RESUMEN
CD36 is one of the important transporters of long-chain fatty acids (LCFAs) in the myocardium. We previously reported that CD36-deficient patients demonstrate a marked reduction of myocardial uptake of LCFA, while myocardial glucose uptake shows a compensatory increase, and are often accompanied by cardiomyopathy. However, the molecular mechanisms and functional role of CD36 in the myocardium remain unknown.The current study aimed to explore the pathophysiological role of CD36 in the heart. Methods: Using wild type (WT) and knockout (KO) mice, we generated pressure overload by transverse aortic constriction (TAC) and analyzed cardiac functions by echocardiography. To assess cardiac hypertrophy and fibrosis, histological and molecular analyses and measurement of ATP concentration in mouse hearts were performed.By applying TAC, the survival rate was significantly lower in KO than that in WT mice. After TAC, KO mice showed significantly higher heart weight-to-tibial length ratio and larger cross-sectional area of cardiomyocytes than those of WT. Although left ventricular (LV) wall thickness in the KO mice was similar to that in the WT mice, the KO mice showed a significant enlargement of LV cavity and reduced LV fractional shortening compared to the WT mice with TAC. A tendency for decreased myocardial ATP concentration was observed in the KO mice compared to the WT mice after TAC operation.These data suggest that the LCFA transporter CD36 is required for the maintenance of energy provision, systolic function, and myocardial structure.
Asunto(s)
Antígenos CD36/genética , Proteínas de Transporte de Ácidos Grasos/metabolismo , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Disfunción Ventricular Izquierda/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Antígenos CD36/fisiología , Metabolismo Energético/fisiología , Fibrosis , Glucosa/metabolismo , Hipertrofia Ventricular Izquierda/complicaciones , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Hipertrofia Ventricular Izquierda/fisiopatología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Miocardio/patología , Miocitos Cardíacos/patología , Presión/efectos adversos , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/fisiopatología , Remodelación VentricularRESUMEN
BACKGROUND: Although transcatheter aortic valve implantation (TAVI) is a new alternative treatment with acceptable midterm results for high surgical risk patients, at present performing the procedure in dialysis patients is not reimbursed in Japan. METHODSâANDâRESULTS: The study group of 17 dialysis patients (mean age, 76.7±5.0 years) underwent TAVI with the SAPIEN/SAPIEN XT. EuroSCORE and STS score were 25.0±19.0% and 15.4±12.3%, respectively. Transiliofemoral and transapical approaches were performed in 7 (41.2%) and 10 patients (58.8%), respectively. ICU and hospital stays after TAVI were 1.8±1.6 and 12.9±12.7 days, respectively. Mean transvalvular gradients at discharge significantly decreased from 45.9±13.3 mmHg to 10.7±4.3 mmHg (P<0.0001) and effective orifice area significantly increased from 0.78±0.17 to 1.69±0.37 cm(2)(P<0.0001). Device success was 87.5%. One patient required a valve-in-valve procedure on 187-postoperative-day for an acute increase in paravalvular leakage caused by initial lower implantation of the device. The overall mortality at 1 year was 0% and clinical efficacies at 30 days, 6 months, and 1 year were 93.8%, 83.3%, and 69.2%, respectively. CONCLUSIONS: Satisfactory early results were achieved with TAVI in Japanese dialysis patients with a high surgical risk, indicating it is a safe and effective alternative for the treatment of aortic valve stenosis in such patients.
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Estenosis de la Válvula Aórtica/terapia , Fallo Renal Crónico/terapia , Diálisis Renal , Reemplazo de la Válvula Aórtica Transcatéter , Anciano , Anciano de 80 o más Años , Estenosis de la Válvula Aórtica/complicaciones , Pueblo Asiatico , Femenino , Estudios de Seguimiento , Humanos , Japón , Fallo Renal Crónico/complicaciones , MasculinoRESUMEN
Sequence regulation of monomers is undoubtedly a challenging issue as an ultimate goal in polymer science. To efficiently produce sequence-controlled copolymers, we herein developed the versatile tandem catalysis, which concurrently and/or sequentially involved ruthenium-catalyzed living radical polymerization and in situ transesterification of methacrylates (monomers: RMA) with metal alkoxides (catalysts) and alcohols (ROH). Typically, gradient copolymers were directly obtained from the synchronization of the two reactions: the instantaneous monomer composition in feed gradually changed via the transesterification of R(1)MA into R(2)MA in the presence of R(2)OH during living polymerization to give R(1)MA/R(2)MA gradient copolymers. The gradient sequence of monomers along a chain was catalytically controlled by the reaction conditions such as temperature, concentration and/or species of catalysts, alcohols, and monomers. The sequence regulation of multimonomer units was also successfully achieved in one-pot by monomer-selective transesterification in concurrent tandem catalysis and iterative tandem catalysis, providing random-gradient copolymers and gradient-block counterparts, respectively. In contrast, sequential tandem catalysis via the variable initiation of either polymerization or in situ transesterification led to random or block copolymers. Due to the versatile adaptability of common and commercially available reagents (monomers, alcohols, catalysts), this tandem catalysis is one of the most efficient, convenient, and powerful tools to design tailor-made sequence-regulated copolymers.
Asunto(s)
Óxidos/química , Polímeros/síntesis química , Rutenio/química , Alcoholes/química , Catálisis , Esterificación , Radicales Libres/síntesis química , Radicales Libres/química , Polímeros/químicaRESUMEN
BACKGROUND: Postprandial hyperlipidemia partially refers to the postprandial accumulation of chylomicrons and chylomicron remnants (CM-R). Many in vitro studies have shown that CM-R has highly atherogenic properties, but consensus is lacking on whether CM-R accumulation correlates with the development of atherosclerotic cardiovascular diseases. We investigated the correlation between CM-R accumulation and the prevalence of coronary artery disease (CAD). DESIGN: Subjects who received a coronary angiography and did not take any lipid-lowering drugs (n = 189) were enrolled. Subjects with coronary artery stenosis (≥ 75%) were diagnosed as CAD. Biochemical markers for glucose and lipid metabolism including fasting apolipoprotein (apo) B-48 concentration were compared between CAD patients (n = 96) and age-, sex-, and body mass index (BMI)-matched non-CAD subjects without overt coronary stenosis (< 75%) (n = 67). We tried to determine which metabolic parameters were correlated with the prevalence of CAD by multiple logistic regression analysis, and whether or not the combination of high apo B-48 and other coronary risk factors (high triglyceride, low HDL-C, high HbA1c or low adiponectin levels) increased the prevalence of CAD. RESULTS: Fasting serum apo B-48 levels were significantly higher in CAD patients than in non-CAD subjects (3·9 ± 2·4 vs. 6·9 ± 2·6 µg/mL, P < 0·0001) and had the most significant correlation with the existence of CAD. The clustering of high fasting apo B-48 levels (> 4·34 µg/mL, the cut-off value) and other coronary risk factors were found to be associated with a stronger risk of CAD compared with single high fasting apo B-48 levels. CONCLUSION: Fasting serum apo B-48 levels significantly correlated with the prevalence of CAD.
Asunto(s)
Apolipoproteína B-48/sangre , Enfermedad de la Arteria Coronaria/sangre , Hiperglucemia/sangre , Lípidos/sangre , Anciano , Enfermedad de la Arteria Coronaria/fisiopatología , Ayuno , Femenino , Humanos , Masculino , Persona de Mediana Edad , Periodo Posprandial , Prevalencia , Factores de Riesgo , Estadística como AsuntoRESUMEN
We developed concurrent tandem living radical polymerization as a novel methodology to efficiently, conveniently, and in one-pot produce gradient copolymers via in situ monomer transformation. The key is to employ a metal alkoxide [Al(Oi-Pr)(3), Ti(Oi-Pr)(4)] and an alcohol solvent (ROH) in ruthenium-catalyzed polymerization of conventional ester-based methyl (meth)acrylate [M(M)A], where the monomer was directly transformed into R(M)A via in situ transesterification to gradually vary the monomer composition during the copolymerization. Typically, methyl methacrylate (MMA) was polymerized with a ruthenium catalyst in the presence of excess ethanol (EtOH) and Al(Oi-Pr)(3) cocatalyst to give well-controlled gradient copolymers from MMA to EMA along the polymer chain, in which the original MMA was gradually converted into ethyl methacrylate (EMA) by the cocatalyst. This concurrent tandem polymerization, in conjunction with a wide variety of alcohols, efficiently and conveniently produced various gradient copolymers including long alkyl chain and PEG pendent groups. The obtained copolymers further exhibited unique physical properties different from the corresponding random and block counterparts.
RESUMEN
A 17-year-old male, who was involved in a baseball club, presented to our emergency department with the complaint of gradual onset of swelling of his right arm. Contrast-enhanced computed tomography showed obstruction of the proximal portion of the right subclavian vein and pulmonary thromboembolism. Venography confirmed an occluded right subclavian vein. The patient was diagnosed with right subclavian vein thrombosis, which is referred to as Paget-Schroetter syndrome (PSS). An ultrasonography for the affected subclavian vein was helpful not only for making an accurate diagnosis of PSS, but also for verifying dynamic venous flow changes depending on the forearm position.
RESUMEN
Plasma high density lipoprotein (HDL)-cholesterol levels are inversely correlated to the risk of atherosclerotic cardiovascular diseases. Reverse cholesterol transport (RCT) is one of the major protective systems against atherosclerosis, in which HDL particles play a crucial role to carry cholesterol derived from peripheral tissues to the liver. Recently, ATP-binding cassette transporters (ABCA1, ABCG1) and scavenger receptor (SR-BI) have been identified as important membrane receptors to generate HDL by removing cholesterol from foam cells. Adiponectin (APN) secreted from adipocytes is one of the important molecules to inhibit the development of atherosclerosis. Epidemiological studies have revealed a positive correlation between plasma HDL-cholesterol and APN concentrations in humans, although its mechanism has not been clarified. Therefore, in the present study, we investigated the role of APN on RCT, in particular, cellular cholesterol efflux from human monocyte-derived and APN-knockout (APN-KO) mice macrophages. APN up-regulated the expression of ABCA1 in human macrophages, respectively. ApoA-1-mediated cholesterol efflux from macrophages was also increased by APN treatment. Furthermore, the mRNA expression of LXRalpha and PPARgamma was increased by APN. In APN-KO mice, the expression of ABCA1, LXRalpha, PPARgamma, and apoA-I-mediated cholesterol efflux was decreased compared with wild-type mice. In summary, APN might protect against atherosclerosis by increasing apoA-I-mediated cholesterol efflux from macrophages through ABCA1-dependent pathway by the activation of LXRalpha and PPARgamma.
Asunto(s)
Adiponectina/fisiología , Aterosclerosis/inmunología , HDL-Colesterol/metabolismo , Macrófagos Peritoneales/metabolismo , Transportador 1 de Casete de Unión a ATP , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1 , Transportadoras de Casetes de Unión a ATP/biosíntesis , Adiponectina/genética , Animales , Apolipoproteína A-I/metabolismo , Transporte Biológico , Células Cultivadas , HDL-Colesterol/sangre , Proteínas de Unión al ADN/biosíntesis , Humanos , Receptores X del Hígado , Ratones , Ratones Noqueados , Receptores Nucleares Huérfanos , PPAR gamma/biosíntesis , Receptores Citoplasmáticos y Nucleares/biosíntesis , Receptores Depuradores de Clase B/biosíntesisRESUMEN
AIMS: CD36 is an important transporter of long-chain fatty acids (LCFAs) in the myocardium. As we have reported previously, CD36-deficient patients demonstrate a marked reduction in myocardial uptake of (123)I-15-(p-iodophenyl)-(R, S)-methyl pentadecanoic acid (BMIPP), which is an analog of LCFAs, while myocardial (18)F-fluorodeoxy-glucose (FDG) uptake is increased. However, it has not been clarified whether energy provision is preserved in patients with CD36 deficiency. The aims of the current study were to investigate the myocardial uptake of glucose and alterations in myocardial metabolites in wild-type (WT) and CD36 knockout (KO) mice. METHODS AND RESULTS: High-resolution positron emission tomography (PET) demonstrated markedly enhanced glucose uptake in KO mouse hearts compared with those of WT mice in real-time. The myocardial protein expression of glucose transporter protein 1 (GLUT1) was significantly enhanced in KO mice compared to WT mice, whereas that of GLUT4 was not altered. While the myocardial expression of genes involved in fatty acid metabolism did not increase in KO mice, that of genes related to glucose utilization compensatorily increased in KO mice. The metabolomic analysis of cardiac tissues revealed that the myocardial concentrations of ATP and phosphocreatine were maintained, even in KO mice. The concentration of 3-hydroxybutyric acid and mRNA expression of hydroxybutyrate dehydrogenase in the heart were significantly higher in KO than in WT mice. CONCLUSION: These data suggest that high-energy phosphate might be preserved by the increased utilization of glucose and ketone bodies in CD36KO mouse hearts under conditions of deficient LCFA uptake.
Asunto(s)
Antígenos CD36/genética , Metabolismo Energético/fisiología , Glucosa/metabolismo , Cuerpos Cetónicos/metabolismo , Miocardio/metabolismo , Ácido 3-Hidroxibutírico/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Antígenos CD36/fisiología , Citrato (si)-Sintasa/metabolismo , Transportador de Glucosa de Tipo 1/metabolismo , Transportador de Glucosa de Tipo 4/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fosfocreatina/metabolismoRESUMEN
OBJECTIVES: Atherosclerotic lesions of the coronary arteries are the pathological basis for myocardial infarction and ischemic cardiomyopathy. Progression of heart failure after myocardial infarction is associated with cardiac remodeling, which has been studied by means of coronary ligation in mice. However, this ligation model requires excellent techniques. Recently, a new murine model, HypoE mouse was reported to exhibit atherogenic Paigen diet-induced coronary atherosclerosis and myocardial infarction; however, the HypoE mice died too early to make possible investigation of cardiac remodeling. Therefore, we aimed to modify the HypoE mouse model to establish a novel model for ischemic cardiomyopathy caused by atherosclerotic lesions, which the ligation model does not exhibit. METHODS AND RESULTS: In our study, the sustained Paigen diet for the HypoE mice was shortened to 7 or 10 days, allowing the mice to survive longer. The 7-day Paigen diet intervention starting when the mice were 8 weeks old was adequate to permit the mice to survive myocardial infarction. Our murine model, called the "modified HypoE mouse", was maintained until 8 weeks, with a median survival period of 36 days, after the dietary intervention (male, nâ=â222). Echocardiography demonstrated that the fractional shortening 2 weeks after the Paigen diet (nâ=â14) significantly decreased compared with that just before the Paigen diet (nâ=â6) (31.4±11.9% vs. 54.4±2.6%, respectively, P<0.01). Coronary angiography revealed multiple diffuse lesions. Cardiac remodeling and fibrosis were identified by serial analyses of cardiac morphological features and mRNA expression levels in tissue factors such as MMP-2, MMP-9, TIMP-1, collagen-1, and TGF-ß. CONCLUSION: Modified HypoE mice are a suitable model for ischemic cardiomyopathy with multiple diffuse lesions and may be considered as a novel and convenient model for investigations of cardiac remodeling on a highly atherogenic background.
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Enfermedad de la Arteria Coronaria/patología , Isquemia Miocárdica/patología , Animales , Aterosclerosis/patología , Colesterol/sangre , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/diagnóstico , Dieta Aterogénica , Modelos Animales de Enfermedad , Femenino , Fibrosis , Insuficiencia Cardíaca/etiología , Masculino , Ratones , Isquemia Miocárdica/etiología , Isquemia Miocárdica/mortalidad , Remodelación Ventricular/genéticaRESUMEN
AIMS: Progranulin (PGRN) is a multifunctional protein known to be involved in inflammation. However, the relation between PGRN and atherosclerosis remains elusive. The aim of this study was to define the role of PGRN in the development of atherosclerosis. METHODS AND RESULTS: First, we checked the expression levels of PGRN in human atherosclerotic plaques. Immunohistochemical analysis showed that PGRN is strongly expressed in foam cells of atherosclerotic plaques. We also found that PGRN is expressed more abundantly in macrophages than in the smooth muscle cells of atherosclerotic lesions in ApoE(-/-) mice fed a high-fat diet for 12 weeks. Next, PGRN(-/-)ApoE(-/-) mice were generated to investigate the effect of PGRN on the development of atherosclerosis. PGRN(-/-)ApoE(-/-) mice exhibited severe atherosclerotic lesions compared with PGRN(+/+)ApoE(-/-) mice, despite their anti-atherogenic lipid profile. These results are partly due to enhanced expression of inflammatory cytokines, adhesion molecules, and decreased expression of endothelial nitric oxide synthase. In addition, lack of PGRN leads to accumulate excessive cholesterol in the macrophages and alter HDL-associated proteins. CONCLUSION: PGRN seems to be involved in the pathogenesis of atherosclerosis, possibly by various anti-atherogenic effects, including modulation of local and/or systemic inflammation.
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Apolipoproteínas E/fisiología , Aterosclerosis/etiología , Péptidos y Proteínas de Señalización Intercelular/fisiología , Animales , