Role Of High-density Lipoprotein Research Articles

High-capacity selective uptake of cholesteryl ester from native LDL during macrophage foam cell formation

Macrophage foam cells are a defining pathologic feature of atherosclerotic lesions. Recent studies have demonstrated that at high concentrations associated with hypercholesterolemia, native LDL induces macrophage lipid accumulation. LDL particles are taken up by macrophages as part of bulk fluid pinocytosis. However, the uptake and metabolism of cholesterol from native LDL during foam cell formation has not been clearly defined. Previous reports have suggested that selective cholesteryl ester (CE) uptake might contribute to cholesterol uptake from LDL independently of particle endocytosis. In this study we demonstrate that the majority of macrophage LDL-derived cholesterol is acquired by selective CE uptake in excess of LDL pinocytosis and degradation. Macrophage selective CE uptake does not saturate at high LDL concentrations and is not down-regulated during cholesterol accumulation. In contrast to CE uptake, macrophages exhibit little selective uptake of free cholesterol (FC) from LDL. Following selective uptake from LDL, CE is rapidly hydrolyzed by a novel chloroquine-sensitive pathway. FC released from LDL-derived CE hydrolysis is largely effluxed from cells but also is subject to ACAT-mediated reesterification. These results indicate that selective CE uptake plays a major role in macrophage metabolism of LDL.

HDL and adaptive immunity: A tale of lipid rafts

Lipid rafts are membrane microdomains enriched with cholesterol, sphingolipids and proteins associated with several relevant biological processes, including signaling, protein transport, adhesion. The functional properties of lipid rafts are strictly depending upon their lipid composition; cholesterol depletion from these microdomains downregulates signaling pathways in several cells, including immune cells and disturb antigen-presenting ability [ [1] Anderson H.A. Hiltbold E.M. Roche P.A. Concentration of MHC class II molecules in lipid rafts facilitates antigen presentation. Nat Immunol. 2000; 1: 156-162 Crossref PubMed Scopus (298) Google Scholar ]. In fact, MHC class II molecules, that play a role in antigen presentation and signal transduction, localize in lipid-rich microdomains in antigen presenting cells (APCs) [ [2] Norata G.D. Pirillo A. Ammirati E. Catapano A.L. Emerging role of high density lipoproteins as a player in the immune system. Atherosclerosis. 2012; 220: 11-21 Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar ]. The number of MHC class II molecules present on the surface of APCs are crucial for the activation of T cells; lipid rafts concentrate MHC-peptide complex on APCs surface, decreasing the amount of antigen required for T cell activation [ [3] Zilber M.T. Setterblad N. Vasselon T. et al. MHC class II/CD38/CD9: a lipid-raft-dependent signaling complex in human monocytes. Blood. 2005; 106: 3074-3081 Crossref PubMed Scopus (74) Google Scholar ]. HDL and ApoA-I inhibit antigen presentation-mediated T cell activation by disrupting lipid rafts in antigen presenting cellsAtherosclerosisVol. 225Issue 1PreviewDepletion of cholesterol by methyl-β-cyclodextrin (MCD) on peptide-loaded antigen presenting cells (APCs) inhibits antigen presentation and T cell activation. However, whether membrane cholesterol efflux induced by high-density lipoprotein (HDL) and apolipoprotein A-I (apoA-I) also results in inhibition of antigen presentation and T cell activation is still unknown. Full-Text PDF

Lecithin:cholesterol acyltransferase: old friend or foe in atherosclerosis?

Lecithin:cholesterol acyltransferase (LCAT) is a key enzyme that catalyzes the esterification of free cholesterol in plasma lipoproteins and plays a critical role in high-density lipoprotein (HDL) metabolism. Deficiency leads to accumulation of nascent preβ-HDL due to impaired maturation of HDL particles, whereas enhanced expression is associated with the formation of large, apoE-rich HDL(1) particles. In addition to its function in HDL metabolism, LCAT was believed to be an important driving force behind macrophage reverse cholesterol transport (RCT) and, therefore, has been a subject of great interest in cardiovascular research since its discovery in 1962. Although half a century has passed, the importance of LCAT for atheroprotection is still under intense debate. This review provides a comprehensive overview of the insights that have been gained in the past 50 years on the biochemistry of LCAT, the role of LCAT in lipoprotein metabolism and the pathogenesis of atherosclerosis in animal models, and its impact on cardiovascular disease in humans.

