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1.
Arch Med Res ; 50(3): 98-104, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31495396

RESUMO

BACKGROUND: High altitude is associated with hypobaric hypoxia, and metabolic modifications. In particular, alterations to lipoprotein-associated enzymes have been reported under hypoxia. OBJECTIVE: To determine the association between paraoxonase 1 (PON-1) and Cholesteryl-ester transfer protein (CETP) activities and altitude in two groups of Argentinean Indigenous schoolchildren living at different altitudes. METHODS: A cross-sectional study compared 151 schoolchildren from San Antonio de los Cobres (SAC), 3,750 m, with 175 schoolchildren from Chicoana (CH), 1,400 m. Anthropometric data, lipids, apolipoprotein (apo) A-I, apo B, plus PON-1 and CETP activities were determined. RESULTS: The prevalence of overweight/obesity was significantly lower in SAC than in CH. Z- BMI (0.3 vs 0.7), Apo A-I/Apo B (1.67 vs. 1.85) and PON-1 (170 vs. 243 nmol/mL.min) were significantly lower in SAC than in CH, respectively. Total cholesterol (156 vs 144 mg/dL), triglycerides (TG) (119 vs. 94 mg/dL), apo A-I (133 vs. 128 mg/dL), apo B (84 vs. 73 mg/dL), hematocrit (48 vs. 41%), transferrin (295 vs. 260 mg/dL) and CETP (181 vs. 150%/mL.h) were significantly higher in SAC than in CH. There was a significant univariate association between altitude and transferrin (r0.38), hematocrit (r0.75), TG (r0.24), apo B (r0.29), PON-1 (r-0.40), and CETP (r0.37). Multiple linear regression analyses showed that altitude was significantly associated with children's TG (ß = 0.28, R2 = 0.14), HDL-C (ß = â€’0.27; R2 = 0.23), apo B (ß = 0.32; R2 = 0.14), CETP (ß = 0.38; R2 = 0.15) and PON-1 (ß = â€’0.36; R2 = 0.16), adjusted for age, gender and BMI. CONCLUSION: SAC children presented a more atherogenic lipid profile, plus lower PON1 and higher CETP activities, than CH children.


Assuntos
Altitude , Arildialquilfosfatase/metabolismo , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Antropometria , Apolipoproteína A-I/análise , Apolipoproteínas B/análise , Argentina/epidemiologia , Aterosclerose/diagnóstico , Criança , Colesterol/sangue , Estudos Transversais , Feminino , Hematócrito , Humanos , Masculino , Obesidade/epidemiologia , Prevalência , Fatores de Risco , Transferrina/análise , Triglicerídeos/sangue
3.
Acta Diabetol ; 56(7): 749-754, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30980187

RESUMO

AIM: The impact of cholesteryl ester transfer protein (CETP) on atherosclerotic development in humans remains unclear. Plasma cholesteryl ester transfer was shown to be associated with carotid intima-media thickness in type 2 diabetic (T2D) patients with adequate metabolic control. Since glycation of CETP may influence cholesteryl ester transfer processes, it is important to determine if plasma cholesteryl ester transfer is still a determinant of carotid intima-media thickness (IMT) in patients with poorly controlled diabetes. The aim of the present study was to determine whether CETP activity influences carotid IMT in T2D patients with poor metabolic control. METHODS: In 110 individuals with T2D, we measured CETP mass concentration with ELISA, CETP activity with a radioactivity method and carotid intima-media thickness with high-resolution real-time B-mode ultrasonography. RESULTS: The mean HbA1C was 8.8 ± 1.7%. Carotid IMT did not correlate with CETP activity in the total population. In T2D patients with HbA1C < 8% (n = 33), mean HbA1C was 6.9% and the correlation between carotid IMT and CETP activity was not significant (p = 0.09). In a multivariable analysis that included the total population, carotid intima-media thickness was positively associated with diabetes duration (p = 0.02) but not with CETP activity or HbA1C. CONCLUSIONS: We observed no correlation between carotid intima-media thickness, a marker of early atherosclerosis, and CETP activity in T2D patients with poor metabolic control. Disease duration, which reflects accumulated metabolic abnormalities, may have blunted the potential effect of CETP on atherosclerosis. Metabolic control appears essential to determine the pro- or anti-atherogenic influence of CETP in patients with T2D.


