Reverse cholesterol transport in type 2 diabetes mellitus

High-density lipoprotein (HDL) plays an important protective role against atherosclerosis, and the anti-atherogenic properties of HDL include the promotion of cellular cholesterol efflux and reverse cholesterol transport (RCT), as well as antioxidant, anti-inflammatory and anticoagulant effects. RCT is a complex pathway, which transports cholesterol from peripheral cells and tissues to the liver for its metabolism and biliary excretion. The major steps in the RCT pathway include the efflux of free cholesterol mediated by cholesterol transporters from cells to the main extracellular acceptor HDL, the conversion of free cholesterol to cholesteryl esters and the subsequent removal of cholesteryl ester in HDL by the liver. The efficiency of RCT is influenced by the mobilization of cellular lipids for efflux and the intravascular remodelling and kinetics of HDL metabolism. Despite the increased cardiovascular risk in people with type 2 diabetes, current knowledge on RCT in diabetes is limited. In this article, abnormalities in RCT in type 2 diabetes mellitus and therapeutic strategies targeting HDL and RCT will be reviewed.     

New insights into the regulation of HDL metabolism and reverse cholesterol transport

The metabolism of high-density lipoproteins (HDL), which are inversely related to risk of atherosclerotic cardiovascular disease, involves a complex interplay of factors regulating HDL synthesis, intravascular remodeling, and catabolism. The individual lipid and apolipoprotein components of HDL are mostly assembled after secretion, are frequently exchanged with or transferred to other lipoproteins, are actively remodeled within the plasma compartment, and are often cleared separately from one another. HDL is believed to play a key role in the process of reverse cholesterol transport (RCT), in which it promotes the efflux of excess cholesterol from peripheral tissues and returns it to the liver for biliary excretion. This review will emphasize 3 major evolving themes regarding HDL metabolism and RCT. The first theme is that HDL is a universal plasma acceptor lipoprotein for cholesterol efflux from not only peripheral tissues but also hepatocytes, which are a major source of cholesterol efflux to HDL. Furthermore, although efflux of cholesterol from macrophages represents only a tiny fraction of overall cellular cholesterol efflux, it is the most important with regard to atherosclerosis, suggesting that it be specifically termed macrophage RCT. The second theme is the critical role that intravascular remodeling of HDL by lipid transfer factors, lipases, cell surface receptors, and non-HDL lipoproteins play in determining the ultimate metabolic fate of HDL and plasma HDL-c concentrations. The third theme is the growing appreciation that insulin resistance underlies the majority of cases of low HDL-c in humans and the mechanisms by which insulin resistance influences HDL metabolism. Progress in our understanding of HDL metabolism and macrophage reverse cholesterol transport will increase the likelihood of developing novel therapies to raise plasma HDL concentrations and promote macrophage RCT and in proving that these new therapeutic interventions prevent or cause regression of atherosclerosis in humans.     

Cellular cholesterol flux studies: methodological considerations

Reverse cholesterol transport (RCT) is the process in which peripheral cells release cholesterol to an extracellular acceptor such as high-density lipoprotein (HDL) which then mediates cholesterol delivery to the liver for excretion. RCT represents a physiological mechanism by which peripheral tissues are protected against excessive accumulation of cholesterol. The first step in RCT is the interaction of the cell with lipoprotein particles, a process that results in both the cellular uptake and release of cholesterol. The various components of this cholesterol flux can be viewed as efflux, influx and net flux. Experimental protocols for measuring each of these components of cholesterol flux are very different, and a number of considerations are required to design experimental approaches for the quantitation of flux parameters. Although many flux studies have been conducted in the past, the recent discoveries of the scavenger receptor B1 (SR-B1) and ATP binding cassette 1 (ABCA1), which mediate the movement of cholesterol between cells and extracellular acceptors, has led to increased interest in studies of cellular cholesterol flux. The aim of this review is to present a discussion of the methodological considerations that should be evaluated during the design and analysis of cellular cholesterol flux experiments.     

