Influence of human low density and high density lipoprotein cholesterol on the in vitro prostaglandin I2 synthetase activity

We investigated in vitro the influence of low density lipoprotein (LDL) cholesterol and high density lioprotein (HDL) cholesterol separated from human serum on prostaglandin I2 synthetase activity studied by the conversion of prostaglandin H2 to prostaglandin I2 by the microsomal fraction of pig aorta. 6-Oxo-prostaglandin F1 alpha was analyzed by gas-liquid chromatography using prostaglandin F1 alpha as internal standard. We found a linear negative correlation (P less than 0.001) between the amount of LDL cholesterol in the incubation solution and prostaglandin I2 synthetase activity, whereas there was a positive correlation (P less than 0.01) between HDL cholesterol and prostaglandin I2 synthesis. A very low concentration of LDL cholesterol and a high concentration of HDL cholesterol stimulated prostaglandin I2 synthesis, whereas a high LDL cholesterol concentration inhibited prostaglandin I2 biosynthesis by 64%. The concentration range of LDL and HDL cholesterol was representative of physiologically low, normal or elevated levels of lipoproteins.     

Metabolism of high-density lipoproteins in cultured rat luteal cells

The uptake of cholesterol from high-density lipoproteins (HDL) labeled with 125I and [3H]cholesterol was examined in cultured rat luteal cells. Luteal cells were incubated with labeled HDL, following which the metabolic fate of the apolipoproteins and cholesterol moieties of the receptor-bound HDL were examined. About 50% of the originally bound HDL apolipoproteins were released into the medium in 24 h by a temperature-dependent process while only 5% of the HDL cholesterol was released unmetabolized. Inclusion of unlabeled HDL in the chase incubation resulted in increased release of apolipoprotein-derived radioactive products without significant change in the release of unmetabolized cholesterol. 60% of the apolipoprotein-derived radioactivity could be precipitated with trichloroacetic acid; the remaining trichloroacetic acid-soluble radioactive fraction was identified as [125I]iodotyrosine. Gel filtration chromatography of the chase-released material showed that the trichloroacetic acid-precipitable products, which contained no detectable amounts of cholesterol, eluted over a range of molecular sizes (9-80 kDa). No intact HDL was retroendocytosed. About 80% of trichloroacetic acid-precipitable products could be immunoadsorbed on anti-apolipoprotein A-I antibody immobilized on CNBr-activated Sepharose, suggesting the presence of fragments containing apolipoprotein A-I. This material was also capable of reassociating with native HDL. Lysosomal inhibitors were partially effective in inhibiting the amount of trichloroacetic acid-soluble products formed. The lysosomal degradation appeared to have no role in the uptake of HDL-derived cholesterol. These studies demonstrate preferential and total uptake of HDL cholesterol by luteal cells, with concomitant degradation of the lipoprotein.     

Regulation of high density lipoprotein receptors in cultured macrophages: role of acyl-CoA:cholesterol acyltransferase

The interaction of human serum high density lipoproteins (HDL) with mouse peritoneal macrophages and human blood monocytes was studied. Saturation curves for binding of apolipoprotein E-free [125I]HDL3 showed at least two components: non-specific binding and specific binding that saturated at approximately 40 micrograms HDL protein/ml. Scatchard analysis of specific binding of apo E-free [125I]-HDL3 to cultured macrophages yielded linear plots indicative of a single class of specific binding sites. Pretreatment of [125I]HDL3 with various apolipoprotein antibodies (anti apo A-I, anti apo A-II, anti apo C-II, anti apo C-III and anti apo E) and preincubation of the cells with anti-idiotype antibodies against apo A-I and apo A-II prior to the HDL binding studies revealed apolipoprotein A-I as the ligand involved in specific binding of HDL. Cellular cholesterol accumulation via incubation with acetylated LDL led to an increase in HDL binding sites as well as an increase in the activity of the cytoplasmic cholesterol esterifying enzyme acyl-CoA:cholesterol acyltransferase (ACAT). Incubation of the cholesterol-loaded cells in the presence of various ACAT inhibitors (Sandoz 58.035, Octimibate-Nattermann, progesterone) revealed a time- and dose-dependent amplification in HDL binding and HDL-mediated cholesterol efflux. It is concluded that the homeostasis of cellular cholesterol in macrophages is regulated in part by the number of HDL binding sites and that ACAT inhibitors enhance HDL-mediated cholesterol efflux from peripheral cells.     

