des triglycérides (TG) par divers facteurs, notamment des enzymes, telles que la lipoprotéine lipase (LPL), et des protéines de transfert lipidique, telles que la protéine de transfert d'esters de cholestérol (CETP). La contribution des niveaux circulants de TG au risque élevé de MCV a été établie dans des modèles multivariés. On pense que les lipoprotéines riches en triglycérides (TGRL) contribuent à l'athérosclérose via leurs particules résiduelles produites lors de la lipolyse des TGRL par la LPL. Des études antérieures ont montré que les HDL sont capables d'empêcher l'accumulation de ces particules residuelles de TGRL dans la paroi artérielle. Il a donc été proposé que le faible taux de HDL-C représente un biomarqueur de niveaux élevés de résidus de TGRL générés par la lipolyse. On ignore actuellement si cette association peut expliquer la relation en forme de U entre le risque CV et le taux de HDL-C. En outre, les mécanismes sous-jacents à l'association entre le HDL-C, les résidus de TG et les MCV restent obscurs. Dans la présente étude, nous proposons une hypothèse selon laquelle les HDL circulants peuvent se charger en lipides, tels que le cholestérol libre (FC) et le phospholipide (PL), et des protéines provenants de la surface des résidus des TGRL générés au cours de la lipolyse médiée par la LPL, puis les transporter vers le foie dans un processus appelé le transport inverse des résidus (RRT). Nous suggérons en outre que les modifications de la RRT sous-tendent les relations entre HDL-C et MCV. Pour évaluer cette hypothèse, nous avons conçu un nouveau test in vitro évaluant les transferts lipidiques des TGRL aux HDL au cours de la lipolyse et l'avons appliqué à plusieurs populations de sujets présentant des taux plasmatiques de HDL-C différents. Les mécanismes de transfert de lipides de surface vers les HDL ont également été étudiés. Nous avons observé que les HDL, isolés par ultracentrifugation ou par déplétion plasmatique de l'apolipoprotéine B, acquéraient des lipides de surface, y compris FC et PL, des TGRL lors d'une lipolyse induite par le LPL à 37 ° C, en fonction du temps, comme l'a révélé la photométrie [...]