Assuntos
Glicemia/metabolismo , Espessura Intima-Media Carotídea , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/metabolismo , Angiopatias Diabéticas/diagnóstico , Idoso , Aterosclerose/complicações , Aterosclerose/diagnóstico , Aterosclerose/metabolismo , Aterosclerose/fisiopatologia , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/fisiopatologia , Progressão da Doença , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Ultrassonografia
4.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1864(7): 1061-1071, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30844432

RESUMO

Very low-density lipoprotein (VLDL) is the main plasma carrier of triacylglycerol that is elevated in pathological conditions such as diabetes, metabolic syndrome, obesity and dyslipidemia. How variations in triacylglycerol levels influence structural stability and remodeling of VLDL and its metabolic product, low-density lipoproteins (LDL), is unknown. We applied a biochemical and biophysical approach using lipoprotein remodeling by lipoprotein lipase and cholesterol ester transfer protein, along with thermal denaturation that mimics key aspects of lipoprotein remodeling in vivo. The results revealed that increasing the triacylglycerol content in VLDL promotes changes in the lipoprotein size and release of the exchangeable apolipoproteins. Similarly, increased triacylglycerol content in LDL promotes lipoprotein remodeling and fusion. These effects were observed in single-donor lipoproteins from healthy subjects enriched in exogenous triolein, in single-donor lipoproteins from healthy subjects with naturally occurring differences in endogenous triacylglycerol, and in LDL and VLDL from pooled plasma of diabetic and normolipidemic patients. Consequently, triacylglycerol-induced destabilization is a general property of plasma lipoproteins. This destabilization reflects a direct effect of triacylglycerol on lipoproteins. Moreover, we show that TG can act indirectly by increasing lipoprotein susceptibility to oxidation and lipolysis and thereby promoting the generation of free fatty acids that augment fusion. These in vitro findings are relevant to lipoprotein remodeling and fusion in vivo. In fact, fusion of LDL and VLDL enhances their retention in the arterial wall and, according to the response-to-retention hypothesis, triggers atherosclerosis. Therefore, enhanced fusion of triacylglycerol-rich lipoproteins suggests a new causative link between elevated plasma triacylglycerol and atherosclerosis.


Assuntos
Lipoproteínas LDL/química , Lipoproteínas VLDL/química , Triglicerídeos/farmacologia , Aterosclerose/etiologia , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Humanos , Lipase Lipoproteica/metabolismo , Lipoproteínas/metabolismo , Lipoproteínas LDL/sangue , Lipoproteínas VLDL/sangue , Estrutura Molecular , Desnaturação Proteica
6.
BMC Syst Biol ; 13(1): 12, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30670016

RESUMO

BACKGROUND: Cholesterylester transfer protein (CETP) modulates the composition of various lipoproteins associated with cardiovascular disease. Despite its central role in lipoprotein metabolism, its mode of action is still not fully understood. Here we present a simple way to estimate CETP-mediated lipid fluxes between different lipoprotein fractions. RESULTS: The model derived adequately describes the observed findings, especially regarding low- and high dense lipoproteins (LDL and HDL), delivering correlation coefficients of R2 = 0.567 (p < 0.001) and R2 = 0.466 (p < 0.001), respectively. These estimated fluxes correlate best among all other measured concentrations and 'lipid per lipoprotein' ratios to the observed fluxes. CONCLUSION: Our model approach is independent of CETP-action's exact mechanistic mode. It is simple and easy to apply, and may be a useful tool in revealing CETP's ambiguous role in lipid metabolism. The model mirrors a diffusion-like exchange of triglycerides between lipoproteins. Cholesteryl ester and triglyceride concentrations measured in HDL, LDL and VLDL are sufficient to apply the model on a plasma sample.


Assuntos
Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Modelos Biológicos , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Transporte Biológico , Humanos
7.
Am J Cardiovasc Drugs ; 19(3): 229-235, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30610681

RESUMO

Cholesteryl ester transfer protein (CETP) plays an important role in lipid metabolism and has presented an attractive target for drug development, primarily resting on the hope that CETP inhibition would reduce cardiovascular events through its ability to increase levels of high-density lipoprotein cholesterol (HDL-C). However, clinical development of CETP inhibitors has proven disappointing, with a spectrum of results spanning from evidence of harm, to futility, to only modest benefit in large-scale cardiovascular outcomes trials. A number of additional insights from genomic studies have suggested potential benefits from these agents in specific clinical settings. We review the current state of CETP inhibitors as an approach to targeting cardiovascular risk.