SR-BI- and ABCA1-mediated cholesterol efflux to serum from patients with Alagille syndrome

Alagille syndrome is associated with bile duct paucity resulting in liver disease. Patients can be divided into mildly and severely icteric groups, with both groups having altered lipoproteins. The incidence of ischemic heart disease is rare in severely cholestatic children despite increased total cholesterol and decreased high density lipoprotein cholesterol (HDL-C). The present studies examine the impact of altered lipid and lipoproteins on scavenger receptor class B type I (SR-BI)- and ABCA1-mediated efflux to serum from both groups. Efflux was compared with serum from 29 patients (15 with normal plasma cholesteryl ester, 14 with low cholesteryl ester). Efflux via SR-BI and ABCA1 was studied using cell systems having either low or high expression levels of these receptors. SR-BI efflux was lower (P = 0.04) with serum from severely icteric patients (3.9 +/- 1.4%) compared with serum from mildly icteric patients (5.1 +/- 1.4%) and was positively correlated with HDL-C and its apolipoproteins. SR-BI-mediated efflux was not correlated with any particular mature HDL but was negatively correlated with small lipid-poor prebeta-1 HDL. Consistent with severely icteric patients having high prebeta-1 HDL levels, the ABCA1 efflux was significantly higher with their serum (4.8 +/- 2.2%) compared with serum from mildly icteric patients (2.0 +/- 0.6%) and was positively correlated with prebeta-1 HDL. These studies demonstrated that prebeta-1 HDL is the preferred acceptor for ABCA1 efflux, whereas many particles mediate SR-BI efflux.     

Detergent-mediated phospholipidation of plasma lipoproteins increases HDL cholesterophilicity and cholesterol efflux via SR-BI

Cellular cholesterol efflux is an early, obligatory step in reverse cholesterol transport, the putative antiatherogenic mechanism by which human plasma high-density lipoproteins (HDL) transport cholesterol from peripheral tissue to the liver for recycling or disposal. HDL-phospholipid content is the essential cholesterol-binding component of lipoproteins and therefore a major determinant of cholesterol efflux. Thus, increased phospholipidation of lipoproteins, particularly HDL, is one strategy for increasing cholesterol efflux. This study validates a simple, new detergent perturbation method for the phospholipidation of plasma lipoproteins; we have quantified the cholesterophilicity of human plasma lipoproteins and the effects of lipoprotein phospholipidation on cholesterophilicity and cellular cholesterol efflux mediated by the class B type I scavenger receptor (SR-BI). We determined that low-density lipoproteins (LDL) are more cholesterophilic than HDL and that LDL has a higher affinity for phospholipids than HDL whereas HDL has a higher phospholipid capacity than LDL. Phospholipidation of total human plasma lipoproteins enhances cholesterol efflux, an effect that occurs largely through the preferential phospholipidation of HDL. We conclude that increasing HDL phospholipid increases its cholesterophilicity, thereby making it a better acceptor of cellular cholesterol efflux. Phospholipidation of lipoproteins by detergent perturbation is a simple way to increase HDL cholesterophilicity and cholesterol efflux in a way that may be clinically useful.     

High‐density Lipoprotein Apolipoprotein A‐I Kinetics in Obesity

Objective: Low plasma concentrations of high‐density lipoprotein (HDL)‐cholesterol and apolipoprotein A‐I (apoA‐I) are independent predictors of coronary artery disease and are often associated with obesity and the metabolic syndrome. However, the underlying kinetic determinants of HDL metabolism are not well understood. Research Methods and Procedures: We pooled data from 13 stable isotope studies to investigate the kinetic determinants of apoA‐I concentrations in lean and overweight—obese individuals. We also examined the associations of HDL kinetics with age, sex, BMI, fasting plasma glucose, fasting insulin, Homeostasis Model Assessment score, and concentrations of apoA‐I, triglycerides, HDL‐cholesterol and low‐density lipoprotein‐cholesterol. Results: Compared with lean individuals, overweight—obese individuals had significantly higher HDL apoA‐I fractional catabolic rate (0.21 ± 0.01 vs. 0.33 ± 0.01 pools/d; p < 0.001) and production rate (PR; 11.3 ± 4.4 vs. 15.8 ± 2.77 mg/kg per day; p = 0.001). In the lean group, HDL apoA‐I PR was significantly associated with apoA‐I concentration (r = 0.455, p = 0.004), whereas in the overweight—obese group, both HDL apoA‐I fractional catabolic rate (r = ?0.396, p = 0.050) and HDL apoA‐I PR (r = 0.399, p = 0.048) were significantly associated with apoA‐I concentration. After adjustment for fasting insulin or Homeostasis Model Assessment score, HDL apoA‐I PR was an independent predictor of apoA‐I concentration. Discussion: In overweight—obese subjects, hypercatabolism of apoA‐I is paralleled by an increased production of apoA‐I, with HDL apoA‐I PR being the stronger determinant of apoA‐I concentration. This could have therapeutic implications for the management of dyslipidemia in individuals with low plasma HDL‐cholesterol.     

The cellular biology of scavenger receptor class B type I

The HDL receptor scavenger receptor class B type I plays an important role in meditating the uptake of HDL-derived cholesterol and cholesteryl ester in the liver and steroidogenic tissues. However, the mechanism by which scavenger receptor class B type I mediates selective cholesterol uptake is unclear. In hepatocytes scavenger receptor class B type I mediates the transcytosis of cholesterol into bile, appears to be expressed on both basolateral and apical membranes, and directly interacts with a PDZ domain containing protein that may modulate the activity of scavenger receptor class B type I. This suggests the involvement of scavenger receptor class B type I in higher order complexes in polarized cells. Scavenger receptor class B type I expression has been shown to alter plasma membrane cholesterol distribution and induce the formation of novel membrane structures, suggesting multiple roles for scavenger receptor class B type I in the cell. A close examination of scavenger receptor class B type I function in polarized cells may yield new insights into the mechanism of scavenger receptor class B type I-mediated HDL selective uptake and the effects of scavenger receptor class B type I on cellular cholesterol homeostasis.     

Effects of cimetidine and ranitidine on high density lipoprotein cholesterol concentrations.

To assess the effect of cimetidine and ranitidine on high density lipoprotein (HDL) cholesterol concentration two groups of eight patients with duodenal ulcer or oesophagitis matched for age, sex, and cigarette consumption were given either cimetidine 1 g daily or ranitidine 300 mg daily for one month. There was no significant change in the cholesterol content of HDL and its subfraction HDL3 after treatment with ranitidine or cimetidine, or in the cholesterol content of the subfraction HDL2 after treatment with ranitidine; the HDL2 cholesterol concentration was, however, significantly increased after treatment with cimetidine. Further studies are being undertaken to establish the mechanism of this effect.     

Secretory phospholipase A2 increases SR-BI-mediated selective uptake from HDL but not biliary cholesterol secretion

High density lipoprotein cholesterol represents a major source of biliary cholesterol. Secretory phospholipase A2 (sPLA2) is an acute phase enzyme mediating decreased plasma HDL cholesterol levels. Clinical studies reported a link between increased sPLA2 expression and the presence of cholesterol gallstones. The aim of our study was to investigate whether the overexpression of human sPLA2 in transgenic mice affects biliary cholesterol secretion and gallstone formation. Liver weight (P < 0.01) and hepatic cholesterol content (P < 0.01) were significantly increased in sPLA2 transgenic mice compared with controls as a result of increased scavenger receptor class B type I (SR-BI)-mediated hepatic selective uptake of HDL cholesterol (P < 0.01), whereas hepatic SR-BI expression remained unchanged. However, biliary cholesterol secretion as well as fecal neutral sterol and fecal bile salt excretion remained unchanged in sPLA2 transgenic mice. Furthermore, gallstone prevalence in response to a lithogenic diet was identical in both groups. These data demonstrate that i) increased flux of cholesterol from HDL into the liver via SR-BI as a result of phospholipase modification of the HDL particle translates neither into increased biliary and fecal sterol output nor into increased gallstone formation, and ii) increased sPLA2 expression in patients with cholesterol gallstones might be a consequence rather than the underlying cause of the disease.     