Lipid-Induced Modulation of Protective Signalling Pathways in Cardiovascular Disease: The Role of High Density Lipoproteins

High density lipoproteins have a well-established, negative correlation with risk of cardiovascular disease. There is currently particular interest in trying to exploit this relationship by raising serum high density lipoprotein cholesterol to lower risk. More recent studies suggest that high density lipoproteins have a more widespread impact on cardiovascular pathophysiology, beyond its involvement in cholesterol metabolism. The lipoprotein influences the functioning of endothelial cells and cardiomyocytes in a manner suggesting a protective effect under conditions of physiological stress. On-going studies are investigating the magnitude of the influence of the lipoprotein on cell function, notably be defining the signalling pathways that are involved. Advances in this area will be discussed in the following review. These studies may identify new avenues that can be explored as potential targets to treat cardiovascular disease. A logical extension is to consider the high density lipoprotein complex itself as a potential therapeutic. In this respect the ability to synthesise artificial high density lipoproteins with functional properties of the native lipoprotein complex is a particularly attractive option. Such studies have already been initiated, as will be discussed below. Keywords: Apolipoprotein AI; cardiomyocyte; endothelium; HDL; ischemia-reperfusion injury; sphingosine-1-phosphate; SAFE pathway

New Roles of HDL in Inflammation and Hematopoiesis

High-density lipoprotein (HDL) levels are inversely associated with coronary heart disease due to HDL's ability to transport excess cholesterol in arterial macrophages to the liver for excretion [i.e., reverse cholesterol transport (RCT)]. However, recent advances highlight additional atheroprotective roles for HDL beyond bulk cholesterol removal from cells through RCT. By promoting cellular free cholesterol (FC) efflux, HDL and its apolipoproteins (apoA-I and apoE) decrease plasma membrane FC and lipid raft content in immune and hematopoietic stem cells, decreasing inflammatory and cell proliferation signaling pathways. HDL and apoA-I also dampen inflammatory signaling pathways independent of cellular FC efflux. In addition, HDL lipid and protein cargo provide protection against parasitic and bacterial infection, endothelial damage, and oxidant toxicity. Here, current knowledge is reviewed regarding the role of HDL and its apolipoproteins in regulating cellular cholesterol homeostasis, highlighting recent advances on novel functions and mechanisms by which HDLs regulate inflammation and hematopoiesis.

Phospholipid Transfer Protein Is Differentially Expressed in Human Arterial and Venous Placental Endothelial Cells and Enhances Cholesterol Efflux to Fetal HDL

Phospholipid (PL) transfer protein (PLTP) plays a crucial role in high-density lipoprotein (HDL) metabolism. In the fetal circulation, HDL particles are the main cholesterol carriers and are involved in maternal-fetal cholesterol transfer across human placental endothelial cells (HPEC). The aim was to investigate local function(s) of PLTP at the fetoplacental endothelium. Because HPEC display morphological and functional diversity when isolated from arteries or veins, we hypothesized that PLTP activity may differ between arterial and venous HPEC. We determined PLTP mRNA and activity levels from isolated HPEC and investigated PLTP-mediated remodeling of fetal HDL particles and their capacity in mediating cholesterol efflux from HPEC. Incubation of fetal HDL with active human plasma PLTP resulted in increased particle size (12.6 vs. 13.2 nm, P < 0.05), with a concomitant increase (3.5-fold) in pre-β-mobile HDL particles. Arterial HPEC showed higher Pltp expression levels and secreted PL transfer activity (1.8-fold, P < 0.001) than venous HPEC. In contrast to adult HDL(3), [(3)H]cholesterol efflux to fetal HDL was 21% higher (P < 0.05) from arterial than from venous HPEC. PLTP-facilitated particle conversion increased the cholesterol efflux capacity of fetal HDL to similar extents (55 and 48%, P < 0.001) from arterial and venous HPEC, respectively. PLTP mediates PL transfer and participates in reverse cholesterol transport pathways at the fetoplacental barrier. Enhanced cellular cholesterol efflux from HPEC to fetal HDL remodeled by PLTP supports the idea of a local atheroprotective role of PLTP in the placental vasculature.