Assuntos
Anticolesterolemiantes/farmacologia , Doenças Cardiovasculares/prevenção & controle , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Animais , Doenças Cardiovasculares/etiologia , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , HDL-Colesterol/sangue , Desenvolvimento de Medicamentos , Humanos , Fatores de Risco
8.
Am J Respir Crit Care Med ; 199(7): 854-862, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30321485

RESUMO

RATIONALE: High-density lipoprotein (HDL) cholesterol (HDL-C) levels decline during sepsis, and lower levels are associated with worse survival. However, the genetic mechanisms underlying changes in HDL-C during sepsis, and whether the relationship with survival is causative, are largely unknown. OBJECTIVES: We hypothesized that variation in genes involved in HDL metabolism would contribute to changes in HDL-C levels and clinical outcomes during sepsis. METHODS: We performed targeted resequencing of HDL-related genes in 200 patients admitted to an emergency department with sepsis (Early Infection cohort). We examined the association of genetic variants with HDL-C levels, 28-day survival, 90-day survival, organ dysfunction, and need for vasopressor or ventilatory support. Candidate variants were further assessed in the VASST (Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock Trial) cohort (n = 632) and St. Paul's Hospital Intensive Care Unit 2 (SPHICU2) cohort (n = 203). MEASUREMENTS AND MAIN RESULTS: We identified a rare missense variant in CETP (cholesteryl ester transfer protein gene; rs1800777-A) that was associated with significant reductions in HDL-C levels during sepsis. Carriers of the A allele (n = 10) had decreased survival, more organ failure, and greater need for organ support compared with noncarriers. We replicated this finding in the VASST and SPHICU2 cohorts, in which carriers of rs1800777-A (n = 35 and n = 12, respectively) had significantly reduced 28-day survival. Mendelian randomization was consistent with genetically reduced HDL levels being a causal factor for decreased sepsis survival. CONCLUSIONS: Our results identify CETP as a critical regulator of HDL levels and clinical outcomes during sepsis. These data point toward a critical role for HDL in sepsis.


Assuntos
Proteínas de Transferência de Ésteres de Colesterol/genética , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , HDL-Colesterol/genética , HDL-Colesterol/metabolismo , Sepse/genética , Sepse/metabolismo , Sobrevida/fisiologia , Idoso , Colúmbia Britânica , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Sepse/fisiopatologia
9.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1864(3): 260-270, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30557627

RESUMO

Intermediate-density lipoproteins (IDLs), the remnants of very-low-density lipoproteins via lipolysis, are rich in cholesteryl ester and are associated with cardiovascular disease. Despite pharmacological interest in IDLs, their three-dimensional (3D) structure is still undetermined due to their variation in size, composition, and dynamic structure. To explore the 3D structure of IDLs, we reconstructed 3D density maps from individual IDL particles using cryo-electron microscopy (cryo-EM) and individual-particle electron tomography (IPET, without averaging from different molecules). 3D reconstructions of IDLs revealed an unexpected polyhedral structure that deviates from the generally assumed spherical shape model (Frias et al., 2007; Olson, 1998; Shen et al., 1977). The polyhedral-shaped IDL contains a high-density shell formed by flat surfaces that are similar to those of very-low-density lipoproteins but have sharper dihedral angles between nearby surfaces. These flat surfaces would be less hydrophobic than the curved surface of mature spherical high-density lipoprotein (HDL), leading to a lower binding affinity of IDL to hydrophobic proteins (such as cholesteryl ester transfer protein) than HDL. This is the first visualization of the IDL 3D structure, which could provide fundamental clues for delineating the role of IDL in lipid metabolism and cardiovascular disease.


Assuntos
Lipoproteínas IDL/química , Lipoproteínas IDL/fisiologia , Imagem Individual de Molécula/métodos , Apolipoproteína A-I/metabolismo , Apolipoproteínas B/metabolismo , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Ésteres do Colesterol/metabolismo , Microscopia Crioeletrônica/métodos , Tomografia com Microscopia Eletrônica/métodos , Voluntários Saudáveis , Humanos , Imagem Tridimensional/métodos , Lipólise/fisiologia , Lipoproteínas/metabolismo , Lipoproteínas HDL/metabolismo , Lipoproteínas IDL/metabolismo , Lipoproteínas LDL/metabolismo , Lipoproteínas VLDL/metabolismo , Plasma/diagnóstico por imagem
10.
Diabetes ; 67(12): 2494-2506, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30213825

RESUMO

In clinical trials, inhibition of cholesteryl ester transfer protein (CETP) raises HDL cholesterol levels but does not robustly improve cardiovascular outcomes. Approximately two-thirds of trial participants are obese. Lower plasma CETP activity is associated with increased cardiovascular risk in human studies, and protective aspects of CETP have been observed in mice fed a high-fat diet (HFD) with regard to metabolic outcomes. To define whether CETP inhibition has different effects depending on the presence of obesity, we performed short-term anacetrapib treatment in chow- and HFD-fed CETP transgenic mice. Anacetrapib raised HDL cholesterol and improved aspects of HDL functionality, including reverse cholesterol transport, and HDL's antioxidative capacity in HFD-fed mice was better than in chow-fed mice. Anacetrapib worsened the anti-inflammatory capacity of HDL in HFD-fed mice. The HDL proteome was markedly different with anacetrapib treatment in HFD- versus chow-fed mice. Despite benefits on HDL, anacetrapib led to liver triglyceride accumulation and insulin resistance in HFD-fed mice. Overall, our results support a physiologic importance of CETP in protecting from fatty liver and demonstrate context selectivity of CETP inhibition that might be important in obese subjects.


Assuntos
Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Proteínas de Transferência de Ésteres de Colesterol/genética , HDL-Colesterol/sangue , Dieta Hiperlipídica , Fígado Gorduroso/genética , Resistência à Insulina/fisiologia , Animais , Anticolesterolemiantes/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Fígado Gorduroso/metabolismo , Camundongos , Camundongos Transgênicos , Oxazolidinonas/farmacologia
11.
Int J Pharm ; 549(1-2): 388-396, 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30107219

RESUMO

CKD-519, a potent cholesteryl ester transfer protein (CETP) inhibitor, is a clinical candidate being developed for the treatment of dyslipidemia. It is considered a Biopharmaceutical Classification System II compound with low solubility and high permeability. The objective of this study was to develop early formulations focusing on the dissolution rate of the compound to achieve dose-dependent exposure. High performance formulation strategies including solid dispersion (SD) and a self-microemulsifying drug delivery system (SMEDDS) were investigated and their in vivo and in vitro correlations were also evaluated in monkeys along with dose optimization in human volunteers. The SD granules were prepared in a fluid bed granulator using microcrystalline cellulose and mannitol as carriers. Poloxamer 407 and Eudragit E PO were each found to be a suitable solubilizing agent and polymer for the improvement of the CKD-519 dissolution rate. Pharmacokinetic studies in monkeys showed that the SD tablets exhibited better absorption than the SMEDDS in a dose-dependent manner from 1.5 mg to 100 mg. The mannitol-based SD tablet formulations were bioequivalent. However, pharmacokinetics studies in humans showed that the dose was saturable above 100 mg of CKD-519. This study was performed to determine how to develop early formulations for clinical studies and to identify rational formulation development strategies for CKD-519 to establish the pharmaceutical proof-of-concept in humans.


Assuntos
Anticolesterolemiantes/administração & dosagem , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Desenvolvimento de Medicamentos/métodos , Hidrocarbonetos Fluorados/administração & dosagem , Oxazóis/administração & dosagem , Administração Oral , Adulto , Animais , Anticolesterolemiantes/química , Anticolesterolemiantes/farmacocinética , Disponibilidade Biológica , Celulose/química , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Método Duplo-Cego , Portadores de Fármacos , Composição de Medicamentos , Excipientes/química , Feminino , Humanos , Hidrocarbonetos Fluorados/química , Hidrocarbonetos Fluorados/farmacocinética , Macaca mulatta , Masculino , Manitol/química , Pessoa de Meia-Idade , Modelos Biológicos , Oxazóis/química , Oxazóis/farmacocinética , Permeabilidade , Poloxâmero/química , Ácidos Polimetacrílicos/química , Estudo de Prova de Conceito , Solubilidade , Comprimidos , Adulto Jovem
12.
Arterioscler Thromb Vasc Biol ; 38(8): 1890-1900, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29976766