The role of the high-density lipoprotein receptor SR-BI in cholesterol metabolism

The HDL receptor scavenger receptor class B type I (SR-BI), which mediates selective HDL cholesterol uptake, plays a role in murine HDL metabolism, reverse cholesterol transport and whole-body cholesterol homeostasis. SR-BI is found in the liver, where its expression is regulated by estrogen, dietary cholesterol and fat, and controls murine plasma HDL cholesterol levels and bile cholesterol secretion. SR-BI is also highly expressed in rodent steroidogenic cells, where it facilitates cholesterol uptake for storage or steroid hormone synthesis and where its expression is regulated by trophic hormones. The detailed mechanism(s) underlying SR-BI-mediated selective cholesterol uptake have not yet been elucidated. Further analysis of the molecular and cellular bases of SR-BI regulation and function should provide new insights into the physiology and pathophysiology of cholesterol metabolism.     

Lipid screening: is it enough to measure total cholesterol concentration?

OBJECTIVES--To determine whether measurement of total cholesterol concentration is sufficient to identify most patients at lipoprotein mediated risk of coronary heart disease without measurement of triglyceride and high density lipoprotein (HDL) cholesterol concentrations. DESIGN--Cross sectional screening programme. SETTING--Six general practices in Oxfordshire. PATIENTS--1901 Men and 2068 women aged 25-59. MAIN OUTCOME MEASURE--Cardiovascular risk as assessed by fasting venous plasma concentrations of total cholesterol, triglyceride, and HDL cholesterol. RESULTS--2931 Patients (74% of those screened) had a total cholesterol concentration of less than 6.5 mmol/l. If the triglyceride concentration had not been measured in these patients isolated hypertriglyceridaemia (greater than or equal to 2.3 mmol/l) would have remained undetected in 185. Among these 185 patients, however, 123 were overweight or obese and only 18 (0.6% of those screened) had an increased risk associated with both a raised triglyceride concentration (greater than or equal to 2.3 mmol/l) and a low HDL cholesterol concentration (less than 0.9 mmol/l). Conversely, in the 790 patients with predominant hypercholesterolaemia (cholesterol concentration greater than or equal to 6.5 mmol/l and triglyceride concentration less than 2.3 mmol/l) measurement of HDL cholesterol concentration showed that 348 (9% of those screened) had only a moderately increased risk with a ratio of total to HDL cholesterol of less than 4.5 and 104 had a low risk with a ratio of less than 3.5. CONCLUSIONS--Fasting triglyceride and HDL cholesterol concentrations identify few patients at increased risk of coronary heart disease if the total cholesterol concentration is less than 6.5 mmol/l. HDL cholesterol and triglyceride concentrations should, however, be measured in patients with a total cholesterol concentration exceeding this value. Total cholesterol concentration alone may overestimate risk in a considerable number of these patients, and measurement of HDL cholesterol concentration allows a more precise estimate of risk. Measurement of the triglyceride concentration is required to characterise the lipoprotein abnormality. A patient should not be started on a drug that lowers lipid concentrations without having had a full lipoprotein assessment including measurement of HDL cholesterol concentration.     

Relationship of the parameters of body cholesterol metabolism with plasma levels of HDL cholesterol and the major HDL apoproteins

The inverse relationship between plasma levels of high density lipoprotein (HDL) and coronary heart disease rates has suggested that HDL might influence body stores of cholesterol. Therefore, we have investigated potential relationships between the parameters of body cholesterol metabolism and the plasma levels of HDL cholesterol and the major HDL apoproteins. The study involved 55 human subjects who underwent long-term cholesterol turnover studies, as well as plasma lipoprotein and apolipoprotein assays. In order to maximize the likelihood of detecting existing relationships, the subjects were selected to span a wide range of plasma levels of lipids, lipoproteins, and apolipoproteins. Single univariate correlation analyses suggested weak but statistically significant inverse relationships of HDL cholesterol and apoA-I levels with the following model parameters: production rate (PR), the mass of rapidly exchanging body cholesterol (M1), the minimum estimate of the mass of slowly exchanging body cholesterol (M3min), and of the mass of total exchangeable body cholesterol (Mtotmin). These correlations, however, were quantitatively quite small (/r/ = 0.28-0.42) in comparison to the strength of the univariate relationships between body weight and PR (r = 0.76), M1 (r = 0.61), M3min (r = 0.58), and Mtotmin (r = 0.78). Correlations for apoA-II and apoE levels were even smaller than those for apoA-I and HDL cholesterol. In additional analyses using multivariate approaches, HDL cholesterol, apoA-I, apoA-II, and apoE levels were all found not to be independent determinants of the parameters of body cholesterol metabolism (/partial r/ less than 0.17, P greater than 0.3 in all cases). Thus the weak univariate correlations reflect relationships of HDL cholesterol and apoA-I levels with physiological variables, such as body size, which are primarily related to the model parameters. We conclude that plasma levels of HDL cholesterol and apoproteins A-I, A-II, and E are not quantitatively important independent determinants of the mass of slowly exchanging body cholesterol or of other parameters of long-term cholesterol turnover in humans. These studies give no support to the hypothesis that the inverse relationship between HDL cholesterol levels and coronary heart disease rates is mediated via an influence of HDL on body stores of cholesterol.     

The role of the ABCA1 transporter and cholesterol efflux in familial hypoalphalipoproteinemia

Defects in the gene encoding for the ATP binding cassette (ABC) transporter A1 (ABCA1) were shown to be one of the genetic causes for familial hypoalphalipoproteinemia (FHA). We investigated the role of ABCA1-mediated cholesterol efflux in Dutch subjects suffering from FHA. Eighty-eight subjects (mean HDL cholesterol levels 0.63 +/- 0.21 mmol/l) were enrolled. Fibroblasts were cultured and loaded with [3H]cholesterol. ABCA1 and non-ABCA1-mediated efflux was studied by using apolipoprotein A-I (apoA-I), HDL, and methyl-beta-cyclodextrin as acceptors. Efflux to apoA-I was decreased in four patients (4/88, 4.5%), and in all cases, a mutation in the ABCA1 gene was found. In the remaining 84 subjects, no correlation between efflux and apoA-I or HDL cholesterol was found. Efflux to both HDL and cyclodextrin, in contrast, did correlate with HDL cholesterol plasma levels (r = 0.34, P = 0.01; and r = 0.27, P = 0.008, respectively). The prevalence of defects in ABCA1-dependent cholesterol efflux in Dutch FHA patients is low. The significant correlation between plasma HDL cholesterol levels and methyl-beta-cyclodextrin-mediated efflux in the FHA patients with normal ABCA1 function suggests that non-ABCA1-mediated efflux might also be important for plasma HDL cholesterol levels in these individuals.     

Effect of bromocriptine on lipid plasma levels in rats

Results show that bromocriptine induced marked alterations in plasma levels of cholesterol and lipids in response to acute and chronic administrations in rats. Two hours after an I.P. dose of 10 mg/kg, bromocriptine mesylate caused significant reductions in plasma levels of total high density lipoprotein (HDL) and high density lipoprotein cholesterol (HDL cholesterol). At a dose of 20 mg/kg, bromocriptine mesylate induced significant elevations in plasma levels of total cholesterol, total HDL, HDL cholesterol, total low density lipoproteins (LDL), and low density lipoprotein cholesterol (LDL cholesterol). Injected at a dose of 4 or 10 mg/kg daily for 14 consecutive days, bromocriptine mesylate caused significant increases in plasma levels of total cholesterol, LDL cholesterol and total LDL whereas the levels of HDL cholesterol, total HDL triglycerides (TG) were reduced. At a dose of 20 mg/kg all parameters were significantly increased. Marked hyperglycaemia was noticed in response to doses of 10, 15 and 20 mg/kg injected daily for 14 consecutive days or 2 hrs after a single administration of 15 mg/kg. Plasma insulin activity was reduced 2 hours after injection of bromocriptine at a dose of 15 mg/kg Likewise, a significant reduction in plasma insulin activity was observed in response to daily I.P. injections of bromocriptine at a dose of 15 mg/kg. Hyperglycaemic and hypoinsulinaemic effects of bromocriptine (acute and chronic) were markedly decreased when sulpiride, a dopaminergic D2 antagonist, was injected at an I.P. dose of 10 mg/kg before bromocriptine. Plasma ACTH activity was significantly increased in response to bromocriptine (15 mg/kg I.P.) in acute and chronic experiments. This effect was markedly diminished when sulpiride was injected prior to bromocriptine. In conclusion, bromocriptine induced marked elevations in plasma levels of total cholesterol and lipids which are likely to be related to hyperglycaemic and hypoinsulinaemic effects.     