Endothelial Lipase Mediates HDL Levels in Normal and Hyperlipidemic Rabbits

Existing evidence suggests that endothelial lipase (EL) plays an important role in high-densitylipoprotein (HDL) metabolism. Because rabbits are a useful animal model for the study of human lipid metabolism and atherosclerosis, we characterized rabbit EL (rEL) expression and investigated its relationship with plasma HDL levels in normal and hyperlipidemic rabbits. We cloned the rEL cDNA and analyzed the EL tissue expression using Northern blotting, real-time RT-PCR, Western blotting, and in situ hybridization. We evaluated the effects of rEL antisense on plasma HDL levels. We found that rEL mRNA was highly expressed in cholesterol synthesis-related organs, including the liver, testis, and adrenal along with its expression in the lung, kidney, bone marrow, and small intestine. Interestingly, Watanabe heritable hyperlipidemic (WHHL) rabbits, a model of human familial hypercholesterolemia, had lower plasma levels of HDLs than normal rabbits. The plasma HDL levels in WHHL rabbits were inversely associated with high levels of plasma rEL proteins and hepatic expression of rEL mRNA. Injection of rEL-specific antisense oligonucleotides into rabbits resulted in the elevation of plasma large HDLs. Furthermore, we demonstrated that rEL mRNA was expressed by both endothelial cells and macrophages in the lesions of aortic atherosclerosis of WHHL rabbits. rEL is expressed in multiple tissues and may have many physiological and pathophysiological functions, such as in the regulation of cholesterol metabolism and atherosclerosis. Our results suggest that EL is an important regulator of plasma HDL levels in rabbits.

Identification of Dehydroxytrichostatin A as a Novel Up-Regulator of the ATP-Binding Cassette Transporter A1 (ABCA1)

The ATP-binding cassette transporter A1 (ABCA1) mediates the cellular efflux of excess cholesterol and phospholipids to lipid-poor apolipoprotein A-I (apoA-I). ABCA1 plays an important role in high-density lipoprotein (HDL) biogenesis and reverse cholesterol transport. By using a cell-based screening model for the ABCA1 up-regulator and column chromatography, an active compound, 9179B, was isolated. Through analysis of its NMR data, 9179B was identified as dehydroxytrichostatin A. We found that 9179B increased the transcription of ABCA1 in a cell-based reporter assay, with an EC50 value of 2.65 μM. 9179B up-regulated ABCA1 expression at both mRNA and protein levels in HepG2 and RAW264.7 cells. It also up-regulated the expression of scavenger receptor class B type I (SR-BI) as well as the uptake of DiI-HDL in RAW264.7 cells. This compound stimulated ApoA-I-mediated cellular cholesterol efflux from RAW 264.7 cells. We further found that 9179B was a potent histone deacetylase (HDAC) inhibitor with an IC50 value of 0.08 μM. Reporter gene assays showed that the regulation of ABCA1 transcription by 9179B was mainly mediated by the −171/−75 bp promoter region. Together, our results indicate that 9179B is an ABCA1 up-regulator and dehydroxytrichostatin A may be a novel anti-atherogenic compound.

Plasma lecithin:cholesterol acyltransferase and carotid intima-media thickness in European individuals at high cardiovascular risk

Lecithin:cholesterol acyltransferase (LCAT) is the enzyme responsible for cholesterol esterification in plasma. LCAT is a major factor in HDL remodeling and metabolism, and it has long been believed to play a critical role in macrophage reverse cholesterol transport (RCT). The effect of LCAT on human atherogenesis is still controversial. In the present study, the plasma LCAT concentration was measured in all subjects (n = 540) not on drug treatment at the time of enrollment in the multicenter, longitudinal, observational IMPROVE study. Mean and maximum intima-media thickness (IMT) of the whole carotid tree was measured by B-mode ultrasonography in all subjects. In the entire cohort, LCAT quartiles were not associated with carotid mean and maximum IMT (P for trend 0.95 and 0.18, respectively), also after adjustment for age, gender, HDL-cholesterol (HDL-C), and triglycerides. No association between carotid IMT and LCAT quartiles was observed in men (P=0.30 and P=0.99 for mean and maximum IMT, respectively), whereas carotid IMT increased with LCAT quartiles in women (P for trend 0.14 and 0.019 for mean and maximum IMT, respectively). The present findings support the concept that LCAT is not required for an efficient reverse cholesterol transport and that a low plasma LCAT concentration and activity is not associated with increased atherosclerosis.

Neutrophil Activation Is Attenuated by High-Density Lipoprotein and Apolipoprotein A-I in In Vitro and In Vivo Models of Inflammation

Neutrophils play a key role in the immune response but can undesirably exacerbate inflammation. High-density lipoproteins (HDL) are antiinflammatory particles, exerting beneficial cardiovascular influences. We determined whether HDL exerts antiinflammatory effects on neutrophils and explored the mechanisms by which these occur. CD11b on activated human neutrophils was significantly attenuated by apolipoprotein A-I (apoA-I) and HDL. The effects of apoA-I were mediated via ABCA1, whereas the effects of HDL were via scavenger receptor BI. Both were associated with a reduction in the abundance of lipid rafts, and a strong correlation between raft abundance and CD11b activation was observed. ApoA-I and HDL reduced neutrophil adhesion to a platelet monolayer under shear flow, as well as neutrophil spreading and migration. ApoA-I also inhibited leukocyte recruitment to the endothelium in an acute in vivo model of inflammation. Finally, infusion of reconstituted HDL in patients with peripheral vascular disease was demonstrated to significantly attenuate neutrophil activation. We describe here a novel role for HDL and apoA-I in regulating neutrophil activation using in vitro, in vivo, and clinical approaches. We also show that these effects of HDL and apoA-I involve a mechanism requiring changes in membrane domain content rather than in cholesterol efflux per se.

Hepatic Deficiency of Low Density Lipoprotein Receptor-related Protein-1 Reduces High Density Lipoprotein Secretion and Plasma Levels in Mice

The low density lipoprotein receptor-related protein-1 (LRP1) is known to serve as a chylomicron remnant receptor in the liver responsible for the binding and plasma clearance of apolipoprotein E-containing lipoproteins. Previous in vitro studies have provided evidence to suggest that LRP1 expression may also influence high density lipoprotein (HDL) metabolism. The current study showed that liver-specific LRP1 knock-out (hLrp1(-/-)) mice displayed lower fasting plasma HDL cholesterol levels when compared with hLrp1(+/+) mice. Lecithin:cholesterol acyl transferase and hepatic lipase activities in plasma of hLrp1(-/-) mice were comparable with those observed in hLrp1(+/+) mice, indicating that hepatic LRP1 inactivation does not influence plasma HDL remodeling. Plasma clearance of HDL particles and HDL-associated cholesteryl esters was also similar between hLrp1(+/+) and hLrp1(-/-) mice. In contrast, HDL secretion from primary hepatocytes isolated from hLrp1(-/-) mice was significantly reduced when compared with that observed with hLrp1(+/+) hepatocytes. Biotinylation of cell surface proteins revealed decreased surface localization of the ATP-binding cassette, subfamily A, member 1 (ABCA1) protein, but total cellular ABCA1 level was not changed in hLrp1(-/-) hepatocytes. Finally, hLrp1(-/-) hepatocytes displayed reduced binding capacity for extracellular cathepsin D, resulting in lower intracellular cathepsin D content and impairment of prosaposin activation, a process that is required for membrane translocation of ABCA1 to facilitate cholesterol efflux and HDL secretion. Taken together, these results documented that hepatic LRP1 participates in cellular activation of lysosomal enzymes and through this mechanism, indirectly modulates the production and plasma levels of HDL.

ABCA1 and ABCG1 expressions are regulated by statins and ezetimibe in Caco-2 cells

Enterocytes play a crucial role in high-density lipoprotein (HDL) biogenesis. Statins and ezetimibe are potent lowering-cholesterol drugs, which can also influence HDL plasma concentrations. We hypothesized that these drugs could modulate the expression of intestinal ABCA1 and ABCG1, two genes involved in HDL metabolism. Caco-2 cells were used as a model of the human intestinal cells and were treated with statins (0.01-1 μmol/L) and/or ezetimibe (0.5-5.0 μmol/L) for 12 h or 24 h. Gene expression was examined using real-time PCR. ABCA1 level was more abundant than ABCG1 in Caco-2 cells. ABCA1 was downregulated after 12-h and 24-h treatment with atorvastatin (0.1 and 1.0 μmol/L) or simvastatin (0.01, 0.1 and 1 μmol/L) (p<0.05). In statin-treated cells, ABCG1 levels remained unaltered. Ezetimibe alone did not induce change of ABCA1 or ABCG1 mRNA levels (p>0.05) but 24-h ezetimibe (2.5 or 5.0 μmol/L) plus simvastatin (1 μmol/L) treatment decreased the transcription of ABCA1 and ABCG1 (p<0.05). Our findings reveal that, at the concentrations studied, statins isolated or combined with ezetimibe, but not ezetimibe alone, downregulate ABCA1 mRNA expression in Caco-2 cells. Moreover, simvastatin combined with ezetimibe treatment also decrease the ABCG1 levels in these cells.

Pitavastatin Increases ABCA1 Expression by Dual Mechanisms: SREBP2-Driven Transcriptional Activation and PPARα-Dependent Protein Stabilization but Without Activating LXR in Rat Hepatoma McARH7777 Cells

Hepatic ATP-binding cassette transporter A1 (ABCA1) plays a key role in high-density lipoprotein (HDL) production by apolipoprotein A-I (ApoA-I) lipidation. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, increase ABCA1 mRNA levels in hepatoma cell lines, but their mechanism of action is not yet clear. We investigated how statins increase ABCA1 in rat hepatoma McARH7777 cells. Pitavastatin, atorvastatin, and simvastatin increased total ABCA1 mRNA levels, whereas pravastatin had no effect. Pitavastatin also increased ABCA1 protein. Hepatic ABCA1 expression in rats is regulated by both liver X receptor (LXR) and sterol regulatory element-binding protein (SREBP2) pathways. Pitavastatin repressed peripheral type ABCA1 mRNA levels and its LXR-driven promoter, but activated the liver-type SREBP-driven promoter, and eventually increased total ABCA1 mRNA expression. Furthermore, pitavastatin increased peroxisome proliferator-activated receptor α (PPARα) and its downstream gene expression. Knockdown of PPARα attenuated the increase in ABCA1 protein, indicating that pitavastatin increased ABCA1 protein via PPARα activation, although it repressed LXR activation. Furthermore, the degradation of ABCA1 protein was retarded in pitavastatin-treated cells. These data suggest that pitavastatin increases ABCA1 protein expression by dual mechanisms: SREBP2-mediated mRNA transcription and PPARα-mediated ABCA1 protein stabilization, but not by the PPAR-LXR-ABCA1 pathway. [Supplementary Figures: available only at http://dx.doi.org/10.1254/jphs.10241FP].

How Do We Approach Low High-density Lipoprotein Cholesterol in 2011?

The prevalence of obesity and of the metabolic syndrome is increasing worldwide, and the management of global cardiovascular disease (CVD) risk requires strategies for the treatment of complex, pro-atherogenic dyslipidaemia. Considerable evidence provides a scientific rationale for the role of high-density lipoprotein (HDL) in atheroprotection. Although HDL function can become altered in pathological states, the quantitative evaluation of HDL cholesterol (HDL-C) in addition to total cholesterol (TC) levels improves the accuracy of CVD risk prediction, and is therefore a component of most global CVD risk assessment models. Non-pharmacological lifestyle interventions, such as diet and exercise for weight loss and smoking cessation, are the mainstay of raising HDL in clinical practice. Several HDL-raising medications are available but, beyond statin therapy, evidence of an incremental clinical benefit is limited. Potent novel HDL therapeutics are emerging that not only increase HDL-C levels but may also improve HDL function. Early data have restored some confidence in the potential of new cholesteryl ester transfer protein (CETP) antagonists in clinical practice. It is essential that clinical trials address vascular burden and patient outcomes, and data from large outcome trials are eagerly awaited.

The role of high-density lipoproteins in reducing the risk of vascular diseases, neurogenerative disorders, and cancer.

High-density lipoprotein (HDL) is one of the major carriers of cholesterol in the blood. It attracts particular attention because, in contrast with other lipoproteins, as many physiological functions of HDL influence the cardiovascular system in favourable ways unless HDL is modified pathologically. The functions of HDL that have recently attracted attention include anti-inflammatory and anti-oxidant activities. High anti-oxidant and anti-inflammatory activities of HDL are associated with protection from cardiovascular disease. Atheroprotective activities, as well as a functional deficiency of HDL, ultimately depend on the protein and lipid composition of HDL. Further, numerous epidemiological studies have shown a protective association between HDL-cholesterol and cognitive impairment. Oxidative stress, including lipid peroxidation, has been shown to be the mediator of the pathologic effects of numerous risk factors of Alzheimer's disease. Lifestyle interventions proven to increase HDL- cholesterol levels including “healthy” diet, regular exercise, weight control, and smoking cessation have also been shown to provide neuro-protective effects. This review will focus on current knowledge of the beneficial effects of HDL-cholesterol as it relates to cardiovascular diseases, breast and lung cancers, non-Hodgkin's lymphoma, as well as its neuroprotective potential in reducing the risk of Alzheimer's disease and dementia.

The inverse association of serum HBV DNA level with HDL and adiponectin in chronic hepatitis B infection

BACKGROUNDThe natural history of hepatitis B virus (HBV) is complex and influenced by the level of viral replication and host factors. The hepatoprotective role of high density lipoproteins (HDL) and adiponectin as host factors on HBV persistence is less well understood.METHODSTo investigate correlation between HBV DNA level with clinical parameters in patients with chronic hepatitis B, 92 male subjects with HBV infection without any risk factors for diabetes were enrolled in this study. Age and BMI of the study population were matched and HBV DNA, ALT, tumor necrosis factor alpha (TNF-α), adiponectin and lipid levels was measured.RESULTSSerum HBV DNA correlated inversely with serum HDL level (r = -0.23; P = 0.014). The median of log copies/ml for HBV DNA (3.67) was considered as cut off point. Patients with HBV DNA level higher than cut off point had lower adiponectin (8.7 ± 5.3 vs 10.7 ± 4.9 μg/ml p = 0.05). Also, adiponectin had a negative correlation with TNF-α (r = -0.21, P = 0.04) and positive correlations with HDL (r = 0.18, P = 0.043).Multivariate regression models show that serum HDL level is an independed factor to predict serum HBV DNA.CONCLUSIONOur findings showed that higher HBV DNA levels are associated with lower HDL and adiponectin but induced TNF-alpha values.

Essential role of HDL on endothelial progenitor cell proliferation with PI3K/Akt/cyclin D1 as the signal pathway

High-density lipoprotein (HDL) is known as an important factor in vascular wall remodeling that also affects gene expression in cell proliferation and differentiation. In this article, the role of HDL on endothelial progenitor cell (EPC) proliferation, angiogenesis and the signal pathway involved was studied, particularly the influence of HDL in strengthening the promoting effect of EPCs on wound healing of the arterial wall in hypercholesterolemic rats. Mononuclear cells isolated from rat bone marrow displayed characteristics of EPCs after cultivation. The role of HDL on EPC function and the signal pathway involved were studied by Western blotting, in vitro migration and 'tube' formation. Re-endothelialization and the number of circulating EPCs were compared between normal rats, hypercholesterolemic rats and hypercholesterolemic rats with HDL treatment. Results showed that HDL participated in the healing process by promoting EPC proliferation, migration and 'tube' formation. HDL activates cyclin D1 via phosphatidylinositol 3-kinase (PI3K)/Akt stimulation. Inhibition of PI3K/Akt via pharmacological or small interfering RNA approaches significantly attenuated HDL-induced EPC migration, proliferation and 'tube' formation. Results of experiments in vivo showed that HDL increased the number of circulating EPCs and promoted re-endothelialization in wound healing. These findings demonstrate for the first time that PI3K/Akt-dependent cyclin D1 activation plays an essential role in HDL-induced EPC proliferation, migration and angiogenesis.

Endothelial lipase and reverse cholesterol transport in type 2 diabetes mellitus.

Aims/Introduction: Endothelial lipase (EL) plays an important role in high-density lipoprotein (HDL) metabolism and experimental data suggest that EL might be proatherogenic. We have investigated whether serum EL concentration is associated with changes in serum capacity to induce cholesterol efflux and arterial stiffness in type 2 diabetes. Serum EL was assayed by ELISA in 172 diabetic patients and 175 controls. The ability of serum to induce cholesterol efflux was measured using a cell culture system and arterial stiffness was determined by measuring pulse wave velocity (PWV) between carotid and femoral arteries. Diabetic patients had significantly higher C-reactive protein (CRP) and EL (27.7 ± 16.6 ng/mL vs 24.0 ± 11.3, P < 0.05). Cholesterol efflux to serum mediated through scavenger receptor class B type I was impaired (15.1 ± 2.5%vs 16.7 ± 3.1, respectively, P < 0.01). In controls, serum EL correlated with cholesterol efflux to serum (r = -0.16, P = 0.025), but only a trend was seen in the diabetic patients. Linear regression showed that in controls, HDL, serum EL and waist circumference were major independent determinants of cholesterol efflux; whereas in the diabetic cohort, the major independent determinants of cholesterol efflux were HDL, CRP and age. PWV was increased in the diabetic patients (P < 0.01), but no association between serum EL and PWV was seen in either groups. Serum EL was increased in diabetic patients, but impaired serum capacity to induce cholesterol efflux in these patients was mainly related to low HDL and subclinical inflammation. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00016.x, 2010).