RESUMO

Objective- SAA (serum amyloid A) is a family of acute-phase reactants that have proinflammatory and proatherogenic activities. SAA is more lipophilic than apoA-I (apolipoprotein A-I), and during an acute-phase response, <10% of plasma SAA is found lipid-free. In most reports, SAA is found exclusively associated with high-density lipoprotein; however, we and others have reported SAA on apoB (apolipoprotein B)-containing lipoproteins in both mice and humans. The goal of this study was to determine whether SAA is an exchangeable apolipoprotein. Approach and Results- Delipidated human SAA was incubated with SAA-free human lipoproteins; then, samples were reisolated by fast protein liquid chromatography, and SAA analyzed by ELISA and immunoblot. Both in vitro and in vivo, we show that SAA associates with any lipoprotein and does not remain in a lipid-free form. Although SAA is preferentially found on high-density lipoprotein, it can exchange between lipoproteins. In the presence of CETP (cholesterol ester transfer protein), there is greater exchange of SAA between lipoproteins. Subjects with diabetes mellitus, but not those with metabolic syndrome, showed altered SAA lipoprotein distribution postprandially. Proteoglycan-mediated lipoprotein retention is thought to be an underlying mechanism for atherosclerosis development. SAA has a proteoglycan-binding domain. Lipoproteins containing SAA had increased proteoglycan binding compared with SAA-free lipoproteins. Conclusions- Thus, SAA is an exchangeable apolipoprotein and increases apoB-containing lipoproteins' proteoglycan binding. We and others have previously reported the presence of SAA on low-density lipoprotein in individuals with obesity, diabetes mellitus, and metabolic syndrome. We propose that the presence of SAA on apoB-containing lipoproteins may contribute to cardiovascular disease development in these populations.


Assuntos
Apolipoproteínas/metabolismo , Proteína Amiloide A Sérica/metabolismo , Idoso , Animais , Apolipoproteína B-100/metabolismo , Apolipoproteínas/sangue , Proteínas de Transferência de Ésteres de Colesterol/genética , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Diabetes Mellitus/sangue , Feminino , Humanos , Lipoproteínas HDL/metabolismo , Masculino , Síndrome Metabólica/sangue , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Pessoa de Meia-Idade , Obesidade/sangue , Período Pós-Prandial , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Proteoglicanas/metabolismo , Proteína Amiloide A Sérica/deficiência , Proteína Amiloide A Sérica/genética
13.
Atherosclerosis ; 276: 39-43, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30029099

RESUMO

Plasma HDL levels have an inverse relationship to coronary artery disease (CAD) risk, which led to the idea that increasing HDL levels therapeutically would ameliorate atherosclerosis. Human genetic deficiency of CETP caused markedly elevated HDL and moderately reduced non-HDL cholesterol levels, suggesting that CETP inhibitors might produce cardiovascular benefit. The CETP inhibitor anacetrapib reproduced the phenotype of homozygous CETP deficiency and showed a highly significant benefit for CAD in the REVEAL trial. However, the magnitude of this effect was moderate, and the mechanism of benefit remains unclear. Insights into the mechanisms underlying macrophage cholesterol efflux and reverse cholesterol transport have come from monogenic human disorders and transgenic mouse studies. In particular, the importance of the ATP binding cassette transporters ABCA1 and ABCG1 in promoting cholesterol efflux from myeloid and other hematopoietic cells has been shown and linked to aberrant myelopoiesis and macrophage inflammation. Recent studies have shown that myeloid deficiency of ABCA1 and ABCG1 leads to macrophage and neutrophil inflammasome activation, which in turn promotes atherosclerotic plaque development and notably the formation of neutrophil extracellular traps (NETs) in plaques. In addition, clonal hematopoiesis has emerged as an important CAD risk factor, likely involving macrophage inflammation and inflammasome activation. Further elucidation of the mechanisms linking plaque accumulation of cholesterol and oxidized lipids to myeloid cell inflammation may lead to the development of new therapeutics specifically targeting atherogenic inflammation, with likely benefit for CAD.


Assuntos
Anti-Inflamatórios/uso terapêutico , Aterosclerose/tratamento farmacológico , Fármacos Cardiovasculares/uso terapêutico , Doença da Artéria Coronariana/tratamento farmacológico , Inflamação/tratamento farmacológico , Lipoproteínas HDL/sangue , Animais , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/imunologia , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Proteínas de Transferência de Ésteres de Colesterol/genética , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/imunologia , Inibidores Enzimáticos/uso terapêutico , Predisposição Genética para Doença , Humanos , Inflamassomos/efeitos dos fármacos , Inflamassomos/imunologia , Inflamassomos/metabolismo , Inflamação/sangue , Inflamação/genética , Inflamação/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Fenótipo , Regulação para Cima
14.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1863(9): 1082-1094, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29883800

RESUMO

Human phospholipid transfer protein (PLTP) mediates the transfer of phospholipids among atheroprotective high-density lipoproteins (HDL) and atherogenic low-density lipoproteins (LDL) by an unknown mechanism. Delineating this mechanism would represent the first step towards understanding PLTP-mediated lipid transfers, which may be important for treating lipoprotein abnormalities and cardiovascular disease. Here, using various electron microscopy techniques, PLTP is revealed to have a banana-shaped structure similar to cholesteryl ester transfer protein (CETP). We provide evidence that PLTP penetrates into the HDL and LDL surfaces, respectively, and then forms a ternary complex with HDL and LDL. Insights into the interaction of PLTP with lipoproteins at the molecular level provide a basis to understand the PLTP-dependent lipid transfer mechanisms for dyslipidemia treatment.


