Mechanisms Of Reverse Cholesterol Transport Research Articles

Influence of inflammation on lipid profile in chronic rheumatic diseases

Chronic inflammatory rheumatic diseases are associated with an increased risk of cardiovascular disease. In this group of patients, inflammation causes various changes in lipid metabolism, which in a chronic course may contribute to an increased risk of atherosclerosis. The most frequent abnormality is decreased serum high-density lipoprotein cholesterol (HDL–C) and increased triglyceride (TG) levels. This imbalance may be due to increased production and secretion of very low-density lipoprotein cholesterol (VLDL–С) in the liver and decreased clearance of TG-rich lipoproteins. The mechanisms by which inflammation lowers HDL–C levels are still unclear. Additionally, there is a persistent increase in lipoprotein (a) (Lp[a]) due to its increased synthesis. Thus, systemic inflammation negatively affects lipoprotein function: LDL–C oxidation becomes more active since there is the decreased ability of HDL–C to prevent this pathway. Moreover, chronic inflammation adversely affects the reverse cholesterol transport mechanism. The greater the severity of the underlying disease is associated with the more pronounced disorders in lipid metabolism. In general, approaches to the correction of lipid metabolism in patients with inflammatory rheumatic diseases are similar to those in patients from the general population.

High-density lipoproteins, reverse cholesterol transport and atherogenesis.

Plasma HDL-cholesterol concentrations correlate negatively with the risk of atherosclerotic cardiovascular disease (ASCVD). According to a widely cited model, HDL elicits its atheroprotective effect through its role in reverse cholesterol transport, which comprises the efflux of cholesterol from macrophages to early forms of HDL, followed by the conversion of free cholesterol (FCh) contained in HDL into cholesteryl esters, which are hepatically extracted from the plasma by HDL receptors and transferred to the bile for intestinal excretion. Given that increasing plasma HDL-cholesterol levels by genetic approaches does not reduce the risk of ASCVD, the focus of research has shifted to HDL function, especially in the context of macrophage cholesterol efflux. In support of the reverse cholesterol transport model, several large studies have revealed an inverse correlation between macrophage cholesterol efflux to plasma HDL and ASCVD. However, other studies have cast doubt on the underlying reverse cholesterol transport mechanism: in mice and humans, the FCh contained in HDL is rapidly cleared from the plasma (within minutes), independently of esterification and HDL holoparticle uptake by the liver. Moreover, the reversibility of FCh transfer between macrophages and HDL has implicated the reverse process - that is, the transfer of FCh from HDL to macrophages - in the aetiology of increased ASCVD under conditions of very high plasma HDL-FCh concentrations.

Cell Signaling in Diabetic Dyslipidemia

Diabetes accompanies several metabolic complications and poor production and clearance of lipoprotein is one of them. Type 2 diabetes mellitus is linked with atherosclerosis, though exact mechanism is still unclear. There are different complications of type 2 diabetes mellitus. Dyslipidemia is one of them. It has been documented that deranged lipid profile is caused by insulin resistance. Dyslipidemia arises due to low level of high density lipoproteins and high level of triglycerides. Diabetic dyslipidimia occurs due to imbalance in reverse cholesterol transport mechanism which is a major risk for cardiovascular diseases. Reverse cholesterol transport is regulated by cell surface receptors scavenger receptor B1 and ATP binding cassette protein-1. These are HDL binding receptors and help to maintain balance of HDL. Genetic and epigenetic factors influence the regulation of cell surface receptors. It plays a significant role in lipid homeostasis. HDL receptors are encoded by SCARB1 and ABCA1 genes. Peroxisome proliferator activated receptor alpha (PPARα) is a down-stream transcriptional activator of SCARB1, ABCA1 and ApoA1 genes.