Selective uptake of HDL cholesteryl esters and cholesterol efflux from mouse peritoneal macrophages independent of SR-BI

Scavenger receptor class B type I (SR-BI) mediates the selective uptake of HDL cholesteryl esters (CEs) and facilitates the efflux of unesterified cholesterol. SR-BI expression in macrophages presumably plays a role in atherosclerosis. The role of SR-BI for selective CE uptake and cholesterol efflux in macrophages was explored. Macrophages and HDL originated from wild-type (WT) or SR-BI knockout (KO; homozygous) mice. For uptake, macrophages were incubated in medium containing 125I-/3H-labeled HDL. For lipid removal, [3H]cholesterol efflux was analyzed using HDL as acceptor. Selective uptake of HDL CE ([3H]cholesteryl oleyl ether - 125I-tyramine cellobiose) was similar in WT and SR-BI KO macrophages. Radiolabeled SR-BI KO-HDL yielded a lower rate of selective uptake compared with WT-HDL in WT and SR-BI KO macrophages. Cholesterol efflux was similar in WT and SR-BI KO cells using HDL as acceptor. SR-BI KO-HDL more efficiently promoted cholesterol removal compared with WT-HDL from both types of macrophages. Macrophages selectively take up HDL CE independently of SR-BI. Additionally, in macrophages, there is substantial cholesterol efflux that is not mediated by SR-BI. Therefore, SR-BI-independent mechanisms mediate selective CE uptake and cholesterol removal. SR-BI KO-HDL is an inferior donor for selective CE uptake compared with WT-HDL, whereas SR-BI KO-HDL more efficiently promotes cholesterol efflux.     

高密度脂蛋白受体(SR-BI)和胆固醇逆转运

近十几年来对小鼠的B类I型清道夫受体(SRBI)的研究,发现它是一种高亲和力的高密度脂蛋白受体,主要在肝脏和类固醇源性组织中表达。该受体能介导胆固醇酯的选择性吸收,在高密度脂蛋白(HDL)的代谢和胆固醇的“逆转运”中起重要作用。动物实验证明SRBI的表达可减少动脉粥样硬化的发生。如果SRBI对人有相似的作用,它将成为一个好的作用靶点用于临床心脑血管疾病的治疗 。     

QTL mapping for genetic determinants of lipoprotein cholesterol levels in combined crosses of inbred mouse strains

To identify additional loci that influence lipoprotein cholesterol levels, we performed quantitative trait locus (QTL) mapping in offspring of PERA/EiJxI/LnJ and PERA/EiJxDBA/2J intercrosses and in a combined data set from both crosses after 8 weeks of consumption of a high fat-diet. Most QTLs identified were concordant with homologous chromosomal regions that were associated with lipoprotein levels in human studies. We detected significant new loci for HDL cholesterol levels on chromosome (Chr) 5 (Hdlq34) and for non-HDL cholesterol levels on Chrs 15 (Nhdlq9) and 16 (Nhdlq10). In addition, the analysis of combined data sets identified a QTL for HDL cholesterol on Chr 17 that was shared between both crosses; lower HDL cholesterol levels were conferred by strain PERA. This QTL colocalized with a shared QTL for cholesterol gallstone formation detected in the same crosses. Haplotype analysis narrowed this QTL, and sequencing of the candidate genes Abcg5 and Abcg8 confirmed shared alleles in strains I/LnJ and DBA/2J that differed from the alleles in strain PERA/EiJ. In conclusion, our analysis furthers the knowledge of genetic determinants of lipoprotein cholesterol levels in inbred mice and substantiates the hypothesis that polymorphisms of Abcg5/Abcg8 contribute to individual variation in both plasma HDL cholesterol levels and susceptibility to cholesterol gallstone formation.     