Assuntos
Lipoproteínas HDL/química , Lipoproteínas LDL/química , Lipoproteínas VLDL/química , Proteínas de Transferência de Fosfolipídeos/química , Fosfolipídeos/química , Transporte Biológico , Proteínas de Transferência de Ésteres de Colesterol/química , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Humanos , Lipoproteínas HDL/metabolismo , Lipoproteínas LDL/metabolismo , Lipoproteínas VLDL/metabolismo , Lipossomos/química , Lipossomos/metabolismo , Lipossomos/ultraestrutura , Microscopia Eletrônica , Proteínas de Transferência de Fosfolipídeos/metabolismo , Fosfolipídeos/metabolismo
15.
J Clin Lipidol ; 12(3): 784-800.e4, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29574070

RESUMO

BACKGROUND: Statins impact the metabolism, concentrations, composition, and function of circulating lipoproteins. OBJECTIVE: We evaluated time course relationships between statin-mediated reduction in atherogenic apolipoprotein B (ApoB)-containing particles and dynamic intravascular remodeling of ApoAI-containing lipoprotein subpopulations in the mixed dyslipidemia of metabolic syndrome. METHODS: Insulin-resistant, hypertriglyceridemic, hypercholesterolemic, obese males (n = 12) were treated with pitavastatin (4 mg/d) and response evaluated at 6, 42, and 180 days. RESULTS: Reduction in low-density lipoprotein (LDL) cholesterol, ApoB, and triglycerides (TGs) was essentially complete at 42 days (-38%, -32%, and -35%, respectively); rapid reduction equally occurred in remnant cholesterol, ApoCII, CIII, and E levels (day 6; -35%, -50%, -23%, and -26%, respectively). Small dense LDLs (LDL4 and LDL5 subpopulations) predominated at baseline and were markedly reduced on treatment (-29% vs total LDL mass). Cholesteryl ester (CE) transfer protein activity and mass decreased progressively (-18% and -16%, respectively); concomitantly, TG depletion (up to -49%) and CE enrichment occurred in all high-density lipoprotein (HDL) particle subpopulations with normalization of CE/TG mass ratio at 180 days. ApoAI was redistributed from LpAI to LpAI:AII particles in HDL2a and HDL3a subpopulations; ApoCIII was preferentially depleted from LpAI:AII-rich particles on treatment. CONCLUSION: Overall, statin action exhibits duality in mixed dyslipidemia, as CE transfer protein-mediated normalization of the HDL CE/TG core lags markedly behind subacute reduction in elevated levels of atherogenic ApoB-containing lipoproteins. Normalization of the HDL neutral lipid core is consistent with enhanced atheroprotective function. The HDL CE/TG ratio constitutes a metabolomic marker of perturbed HDL metabolism in insulin-resistant states, equally allowing monitoring of statin impact on HDL metabolism, structure, and function.


Assuntos
Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Dislipidemias/complicações , Dislipidemias/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lipoproteínas/sangue , Síndrome Metabólica/complicações , Dislipidemias/sangue , Dislipidemias/metabolismo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lipoproteínas/química , Masculino , Pessoa de Meia-Idade , Fenótipo , Fatores de Tempo , Resultado do Tratamento
16.
J Lipid Res ; 59(5): 772-783, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29487091

RESUMO

Most of the cholesterol in plasma is in an esterified form that is generated in potentially cardioprotective HDLs. Cholesteryl ester transfer protein (CETP) mediates bidirectional transfers of cholesteryl esters (CEs) and triglycerides (TGs) between plasma lipoproteins. Because CE originates in HDLs and TG enters the plasma as a component of VLDLs, activity of CETP results in a net mass transfer of CE from HDLs to VLDLs and LDLs, and of TG from VLDLs to LDLs and HDLs. As inhibition of CETP activity increases the concentration of HDL-cholesterol and decreases the concentration of VLDL- and LDL-cholesterol, it has the potential to reduce atherosclerotic CVD. This has led to the development of anti-CETP neutralizing monoclonal antibodies, vaccines, and antisense oligonucleotides. Small molecule inhibitors of CETP have also been developed and four of them have been studied in large scale cardiovascular clinical outcome trials. This review describes the structure of CETP and its mechanism of action. Details of its regulation and nonlipid transporting functions are discussed, and the results of the large scale clinical outcome trials of small molecule CETP inhibitors are summarized.


Assuntos
Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/química , Humanos , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/química
17.
J Am Heart Assoc ; 7(6)2018 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-29525783

RESUMO

BACKGROUND: Lipopolysaccharide (LPS) decreases hepatic CETP (cholesteryl ester transfer protein) expression albeit that the underlying mechanism is disputed. We recently showed that plasma CETP is mainly derived from Kupffer cells (KCs). In this study, we investigated the role of KC subsets in the mechanism by which LPS reduces CETP expression. METHODS AND RESULTS: In CETP-transgenic mice, LPS markedly decreased hepatic CETP expression and plasma CETP concentration without affecting hepatic macrophage number. This was paralleled by decreased expression of the resting KC markers C-type lectin domain family 4, member f (Clec4f) and V-set and immunoglobulin domain containing 4 (Vsig4), while expression of the infiltrating monocyte marker lymphocyte antigen 6 complex locus C (Ly6C) was increased. Simultaneously, the ratio of plasma high-density lipoprotein-cholesterol over non-high-density lipoprotein-cholesterol transiently increased. After ablation hepatic macrophages via injection with liposomal clodronate, the reappearance of hepatic gene and protein expression of CETP coincided with Clec4f and Vsig4, but not Ly6C. Double-immunofluorescence staining showed that CETP co-localized with Clec4f+ KCs and not Ly6C+ monocytes. In humans, microarray gene-expression analysis of liver biopsies revealed that hepatic expression and plasma level of CETP both correlated with hepatic VSIG4 expression. LPS administration decreased the plasma CETP concentration in humans. In vitro experiments showed that LPS reduced liver X receptor-mediated CETP expression. CONCLUSIONS: Hepatic expression of CETP is exclusively confined to the resting KC subset (ie, F4/80+Clec4f+Vsig4+Ly6C-). LPS activated resting KCs, leading to reduction of Clec4f and Vsig4 expression and reduction of hepatic CETP expression, consequently decreasing plasma CETP and raising high-density lipoprotein (HDL)-cholesterol. This sequence of events is consistent with the anti-inflammatory role of HDL in the response to LPS and may be relevant as a defense mechanism against bacterial infections.


Assuntos
Antígenos Ly/metabolismo , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Dislipidemias/metabolismo , Macrófagos do Fígado/efeitos dos fármacos , Lectinas Tipo C/metabolismo , Lipopolissacarídeos/farmacologia , Fígado/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Receptores de Complemento/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Antígenos Ly/genética , Células Cultivadas , Proteínas de Transferência de Ésteres de Colesterol/sangue , Proteínas de Transferência de Ésteres de Colesterol/genética , Modelos Animais de Doenças , Dislipidemias/sangue , Dislipidemias/genética , Dislipidemias/patologia , Feminino , Humanos , Macrófagos do Fígado/metabolismo , Macrófagos do Fígado/patologia , Lectinas Tipo C/genética , Lipídeos/sangue , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Transgênicos , Fenótipo , Receptores de Complemento/genética , Receptores Acoplados a Proteínas-G/genética , Transdução de Sinais/efeitos dos fármacos
18.
Food Res Int ; 104: 126-133, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29433777

RESUMO

The effects of CPe-III on hyperlipidemic mice were investigated, along with molecular docking and dynamics analyses between CPe-III and CETP. This study was conducted in order to explore the lipid metabolism potential and mechanism of CPe-III. CPe-III significantly (P<0.05) reduced serum total cholesterol, triglyceride and hepatic triglyceride levels and increased serum superoxide dismutase activity. CPe-III reversed liver changes induced by a high-fat diet and significantly (P<0.05) reduced kidney and epididymal fat indices. The activities of hepatic lipase and lipoprotein lipase, as well as fecal fat excretion, were significantly (P<0.05) enhanced. Furthermore, CPe-III was found to bind in the cavity of CETP, forming four stable hydrogen bonds. Hydrophobic interactions were the main driving force during binding. This study demonstrates that CPe-III improves dyslipidemia in mice. The binding of CPe-III to CETP demonstrates that CPe-III blocks cholesterol transport. These results indicate that CPe-III may be useful as an adjuvant element for hyperlipidemia and atherosclerosis therapies.