Impact of Cialis on Haemoglobin Concentration and Lipid Profile of Wistar Male Rats

Erectile dysfunction (ED) is the consistent or recurrent inability of a man to attain and/or maintain a penile erection enough for sexual activity, currently phosphodiesterase (PDE) inhibitors are used in the treatment of erectile dysfunction. This research work is set out to determine the lipid profile and haemoglobin concentration of wistar male rats administered with cialis, forty-five male albino wistar rats with an average weight of 100 g were used for the study. Cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL) and triglycerides concentration increased non-significantly at the 7th, 14th and 21st day following treatment, haemoglobin concentration also increased but its increase was significant as compared to the control animals. The elevated lipid profile with corresponding increase in hematocrit is as a result of reverse cholesterol transport mechanism. However due to the observed effect of the drug on lipid profile, utilization of the drug should be monitored as elevated lipid profile could pose as a risk factor for the development of other diseases.

Catechins Green Tea GMB4 Clone Increases mRNA of ABCA1 through LXR Signaling in Cultured Macrophage Exposed OX-LDL

Inhibition of atherogenesis through inhibition of lipid metabolism has not been explored while other inhibitions through inflammation, endothelial dysfunction and free radicals have done. Inhibition of atherogenesis via inhibition of lipid metabolism can be done through the mechanism of Reverse Cholesterol Transport (RCT). Signaling pathways that play a role in this mechanism is LXR signaling. LXR activation by an LXR agonist led increasing cholesterol efflux. Catechins based on bioinformatics study showed as a potent candidate LXR agonists that can be used as an inhibitor of atherogenesis. This study aims to prove that the administration Catechins green tea Clone GMB4 can prevent atherosclerosis through increasing mechanism cholesterol efflux from macrophage by taking effect of ABCA1, ABCG1, SRB1 gene expression in cultured macrophages were exposed ox-LDL. Long-term goals of the outcome of the research are the use of Catechins Green Tea Clones GMB4 as an inhibitor of atherogenesis so that it can be used as a complementary therapy for the treatment of atherosclerosis and cardiovascular diseases. The research is divided into 5 groups, namely the culture of macrophages without exposed ox-LDL, culture exposed ox-LDL and groups of Catechins dose I, II, III. In vitro study showed that administration of Catechins increases mRNA of ABCA1, whereas mRNA ABCG1 and SRB1 decreased at all three doses given. The result of protein profilling was identified a protein with a molecular weight of 70 kDa by SDS-PGE with silver staining.

Beyond Statins: Emerging Evidence for HDL-Increasing Therapies and Diet in Treating Cardiovascular Disease

Coronary heart disease continues to be the leading cause of death in the United States. Current attempts to treat atherosclerosis and coronary artery disease often involve pharmaceutical and surgical treatments. While these treatments are successful in managing the pain from coronary heart disease, they do little to prevent or stop it. There are a number of clinical strategies that are currently being researched to treat atherosclerosis through HDL-increasing therapies. These clinical studies have shown positive effects through nutritional intervention, exercise, stress reduction, and tobacco and alcohol cessation. These treatment options are explored in greater detail, including their potential to halt and even reverse atherosclerosis. The results from these recent studies and how they relate to the mechanism of reverse cholesterol transport are also critically examined. Reverse cholesterol transport is a multistep process resulting in the net movement of cholesterol from peripheral tissues back to the liver via the plasma. The mechanism of reverse cholesterol transport is also further explored in this review.

Plasma levels of Apolipoprotein A1 and Lecithin:Cholesterol Acyltransferase in type 2 diabetes mellitus: Correlations with haptoglobin phenotypes