The effect of cholesteryl ester transfer protein overexpression and inhibition on reverse cholesterol transport

AIMS: Cholesteryl ester transfer protein (CETP) has a well-established role in lipoprotein metabolism, but the effect of its overexpression or inhibition on the efficiency of reverse cholesterol transport (RCT) is unclear. METHODS AND RESULTS: Neither overexpression of CETP nor treatment with CETP inhibitor Torcetrapib of RAW 264.7 macrophages or HepG2 hepatocytes affected cholesterol efflux in vitro. Overexpression of CETP or treatment with Torcetrapib, respectively, stimulated or inhibited HDL cholesteryl ester uptake by HepG2 but not by RAW 264.7 cells. When RAW 264.7 cells transfected with CETP or ATP binding cassette transporter A1 (ABCA1) were injected intraperitoneally into mice, cholesterol egress from macrophages was elevated for ABCA1- but not for CETP-transfected macrophages. Systemic expression of CETP in mice by adenoviral infection stimulated egress of cholesterol to plasma and liver without affecting HDL levels. Treatment with Torcetrapib did not affect appearance of macrophage cholesterol in plasma and liver, but inhibited its excretion into feces. Treatment of hamsters with Torcetrapib led to elevation of HDL cholesterol, an increase in the capacity of plasma to support cholesterol efflux, and increased egress of cholesterol from macrophages to plasma and feces in vivo. CONCLUSION: Both increased (mice study) and decreased (hamster study) CETP activity could result in enhanced RCT.     

Hypocholesterolemia, foam cell accumulation, but no atherosclerosis in mice lacking ABC-transporter A1 and scavenger receptor BI

High-density lipoprotein (HDL) mediated reverse cholesterol transport (RCT) is regarded to be crucial for prevention of foam cell formation and atherosclerosis. ABC-transporter A1 (ABCA1) and scavenger receptor BI (SR-BI) are involved in the biogenesis of HDL and the selective delivery of HDL cholesterol to the liver, respectively. In the present study, we phenotypically characterized mice lacking these two proteins essential for HDL metabolism. ABCA1 × SR-BI double knockout (dKO) mice showed severe hypocholesterolemia mainly due to HDL loss, despite a 90% reduction of HDL cholesterol uptake by liver. VLDL production was increased in dKO mice. However, non-HDL cholesterol levels were reduced, probably due to enhanced clearance via LRP1. Hepatobiliary cholesterol transport and fecal sterol excretion were not impaired in dKO mice. In contrast, the macrophage RCT in dKO mice was markedly impaired as compared to WT mice, associated with the accumulation of macrophage foam cells in the lung and Peyer's patches. Strikingly, no atherosclerotic lesion formation was observed in dKO mice. In conclusion, both ABCA1 and SR-BI are essential for maintaining a properly functioning HDL-mediated macrophage RCT, while the potential anti-atherosclerotic functions of ABCA1 and SR-BI are not evident in dKO mice due to the absence of pro-atherogenic lipoproteins.     

High density lipoproteins and arteriosclerosis. Role of cholesterol efflux and reverse cholesterol transport

High density lipoprotein (HDL) cholesterol is an important risk factor for coronary heart disease, and HDL exerts various potentially antiatherogenic properties, including the mediation of reverse transport of cholesterol from cells of the arterial wall to the liver and steroidogenic organs. Enhancement of cholesterol efflux and of reverse cholesterol transport (RCT) is considered an important target for antiatherosclerotic drug therapy. Levels and composition of HDL subclasses in plasma are regulated by many factors, including apolipoproteins, lipolytic enzymes, lipid transfer proteins, receptors, and cellular transporters. In vitro experiments as well as genetic family and population studies and investigation of transgenic animal models have revealed that HDL cholesterol plasma levels do not necessarily reflect the efficacy and antiatherogenicity of RCT. Instead, the concentration of HDL subclasses, the mobilization of cellular lipids for efflux, and the kinetics of HDL metabolism are important determinants of RCT and the risk of atherosclerosis.     