Assuntos
Anticolesterolemiantes/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Cicer/química , Hiperlipidemias/tratamento farmacológico , Lipídeos/sangue , Oligopeptídeos/farmacologia , Sementes/química , Adiposidade/efeitos dos fármacos , Animais , Anticolesterolemiantes/isolamento & purificação , Anticolesterolemiantes/metabolismo , Sítios de Ligação , Biomarcadores/sangue , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Regulação para Baixo , Ligações de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Hiperlipidemias/sangue , Hiperlipidemias/fisiopatologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Camundongos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Oligopeptídeos/isolamento & purificação , Oligopeptídeos/metabolismo , Ligação Proteica
19.
Mol Cell Biochem ; 440(1-2): 167-187, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28828539

RESUMO

Coronary artery disease, the leading cause of death in the developed and developing countries, is prevalent in diabetes mellitus with 68% cardiovascular disease (CVD)-related mortality. Epidemiological studies suggested inverse correlation between HDL and CVD occurrence. Therefore, low HDL concentration observed in diabetic patients compared to non-diabetic individuals was thought to be one of the primary causes of increased risks of CVD. Efforts to raise HDL level via CETP inhibitors, Torcetrapib and Dalcetrapib, turned out to be disappointing in outcome studies despite substantial increases in HDL-C, suggesting that factors beyond HDL concentration may be responsible for the increased risks of CVD. Therefore, recent studies have focused more on HDL function than on HDL levels. The metabolic environment in diabetes mellitus condition such as hyperglycemia-induced advanced glycation end products, oxidative stress, and inflammation promote HDL dysfunction leading to greater risks of CVD. This review discusses dysfunctional HDL as one of the mechanisms of increased CVD risks in diabetes mellitus through adversely affecting components that support HDL function in cholesterol efflux and LDL oxidation. The dampening of reverse cholesterol transport, a key process that removes cholesterol from lipid-laden macrophages in the arterial wall, leads to increased risks of CVD in diabetic patients. Therapeutic approaches to keep diabetes under control may benefit patients from developing CVD.


Assuntos
Doença da Artéria Coronariana/sangue , Complicações do Diabetes/sangue , Diabetes Mellitus/sangue , Lipoproteínas HDL/sangue , Animais , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/patologia , Complicações do Diabetes/tratamento farmacológico , Complicações do Diabetes/patologia , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/patologia , Humanos , Lipoproteínas LDL/sangue , Oxirredução
20.
J Biomol Struct Dyn ; 36(10): 2567-2580, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28777919

RESUMO

Although the pharmacological inhibition of cholesterol ester transport protein (CETP) has been proposed as a method of preventing and treating cardiovascular disease (CVD), the adverse effects of current inhibitors have cast doubt on the interaction mechanisms of inhibitors and CETP. In response, a molecular dynamics simulation was used to investigate their interaction and shed light on the lipid exchange mechanism of CETP. Results showed that torcetrapib, anacetrapib, and evacetrapib can induce the incremental rigidity of CETP, yet decrease the stability of Helix X and the hydrophobic tunnel of CETP, with passable binding abilities (ΔGbind, -61.08, -64.23, and -61.57 kcal mol-1). During their binding processes, Van der Waals components (ΔEvdw + ΔGSA) play a dominant role, and the inhibitory effects closely correlated with residues Cys13, Val198, Gln199, Ser230, His232, and Phe263, which could reduce the flexibility of N- and C- termini and Helix X, as well as the stability of hydrophobic tunnel, into which the three inhibitors could enter and promote the formation of intramolecular H-bonds such as Thr138-Asn192 and Arg37-Glu186. Additionally, the three inhibitors could restrain the formation of an opening at the CETP N-terminal, which given the other findings suggests the tunneling mechanism of CETP transfer. The paper closes with an explanation of conceivable causes of the insufficient efficacy of the inhibitors, and puts forward the rationality in targeting the CETP distal end for CVD therapies.


Assuntos
Anticolesterolemiantes/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Anticolesterolemiantes/química , Benzodiazepinas/química , Benzodiazepinas/farmacologia , Sítios de Ligação , Proteínas de Transferência de Ésteres de Colesterol/química , Ligações de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Oxazolidinonas/química , Oxazolidinonas/farmacologia , Ligação Proteica , Estrutura Secundária de Proteína , Quinolinas/química , Quinolinas/farmacologia , Solventes/química , Termodinâmica
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