BackgroundPrevious studies have demonstrated that hemoglobin-haptoglobin (Hb-Hp) complex plays a role in developing vascular complications in type 2 diabetes mellitus (T2DM). The complexes bind with Apolipoprotein A1 (ApoA1) of high-density lipoprotein (HDL), affecting the function of Lecithin:Cholesterol Acyltransferase (LCAT), and impairing the reverse cholesterol transport mechanism (RCT). This study investigated the influence of Hp phenotypes on serum levels of ApoA1 and LCAT in patients with T2DM. MethodsThe study comprised 131 T2DM patients and 111 matching healthy controls. Fasting blood glucose, HbA1C, and lipid profile were determined by chemistry autoanalyzer, LCAT and ApoA1 by ELISA, and Hp phenotypes by gel electrophoresis. ResultsIrrespective of Hp phenotypes, fasting blood glucose, HbA1C, and lipid profile were significantly higher in patients than in controls, while HDL-cholesterol, ApoA1, and LCAT were lower. ApoA1 correlated positively with LCAT (r=0.223, p=0.024) and HDL-cholesterol (r=0.255, 0.003) in patients only.When Hp polymorphism was taken into account, the levels of LCAT and ApoA1 were significantly lower in patients with Hp2-2 than that in patients of Hp1-1 and/or Hp2-1. Correlations between ApoA1 and each of HDL-cholesterol and LCAT (r=0.239, p=0.046, and r=0.252, p=0.040, respectively) were also observed, but only in patients with Hp2-2 phenotype. ConclusionsThe reduced levels of LCAT and ApoA1 observed in this study support the suggestion that T2DM patients with Hp2-2 phenotype could have altered RCT mechanism and increased risk of developing cardiovascular disease.

An agomir of miR-144-3p accelerates plaque formation through impairing reverse cholesterol transport and promoting pro-inflammatory cytokine production.

AimsATP-binding cassette transporter A1 (ABCA1) mediates the efflux of cholesterol and phospholipids to lipid-poor apolipoproteins, which then form nascent HDL, a key step in the mechanism of reverse cholesterol transport (RCT). While a series of microRNAs (miRNAs) have been identified as potent post-transcriptional regulators of lipid metabolism, their effects on ABCA1 function and associated mechanisms remain unclear.Methods and ResultsABCA1 was identified as a potential target of miR-144-3p, based on the results of bioinformatic analysis and the luciferase reporter assay, and downregulated after transfection of cells with miR-144-3p mimics, as observed with real-time PCR and western blot. Moreover, miR-144-3p mimics (agomir) enhanced the expression of inflammatory factors, including IL-1β, IL-6 and TNF-α, in vivo and in vitro, inhibited cholesterol efflux in THP-1 macrophage-derived foam cells, decreased HDL-C circulation and impaired RCT in vivo, resulting in accelerated pathological progression of atherosclerosis in apoE−/− mice. Clinical studies additionally revealed a positive correlation of circulating miR-144-3p with serum CK, CK-MB, LDH and AST in subjects with AMI.ConclusionsOur findings clearly indicate that miR-144-3p is essential for the regulation of cholesterol homeostasis and inflammatory reactions, supporting its utility as a potential therapeutic target of atherosclerosis and a promising diagnostic biomarker of AMI.

Cholesterol acceptor capacity is preserved by different mechanisms in preterm and term fetuses

Fetal serum cholesterol and lipoprotein concentrations differ between preterm and term born neonates. An imbalance of the flow of cholesterol from the sites of synthesis or efflux from cells of peripheral organs to the liver, the reverse cholesterol transport (RCT), is linked to atherosclerosis and cardiovascular disease (CVD). Preterm delivery is a risk factor for the development of CVD. Thus, we hypothesized that RCT is affected by a diminished cholesterol acceptor capacity in preterm as compared to term fetuses. Cholesterol efflux assays were performed in RAW264.7, HepG2, and HUVEC cell lines. In the presence and absence of ABC transporter overexpression by TO-901317, umbilical cord sera of preterm and term born neonates (n=28 in both groups) were added. Lipid components including high density lipoprotein (HDL), low density lipoprotein (LDL), apolipoprotein A1, and apolipoprotein E were measured and related to fractional cholesterol efflux values. We found overall, fractional cholesterol efflux to remain constant between the study groups, and over gestational ages at delivery, respectively. However, correlation analysis revealed cholesterol efflux values to be predominantly related to HDL concentration at term, while in preterm neonates, cholesterol efflux was mainly associated with LDL. In conclusion cholesterol acceptor capacity during fetal development is kept in a steady state with different mechanisms and lipid fractions involved at distinct stages during the second half of fetal development. However, RCT mechanisms in preterm neonates seem not to be involved in the development of CVD later in life suggesting rather changes in the lipoprotein pattern causative.