Functional heterogeneity of high density lipoproteins and its future therapeutic indication

The atheroprotective effect of HDL is well-established, the implication being that the higher the plasma levels of HDL,the bigger the benefit to all individuals.Such a supposition has led to the development of "HDL therapy".It has fast become apparent however that assuming therapeutic benefits by merely raising HDL levels is highly simplistic.The most established atheroprotective function of HDL is its role in reverse cholesterol transport(RCT). However other functions of HDL not directly related to RCT may also contribute significantly to its atheioprotective properties.As well,there are many examples where the functionality of HDL changes discordantly to its concentration such that high levels of HDL can be pro-rather than antiatherogenic under certain metabolic conditions.In humans,the ability of HDL to support cholesterol efflux and maintain endothelial function,or antioxidant function can be diminished despite higher HDL levels.Conversely, apoA-IMilano mutation leads to lower HDL levels,but enhances HDL functionality.We and others have recently shown that HDL also has potent anti-inflammatory actions and can also influence the immune system.The inference of these findings are that first,changes in RCT and HDL functionality are as important,if not more so,than its changes in concentration,and second,that these changes are independent of each other.Thus,"HDL therapy" must consider alterations in RCT and HDL functionality as a result of the treatment and the implications that these changes have on the overall atheroprotective effect of the treatment.     

Importance of different pathways of cellular cholesterol efflux

The removal of excess free cholesterol from cells by HDL or its apolipoproteins is important for maintaining cellular cholesterol homeostasis. This process is most likely compromised in the atherosclerotic lesion because the development of atherosclerosis is associated with low HDL cholesterol. Multiple mechanisms for efflux of cell cholesterol exist. Efflux of free cholesterol via aqueous diffusion occurs with all cell types but is inefficient. Efflux of cholesterol is accelerated when scavenger receptor class-B type I (SR-BI) is present in the cell plasma membrane. Both diffusion-mediated and SR-BI-mediated efflux occur to phospholipid-containing acceptors (ie, HDL and lipidated apolipoproteins); in both cases, the flux of cholesterol is bidirectional, with the direction of net flux depending on the cholesterol gradient. The ATP-binding cassette transporter AI (ABCA1) mediates efflux of both cellular cholesterol and phospholipid. In contrast to SR-BI-mediated flux, efflux via ABCA1 is unidirectional, occurring to lipid-poor apolipoproteins. The relative importance of the SR-BI and ABCA1 efflux pathways in preventing the development of atherosclerotic plaque is not known but will depend on the expression levels of the two proteins and on the type of cholesterol acceptors available.     

ATP-binding cassette transporters G1 and G4 mediate cellular cholesterol efflux to high-density lipoproteins

The mechanisms responsible for the inverse relationship between plasma high-density lipoprotein (HDL) levels and atherosclerotic cardiovascular disease are poorly understood. The ATP-binding cassette transporter A1 (ABCA1) mediates efflux of cellular cholesterol to lipid-poor apolipoproteins but not to HDL particles that constitute the bulk of plasma HDL. We show that two ABC transporters of unknown function, ABCG1 and ABCG4, mediate isotopic and net mass efflux of cellular cholesterol to HDL. In transfected 293 cells, ABCG1 and ABCG4 stimulate cholesterol efflux to both smaller (HDL-3) and larger (HDL-2) subclasses but not to lipid-poor apoA-I. Treatment of macrophages with an liver X receptor activator results in up-regulation of ABCG1 and increases cholesterol efflux to HDL. RNA interference reduced the expression of ABCG1 in liver X receptor-activated macrophages and caused a parallel decrease in cholesterol efflux to HDL. These studies indicate that ABCG1 and ABCG4 promote cholesterol efflux from cells to HDL. ABCG1 is highly expressed in macrophages and probably mediates cholesterol efflux from macrophage foam cells to the major HDL fractions, providing a mechanism to explain the relationship between HDL levels and atherosclerosis risk.     

Administration of hydrogen-saturated saline decreases plasma low-density lipoprotein cholesterol levels and improves high-density lipoprotein function in high-fat diet-fed hamsters

Hydrogen (dihydrogen; H(2)) has an antiatherosclerotic effect in apolipoprotein (apo) E knockout mice. The goals of this study were to further characterize the effects of H(2) on the content, composition, and biological activities of plasma lipoproteins in golden hamsters. Plasma analysis by enzymatic method and fast protein liquid chromatography showed that 4-week intraperitoneal injection of hydrogen-saturated saline remarkably decreased plasma total cholesterol and low-density lipoprotein (LDL) cholesterol levels in high-fat diet-fed hamsters. Sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis of apolipoproteins from ultracentrifugally isolated plasma lipoproteins revealed a marked decrease of apo B100 and apo B48 in LDL. A profound decrease of apo E level in very low-density lipoprotein was also observed. Besides, we determined the functional quality of high-density lipoprotein (HDL) particles isolated from H(2)-treated and control mice. H(2) significantly improved HDL functionality assessed in 2 independent ways, namely, (1) stimulation of cholesterol efflux from macrophage foam cells by measuring HDL-induced [(3)H]cholesterol efflux and (2) protection against LDL oxidation as a measure of Cu(2+)-induced thiobarbituric acid reactive substances formation. Administration of hydrogen-saturated saline decreases plasma LDL cholesterol and apo B levels and improves hyperlipidemia-injured HDL functions, including the capacity of enhancing cellular cholesterol efflux and playing antioxidative properties, in high-fat diet-fed hamsters.     

Cholesterol efflux pathways and other potential mechanisms involved in the athero-protective effect of high density lipoproteins

Plasma high density lipoprotein (HDL) levels bear a strong independent inverse relationship with atherosclerotic cardiovascular disease. Although HDL has anti-oxidant, anti-inflammatory, vasodilating and anti-thrombotic properties, the central anti-atherogenic activity of HDL is likely to be its ability to remove cholesterol and oxysterols from macrophage foam cells, smooth muscle cells and endothelial cells in the arterial wall. To some extent, the pleotropic athero-protective properties of HDL may be related to its ability to promote sterol and oxysterol efflux from arterial wall cells, as well as to detoxify oxidized phospholipids. In cholesterol-loaded macrophages, activation of liver X receptors (LXRs) leads to increased expression of adenosine triphosphate (ATP) binding cassetter transporter (ABCA1), ATP binding cassetter transporter gene (ABCG1) and apoE and promotes cholesterol efflux. ABCA1 stimulates cholesterol efflux to lipid-poor apolipoproteins, whilst ABCG1 promotes efflux of cholesterol and oxysterols to HDL. Despite some recent setbacks in the clinical arena, there is still intense interest in therapeutically targeting HDL and macrophage cholesterol efflux pathways, via treatments with niacin, cholesterol ester transfer protein inhibitors, LXR activators and infusions of apoA-1, phospholipids and peptides.     

Beyond high-density lipoprotein cholesterol levels evaluating high-density lipoprotein function as influenced by novel therapeutic approaches

A number of therapeutic strategies targeting high-density lipoprotein (HDL) cholesterol and reverse cholesterol transport are being developed to halt the progression of atherosclerosis or even induce regression. However, circulating HDL cholesterol levels alone represent an inadequate measure of therapeutic efficacy. Evaluation of the potential effects of HDL-targeted interventions on atherosclerosis requires reliable assays of HDL function and surrogate markers of efficacy. Promotion of macrophage cholesterol efflux and reverse cholesterol transport is thought to be one of the most important mechanisms by which HDL protects against atherosclerosis, and methods to assess this pathway in vivo are being developed. Indexes of monocyte chemotaxis, endothelial inflammation, oxidation, nitric oxide production, and thrombosis reveal other dimensions of HDL functionality. Robust, reproducible assays that can be performed widely are needed to move this field forward and permit effective assessment of the therapeutic potential of HDL-targeted therapies.     

Experimental Models for the Investigation of High-Density Lipoprotein–Mediated Cholesterol Efflux

Reduction of low-density lipoprotein cholesterol by statin therapy has only modestly decreased coronary heart disease (CHD)-associated mortality in developed countries, which has prompted the search for alternative therapeutic strategies for CHD. Epidemiologic and interventional studies have clearly established an inverse association between plasma levels of high-density lipoprotein (HDL) cholesterol and incidence of atherosclerosis. The atheroprotective benefits of HDL are not only dependent on HDL concentrations (quantity), but also on HDL function (quality). Therefore, several techniques have been recently developed to assess the different properties of HDL. Because reverse cholesterol transport (RCT) is considered a key player in the beneficial action of HDL, this review focuses on the different methods used to evaluate cholesterol efflux. Measuring the in vivo function of HDL could be of significant importance for both the clinical evaluation of an individual patient and to evaluate the effectiveness of different RCT-enhancing therapeutic approaches.     

Therapeutic interventions targeted at the augmentation of reverse cholesterol transport

PURPOSE OF REVIEW: Serum high-density lipoproteins (HDLs) and reverse cholesterol transport (RCT) are important therapeutic targets in the management of atherosclerotic disease. This review summarizes the pathway of RCT and the currently available means by which investigators are attempting to modulate HDL levels and increase rates of RCT. RECENT FINDINGS: Low levels of HDL are commonly encountered in patients with atherosclerotic disease. HDLs mediate a substantial number of antiatherogenic effects along blood vessel walls. One of the most important of these antiatherogenic mechanisms is RCT, a series of reactions by which HDL is able to facilitate the net translocation of cholesterol from peripheral cells to the liver for excretion. There is scientific evidence supporting the concept of RCT in both animals and humans. To facilitate RCT, it is important that therapeutic effort be made to raise serum levels of HDL. Statins, fibrates, niacin, thiazolidinediones, and various combinations of these drugs all raise HDL levels. However, in many high-risk patients with established atherosclerotic disease, the elevations in HDL achieved with these medications are frequently inadequate. Newer agents designed to raise HDL and promote RCT are currently being developed, including infusible bioengineered HDL, edible HDL composed of D-amino acids, and agents capable of inhibiting cholesterol ester transfer protein, among others. SUMMARY: Established therapies for raising HDL can be effective either as monotherapy or when used in combination. Newer strategies are being developed to exploit more specifically the capacity of HDL to drive RCT and either prevent or reverse the course of atherosclerotic disease.     

淋巴管参与胆固醇逆向转运

细胞需要胆固醇才能生存,但过量的胆固醇对细胞具有毒性,因此细胞需要调节胆固醇的稳态。细胞内胆固醇被转运到高密度脂蛋白载脂蛋白AI,会以胆固醇逆向转运的方式返回肝脏代谢。胆固醇逆向转运不仅是维持细胞胆固醇稳态所需的生理过程,而且对动脉粥样硬化发展起到潜在的抑制作用。目前的研究主要集中在细胞胆固醇流出的最初途径和最终代谢上,但关于胆固醇是如何离开血液却知之甚少。越来越多的研究表明,在胆固醇逆向转运过程中高密度脂蛋白需要通过淋巴管转运以返回到肝脏代谢。因此,研究高密度脂蛋白从血液流入外周组织的过程,以及它是怎样通过淋巴管转运对治疗动脉粥样硬化具有重要意义。本综述主要介绍淋巴管与胆固醇逆向转运之间的联系,为治疗动脉粥样硬化性心血管疾病提供新的策略。     

Role of Hepatic Lipase and Endothelial Lipase in High-Density Lipoprotein—Mediated Reverse Cholesterol Transport

Reverse cholesterol transport (RCT) constitutes a key part of the atheroprotective properties of high-density lipoproteins (HDL). Hepatic lipase (HL) and endothelial lipase (EL) are negative regulators of plasma HDL cholesterol levels. Although overexpression of EL decreases overall macrophage-to-feces RCT, knockout of both HL and EL leaves RCT essentially unaffected. With respect to important individual steps of RCT, current data on the role of EL and HL in cholesterol efflux are not conclusive. Both enzymes increase hepatic selective cholesterol uptake; however, this does not translate into altered biliary cholesterol secretion, which is regarded the final step of RCT. Also, the impact of HL and EL on atherosclerosis is not clear cut; rather it depends on respective experimental conditions and chosen models. More mechanistic insights into the diverse biological properties of these enzymes are therefore required to firmly establish EL and HL as targets for the treatment of atherosclerotic cardiovascular disease.     

Paraoxonase 1 (PON1) enhances HDL-mediated macrophage cholesterol efflux via the ABCA1 transporter in association with increased HDL binding to the cells: a possible role for lysophosphatidylcholine

We investigated the role of HDL-associated paraoxonase 1 (PON1) in HDL-mediated macrophage cholesterol efflux by using HDL derived from wild type mice (Control-HDL), from human PON1-transgenic mice (HDL-PON1Tg) or from PON1-knockout mice (HDL-PON1(0)). Cholesterol efflux from mouse peritoneal macrophages (MPM) or from J774 A.1 macrophage cell line by HDL-PON1Tg, was significantly increased (by 60%) compared to HDL-PON1(0). We demonstrated that this PON1 effect was associated with an increased HDL binding to the cells, as the binding of HDL-PON1Tg (or HDL-PON1(0) that was enriched with PON1) was increased by 50% compared to that of HDL-PON1(0). Using either a cAMP analogue, to increase ABCA1 receptor expression, or rabbit anti-mouse SR-BI specific antibody to block the SR-BI receptor, PON1 stimulation of HDL binding and of HDL-mediated macrophage cholesterol efflux, were both found to involve the ABCA1 transporter. Studies with PON1 specific inhibitors revealed that PON1 activity was required for its stimulation of HDL-mediated macrophage cholesterol efflux. Upon incubation of macrophages with Control-HDL or with HDL-PON1Tg, macrophage lysophosphatidylcholine (LPC) content was increased by 3.7- and 7.5-fold, respectively. Such an LPC enrichment of macrophages resulted in up to 60% increased HDL binding to the cells, and a 41% increased HDL-mediated cholesterol efflux. Similarly, macrophage loading with LPC (by either adding LPC, or PON1 or phospholipase A(2)) significantly increased apolipoprotein A-I (apoA-I) mediated cholesterol efflux by 104, 65 and 56%, respectively, in ABCA1 overexpressing macrophages. We conclude that HDL-associated PON1 may contribute to the attenuation of atherosclerosis development by its ability to act on macrophage phospholipids, to form LPC, in turn, stimulates HDL binding and HDL-mediated macrophage cholesterol efflux via the ABCA1 transporter.     

Targeting High Density Lipoproteins in the Prevention of Cardiovascular Disease?

Recent studies involving HDL-raising therapeutics have greatly changed our understanding of this field. Despite effectively raising HDL-C levels, niacin remains of uncertain clinical benefit. Synthetic niacin receptor agonists are unlikely to raise HDL-C or have other beneficial effects on plasma lipids. Despite the failure in phase 3 of 2 CETP inhibitors, 2 potent CETP inhibitors that raise HDL-C levels by >100?% (and reduce LDL-C substantially) are in late stage clinical development. Infusions of recombinant HDL containing ??wild-type?? apoA-I or apoA-I Milano, as well as autologous delipidated HDL, all demonstrated promising early results, and remain in clinical development. A small molecule that causes upregulation of endogenous apoA-I production is also in clinical development. Finally, upregulation of macrophage cholesterol efflux pathways through agonism of liver X receptors or antagonism of miR-33 remains of substantial interest. The field of HDL therapeutics is poised to transition from the ??HDL-cholesterol hypothesis?? to the ??HDL flux hypothesis?? in which the impact on flux from macrophage to feces is deemed to be of greater therapeutic benefit than the increase in steady-state concentrations of HDL cholesterol.     

Pancreatic β-cell function relates positively to HDL functionality in well-controlled type 2 diabetes mellitus

BackgroundHigh density lipoproteins (HDLs) have been implicated in glucose homeostasis. Among subjects with normal fasting glucose (NFG), impaired fasting glucose (IFG) and Type 2 diabetes mellitus (T2DM) we tested whether pancreatic β-cell function relates to HDL functionality, as determined by HDL anti-oxidative capacity and cellular cholesterol efflux to plasma.Subjects and methodsHDL anti-oxidative capacity (inhibition of LDL oxidation in vitro), cellular cholesterol efflux (the ability of plasma to stimulate cholesterol efflux out of cultured fibroblasts obtained from a single human donor), glucose and insulin were determined in fasting plasma samples from 37 subjects with NFG, 36 with IFG and 22 with T2DM (no glucose lowering drug or insulin treatment; HbA1c 6.0 ± 1.0%). Homeostasis model assessment was used to estimate pancreatic β-cell function (HOMA-β) and insulin resistance (HOMAir).ResultsHOMA-β was lowest, whereas HOMAir was highest in T2DM (P < 0.01 and P < 0.001 vs. NFG). HDL anti-oxidative capacity and cellular cholesterol efflux did not differ significantly according to glucose tolerance category. In univariate analysis and after controlling for HOMAir both HDL anti-oxidative capacity (P < 0.05) and cellular cholesterol efflux (P < 0.01) were positively correlated with HOMA-β in T2DM, but not in NFG and IFG. In age-, sex- and HOMAir-adjusted analyses, T2DM status interacted positively with HDL anti-oxidative capacity (P = 0.001) and cellular cholesterol efflux (P = 0.042) on HOMA-β. HbA1c interacted similarly with HDL functionality measures on HOMA-β.ConclusionsPancreatic β-cell function relates to pathophysiologically relevant measures of HDL function in T2DM, but not in NFG and IFG. Better HDL functionality may contribute to maintenance of β-cell function in subjects with well-controlled T2DM.     

激活巨噬细胞抑制载脂蛋白AI促细胞胆固醇流出能力

为探讨巨噬细胞活化对载脂蛋白ＡＩ促胆固醇外流能力的影响,用炎症诱发剂活化鼠腹腔巨噬细胞,３Ｈ标记乙酰低密度脂蛋白作泡沫细胞诱导物,巨噬细胞衍化的泡沫细胞与载脂蛋白ＡＩ孵育一段时间后,测定由细胞释放入培养基中的３Ｈ标记胆固醇量。结果发现,载脂蛋白ＡＩ浓度为２０ｍｇ／Ｌ时,从被活化的细胞释放至基质中的３Ｈ标记胆固醇量［（４．１５±０．４１）×１０－１ｄｐｍ／ｇ细胞蛋白］显著低于未被活化的细胞［（５．６９±０．１２）×１０－１ｄｐｍ／ｇ细胞蛋白］（Ｐ＜０．０１）,但高密度脂蛋白清除细胞胆固醇能力两组细胞无显著差异。提示巨噬细胞活化可显著抑制载脂蛋白ＡＩ促细胞胆固醇外流能力。