Selective CETP Inhibition and PPARα Agonism Increase HDL Cholesterol and Reduce LDL Cholesterol in Human ApoB100/Human CETP Transgenic Mice

Cholesteryl ester transfer protein (CETP) plays a key role in high-density lipoprotein (HDL) cholesterol metabolism, but normal mice are deficient in CETP. In this study, transgenic mice expressing both human apolipoprotein B 100 (ApoB-100) and human CETP (hApoB100/hCETP) were used to characterize the effects of CETP inhibition and peroxisome proliferator-activated receptor alpha (PPARalpha) agonism on lipid profiles. Torcetrapib (3, 10, and 30 mg/kg), a CETP inhibitor, fenofibrate (30 mg/kg), a weak PPARalpha agonist, and GW590735 (3 and 10 mg/kg), a potent and selective PPARalpha agonist were given orally for 14 days to hApoB100/hCETP mice and lipid profiles were assessed. The average percentages of HDL, low-density lipoprotein (LDL), and very-low-density lipoprotein (VLDL) cholesterol fractions in hApoB100/hCETP mice were 34.8%, 61.6%, and 3.6%, respectively, which is similar to those of normolipidemic humans. Both torcetrapib and fenofibrate significantly increased HDL cholesterol and reduced LDL cholesterol, and there was a tendency for torcetrapib to reduce VLDL cholesterol and triglycerides. GW590735 significantly increased HDL cholesterol, decreased LDL and VLDL cholesterol, and significantly reduced triglycerides. Maximal increases in HDL cholesterol were 37%, 53%, and 84% with fenofibrate, torcetrapib, and GW590735, respectively. These results, in mice that exhibit a more human-like lipid profile, demonstrate an improved lipid profile with torcetrapib, fenofibrate, and GW590735, and support the use of selective PPARalpha agonism for the treatment of lipid disorders. In addition, these data demonstrate the use of hApoB100/hCETP transgenic mice to identify, characterize, and screen compounds that increase HDL cholesterol.

Cholesterol Ester Transfer Protein (CETP), Postprandial Lipemia and Hypolipidemic Drugs

Cholesterol ester transfer protein (CETP) plays a significant role in high density lipoprotein (HDL) metabolism and reverse cholesterol transport (RCT). A reduction in CETP activity leads to an increase in HDL-cholesterol levels. However, the relationship between reduced CETP function and atherosclerosis is complex and confusing. In the hypertriglyceridemic state, CETP is highly expressed and RCT leads to the formation of small dense low density lipoprotein (LDL) and small dense HDL, both of which are involved in the progression of atherosclerosis. Significant associations of the B1B1 genotype with higher plasma CETP concentration and/or CETP activity and lower HDL cholesterol were reported in several, but not all, studies. The magnitude of postprandial lipemia is also associated with plasma CETP concentration and lipoprotein content and size. Several conditions such as metabolic syndrome, hypertension, insulin resistance, obesity and familial hypercholesterolaemia are characterized by a more pronounced postprandial hypertriglyceridemia and delayed TG clearance than normal states. Thus, CETP is considered as a candidate target for drug therapy. A number of synthetic CETP inhibitors (CGS25159 and JTT-705) were evaluated in animals with satisfactory results. In humans, two CETP inhibitors were evaluated, JTT-705 and torcetrapib, leading to HDL increase. However, torcetrapib administration was associated with an increase in blood pressure and other "off-target" effects. It is also not clear whether the HDL produced during treatment with torcetrapib is bioactive (i.e. an "on target" undesirable action). In the current review, CETP function regarding lipid metabolism (in fasting and fed states) from human and animal studies as well as the current knowledge on CETP inhibitors are discussed. We also discuss gender influence on the action of hypolipidemic drugs and their effect on CETP mass and activity, as well as on the lipid profile.