Adrenergic mechanisms in control of plasma lipid concentrations.

The mechanisms of the changes in plasma lipids concentrations observed after beta-blockade were examined in 53 patients with hypertension receiving treatment with atenolol, metoprolol, propranolol, and oxprenolol in a randomised cross-over trial. Significant increases in mean plasma total and very-low-density lipoprotein (VLDL) triglyceride and reductions in high-density lipoprotein (HDL) cholesterol and free fatty acids concentrations wer observed with all four drugs, the increase in plasma triglyceride concentration being greatest after propranolol and oxprenolol. No significant changes were observed in total of LDL cholesterol concentrations, but HDL:LDL ratios and HDL cholesterol as a proportion of total cholesterol fell significantly. Thus plasma lipid concentrations should be monitored after three to six months of long-term treatment. Changes in triglyceride, HDL cholesterol and free fatty acid concentrations were associated with a highly significant reduction in clearance of soya oil (Intralipid) in 25 patients studied but were unrelated to changes in blood pressure. The fall in HDL cholesterol and rise in free fatty acid concentrations were significantly less in those with initially reduced HDL cholesterol or raised free fatty acid concentrations respectively. It is proposed that unopposed alpha stimulation inhibits lipoprotein lipase with a subsequent rise in plasma triglyceride and fall in HDL cholesterol concentration. Analysis of the relation between pretreatment concentrations and subsequent changes suggests that excessive alpha stimulation may impair production of HDL cholesterol in those with low HDL cholesterol concentrations before treatment. Subtle catecholamine-mediated changes in plasma lipid concentrations might provide a mechanism for the relation between stress and the development of cardiovascular events.     

SR-BI的分子结构及其表达调控

小鼠B族Ⅰ型清道夫受体是目前已确认的唯一真正介导细胞与高密度脂蛋白作用的膜受体,主要在肝脏和固醇生成组织中表达,并受促激素、胆固醇、饮食以及药理等因素所调控。该受体介导高密度脂蛋白-胆固醇酯的选择性吸收,是调节胆固醇逆转运的唯一靶点,在高密度脂蛋白代谢和胆固醇运输中起重要作用。该基因缺陷对不同的组织具有不同的影响。它有可能作为一个新的治疗靶点来预防和治疗动脉粥样硬化性心脑血管疾病。对其分子结构、表达调控及相关研究作了详细介绍。     

Robust passive and active efflux of cellular cholesterol to a designer functional mimic of high density lipoprotein

The ability of HDL to support macrophage cholesterol efflux is an integral part of its atheroprotective action. Augmenting this ability, especially when HDL cholesterol efflux capacity from macrophages is poor, represents a promising therapeutic strategy. One approach to enhancing macrophage cholesterol efflux is infusing blood with HDL mimics. Previously, we reported the synthesis of a functional mimic of HDL (fmHDL) that consists of a gold nanoparticle template, a phospholipid bilayer, and apo A-I. In this work, we characterize the ability of fmHDL to support the well-established pathways of cellular cholesterol efflux from model cell lines and primary macrophages. fmHDL received cell cholesterol by unmediated (aqueous) and ABCG1- and scavenger receptor class B type I (SR-BI)-mediated diffusion. Furthermore, the fmHDL holoparticle accepted cholesterol and phospholipid by the ABCA1 pathway. These results demonstrate that fmHDL supports all the cholesterol efflux pathways available to native HDL and thus, represents a promising infusible therapeutic for enhancing macrophage cholesterol efflux. fmHDL accepts cholesterol from cells by all known pathways of cholesterol efflux: unmediated, ABCG1- and SR-BI-mediated diffusion, and through ABCA1.