Inhibitory effect of Piper betel leaf extracts on copper-mediated LDL oxidation and oxLDL-induced lipid accumulation via inducing reverse cholesterol transport in macrophages

Piper betel leaf (PBL) has the biological capabilities of detoxification and can work as an anti-inflammatory agent and an anti-oxidant. In this study, we evaluated the anti-oxidative activity of the extract of Piper betel leaves (PBLs) on the basis of Cu2+-mediated oxidation, and its ability to prevent foam cell formation in a model for oxidised low density lipoprotein (oxLDL)-induced lipid accumulation in macrophages. Our data demonstrated that PBLs were able to inhibit LDL oxidation in vitro and are able to reduce the lipid accumulation in macrophages. We showed the underlying mechanisms to be the following: PBLs up-regulated the protein levels of the class A and class B scavenger receptors, the membrane lipid transporter ABCA1, and its upstream regulator Liver X receptor (LXR) in the macrophages exposed to oxLDL. The results suggested that PBLs activated the reverse cholesterol transport mechanism to enhance the metabolism of the oxLDL that could prevent both lipid accumulation and foam cell formation and further minimise the possible damage of vessels caused by the oxLDL.

Intravascular infusion of autologous delipidated plasma induces antiatherogenic lipoproteins and causes regression of atherosclerosis <br>—Studies in non-primates, monkeys and humans

Atherosclerosis is the primary pathophysiological cause of heart disease and cerebrovascular disease. It is responsible for more than 20% of deaths worldwide each year. Treatments for atherosclerosis may include lifestyle changes, drugs, and medical procedures or surgery. There is a need for a rapid and effective treatment for this disease. In 1976, it was hypothesized that a multifunctional plasma delipidation process when applied to hyperlipidemic patients would lead to rapid regression of atherosclerosis. The procedure has now been applied to a variety of non-primates, primates and humans. In all models studied, large quantities of antiatherogenic lipoprotein particles were generated that led to the mechanisms of reverse cholesterol transport. Trends to regression and actual regression of atherosclerosis have now been reported using a specific plasma delipidation process consisting of lipid extraction from plasma with mixtures of butanol and ethers.

ProAlgaZyme and its subfractions increase plasma HDL cholesterol via upregulation of ApoA1, ABCA1, and SRB1, and inhibition of CETP in hypercholesterolemic hamsters

ProAlgaZyme and its subfractions increase plasma HDL cholesterol via upregulation of ApoA1, ABCA1, and SRB1, and inhibition of CETP in hypercholesterolemic hamsters Andreea Geamanu, Nadia Saadat, Arvind Goja, Monika Wadehra, Xiangming Ji, Smiti V GuptaNutrition and Food Science, Wayne State University, Detroit, MI, USABackground: Plasma HDL cholesterol levels are inversely related to cardiovascular disease, which is the leading cause of death worldwide. This study investigated the effect of an algae infusion, ProAlgaZyme (PAZ), and its subfractions (P1, P2, P3, P4) on plasma HDL in a hamster model.Methods: Sixty male golden Syrian hamsters (8 weeks old) were randomized into controls (W) or PAZ (P), P1, P2, P3, and P4 (n = 10 per group). An infusion of either 5% (P1, P2, P3) or 20% (P, P4) concentration (v/v) was administered via the drinking water for 4 weeks, while the hamsters were being fed a high-fat diet (30% of calories from fat). Serum lipids were assayed and liver samples subjected to reverse transcription polymerase chain reaction to determine the relative transcription levels of genes involved in HDL/reverse cholesterol transport metabolism, ie, ApoA1, ABCA1, CETP, and SRB1.Results: Non-HDL cholesterol was significantly reduced in the P (P < 0.05), P3 and P4 (P < 0.001) groups as compared with the W group, while HDL cholesterol showed a significant increase in the P, P3, and P4 groups (P < 0.001). Moreover, the total cholesterol/HDL ratio was significantly improved in the P, P1, and P2 (P < 0.05), and P3 and P4 (P < 0.001) groups. The shift in cholesterol towards the higher density fractions was validated by density gradient ultracentrifugation. Real-time quantitative polymerase chain reaction showed a significant increase in hepatic ApoA1 (P, P4) and ABCA1 (P3, P4) expression, consistent with an increase in HDL production, biogenesis, and maturation. A two-fold increase in SRB1 expression indicates that P4 further augments the reverse cholesterol transport mechanism. Reduction of CETP expression (P4) is consistent with a decrease in the transfer of cholesteryl ester to LDL, further increasing the amount of cholesterol held as HDL particles.Conclusion: ProAlgaZyme and its subfractions significantly improved the plasma cholesterol profile by lowering non-HDL and increasing HDL, possibly via the reverse cholesterol transport mechanism.Keywords: ProAlgaZyme, ApoA1, ABCA1, SRB1, CETP, reverse cholesterol transport

Regulation of foam cells by adenosine.

Macrophages rely on reverse cholesterol transport mechanisms to rid themselves of excess cholesterol. By reducing accumulation of cholesterol in the artery wall, reverse cholesterol transport slows or prevents development of atherosclerosis. In stable macrophages, efflux mechanisms balance influx mechanisms, and accumulating lipids do not overwhelm the cell. Under atherogenic conditions, inflow of cholesterol exceeds outflow, and the cell is ultimately transformed into a foam cell, the prototypical cell in the atherosclerotic plaque. Adenosine is an endogenous purine nucleoside released from metabolically active cells by facilitated diffusion and generated extracellularly from adenine nucleotides. Under stress conditions, such as hypoxia, a depressed cellular energy state leads to an acute increase in the extracellular concentration of adenosine. Extracellular adenosine interacts with 1 or more of a family of G protein-coupled receptors (A(1), A(2A), A(2B), and A(3)) to modulate the function of nearly all cells and tissues. Modulation of adenosine signaling participates in regulation of reverse cholesterol transport. Of particular note for the development of atherosclerosis, activation of A(2A) receptors dramatically inhibits inflammation and protects against tissue injury. Potent antiatherosclerotic effects of A(2A) receptor stimulation include inhibition of macrophage foam cell transformation and upregulation of the reverse cholesterol transport proteins cholesterol 27-hydroxylase and ATP binding cassette transporter A1. Thus, A(2A) receptor agonists may correct or prevent the adverse effects of inflammatory processes on cellular cholesterol homeostasis. This review focuses on the importance of extracellular adenosine acting at specific receptors as a regulatory mechanism to control the formation of foam cells under conditions of lipid loading.

The origin and metabolism of a nascent pre-β high density lipoprotein involved in cellular cholesterol efflux.

The pre-β HDL fraction constitutes a heterogeneous population of discoid nascent HDL particles. They transport from 1 to 25 % of total human plasma apo A-I. Pre-β HDL particles are generated de novo by interaction between ABCA1 transporters and monomolecular lipid-free apo A-I. Most probably, the binding of apo A-I to ABCA1 initiates the generation of the phospholipid-apo A-I complex which induces free cholesterol efflux. The lipid-poor nascent pre-β HDL particle associates with more lipids through exposure to the ABCG1 transporter and apo M. The maturation of pre-β HDL into the spherical α-HDL containing apo A-I is mediated by LCAT, which esterifies free cholesterol and thereby forms a hydrophobic core of the lipoprotein particle. LCAT is also a key factor in promoting the formation of the HDL particle containing apo A-I and apo A-II by fusion of the spherical α-HDL containing apo A-I and the nascent discoid HDL containing apo A-II. The plasma remodelling of mature HDL particles by lipid transfer proteins and hepatic lipase causes the dissociation of lipid-free/lipid-poor apo A-I, which can either interact with ABCA1 transporters and be incorporated back into pre-existing HDL particles, or eventually be catabolized in the kidney. The formation of pre-β HDL and the cycling of apo A-I between the pre-β and α-HDL particles are thought to be crucial mechanisms of reverse cholesterol transport and the expression of ABCA1 in macrophages may play a main role in the protection against atherosclerosis.

Plasma triglyceride levels and body mass index values are the most important determinants of preβ-1 HDL concentrations in patients with various types of primary dyslipidemia

ObjectiveExperimental studies have shown that the preβ-1 subclass of high-density lipoprotein particles (preβ-1 HDL) may play an important role in the reverse cholesterol transport pathway as the initial acceptors of cellular cholesterol. The aim of the present study was the direct comparison of preβ-1 HDL values in individuals with various types of primary dyslipidemias. MethodsFour hundred and eighty-six unrelated individuals were included in the study. According to their lipid values study participants were subdivided into four groups: control group (n=206), type IIA dyslipidemia group (n=148), type IIB dyslipidemia group (n=49) and type IV dyslipidemia group (n=83). ResultsAll dyslipidemic patients displayed higher concentrations of preβ-1 HDL compared to control individuals. However, patients with dyslipidemias characterized by an abnormal catabolism of triglyceride-rich lipoproteins (such as dyslipidemias of type IIB and IV) tend to have higher preβ-1 HDL values compared to patients with hypercholesterolemia, and this increase is proportional to the degree of hypertriglyceridemia. In addition, patients with metabolic syndrome exhibited significantly higher levels of preβ-1 HDL compared to individuals that do not fulfill the criteria for the diagnosis of this syndrome. Multiple regression analysis revealed that serum triglyceride concentrations and body mass index (BMI) values were the most important determinants of preβ-1 HDL levels in our population. ConclusionAll dyslipidemic patients exhibit increased preβ-1 HDL concentrations as compared to normolipidemic individuals. Whether this increase represents a defensive mechanism against atherosclerosis or it is indicative of impaired maturation of HDL particles and thus of a defective reverse cholesterol transport mechanism remains to be established.

Effects of acceptor composition and mechanism of ABCG1-mediated cellular free cholesterol efflux

Among the known mechanisms of reverse cholesterol transport (RCT), ATP binding cassette transporter G1 (ABCG1)-mediated free cholesterol (FC) transport is the most recent and least studied. Here, we have characterized the efficiencies of different acceptors using baby hamster kidney (BHK) cells transfected with human ABCG1 cDNA, which is inducible upon treatment with mifepristone. When normalized on particle number and particle surface area, the acceptor efficiency for FC efflux was as follows: small unilamellar vesicles (SUV)>LDL>reconstituted HDL>HDL2 = HDL3. Based on phospholipid content, the order was reversed. ABCG1 also mediated phospholipid efflux to human serum and HDL3. ABCG1-mediated FC efflux correlated significantly with a number of HDL subfractions and components in serum collected from 25 normolipidemic individuals: apolipoprotein A-II (apoA-II) (r2 = 0.7), apolipoprotein A-I (apoA-I) (r2 = 0.5), HDL-C (r2 = 0.4), HDL-PL (r2 = 0.4), α-2 HDL (r2 = 0.4), and preβ HDL (r2 = 0.2). ABCG1 did not enhance influx of FC or cholesteryl oleyl ether (COE) when cells were incubated with radiolabeled HDL3. ABCG1 expression did not increase the association of HDL3 with cells. Compared with control cells, ABCG1 expression significantly increased the FC pool available for efflux and the rate constant for efflux. In conclusion, composition and particle size determine the acceptor efficiency for ABCG1-mediated efflux. ABCG1 increases cell membrane FC pools and changes its rate of desorption into the aqueous phase without enhancing the association with the acceptor.

Effects of Highly Active Antiretroviral Therapy on Reverse Cholesterol Transport

Long-term usage of protease inhibitor (PI)-containing regimens to treat HIV infection, has been associated with adverse events including dyslipidemia. PI can significantly increase serum triglycerides, cholesterol and decrease high density lipoprotein (HDL)-cholesterol among seronegativeand HIV-infected patients. Our aim was to investigate effects of combination of antiretroviral drugs on reverse cholesterol transport using human hepatoma cell line, HepG2 and C57BL/6 mouse model systems. Our in vitro data indicates that PI significantly inhibited mRNA expression of cytochrome P450 7A1 (CYP7A1), that catalyzes the first rate-limiting step in the conversion of cholesterol to bile acids. PI also inhibited the ATP-binding cassette transporter (ABCA1) gene expression that transports intracellular cholesterol and phospholipids to cell surface-bound apolipoproteins and forms nascent HDL. Both, CYP7A1 and ABCA1 are negatively regulated by the nuclear receptor, farensoid X-receptor (FXR). In our studies PI significantly increased expression of FXR and liver X receptor (LXR) in HepG2 cells (p<0.05). We are currently investigating molecular mechanisms of reverse cholesterol transport in C57BL/6 mice treated with and without combination of antiretroviral drugs. Understanding the molecular mechanisms can help to identify new molecular targets to treat HAART-associated metabolic disorders. [Partially supported by a grant (G12RR003061) from the RCMI Program NCRR, NIH]

Molecular Mechanism of Reverse Cholesterol Transport: Reaction of Pre-β-Migrating High-Density Lipoprotein with Plasma Lecithin/Cholesterol Acyltransferase

A 70-75 kDa high-density lipoprotein (HDL) particle with pre-beta-electrophoretic migration (pre-beta(1)-HDL) has been identified in several studies as an early acceptor of cell-derived cholesterol. However, the further metabolism of this complex has not been determined. Here we sought to identify the mechanism by which cell-derived cholesterol was esterified and converted to mature HDL as part of reverse cholesterol transport (RCT). Human plasma selectively immunodepleted of pre-beta(1)-HDL was used to study factors regulating pre-beta(1)-HDL production. A major role for phospholipid transfer protein (PLTP) in the recycling of pre-beta(1)-HDL was identified. Cholesterol binding, esterification by lecithin/cholesterol acyltransferase (LCAT) and transfer by cholesteryl ester transfer protein (CETP) were measured using (3)H-cholesterol-labeled cell monolayers. LCAT bound to (3)H-free cholesterol (FC)-labeled pre-beta(1)-HDL generated cholesteryl esters at a rate much greater than the rest of HDL. The cholesteryl ester produced in pre-beta(1)-HDL in turn became the preferred substrate of CETP. Selective LCAT-mediated reactivity with pre-beta(1)-HDL represents a novel mechanism increasing the efficiency of RCT.

Infection and inflammation-induced proatherogenic changes of lipoproteins.

Epidemiologic studies suggest a link between infection/inflammation and atherosclerosis. During the acute-phase response to infection and inflammation, cytokines induce tissue and plasma events that lead to changes in lipoprotein. Many of these changes are similar to those proposed to promote atherogenesis. The changes of lipoproteins during infection and inflammation are reviewed with a focus on those that are potentially proatherogenic. Hypertriglyceridemia, elevated triglyceride-rich lipoproteins, the appearance of small dense low-density lipoproteins, increased platelet-activating factor acetylhydrolase activity, and secretory phospholipase A(2), sphingolipid-enriched lipoproteins, and decreased high-density lipoprotein (HDL) cholesterol are changes that could promote atherogenesis. Moreover, alterations of proteins associated with HDL metabolism (e.g., paraoxonase, apolipoprotein A-I, lecithin:cholesterol acyltransferase, cholesterol ester transfer protein, hepatic lipase, phospholipid transfer protein, and serum amyloid A) could decrease the ability of HDL to protect against atherogenesis through antioxidation and reverse cholesterol transport mechanisms. These proatherogenic changes of lipoproteins may contribute to the link between infection/inflammation and atherosclerosis.

10 Molecular mechanisms of reverse cholesterol transport

10 Molecular mechanisms of reverse cholesterol transport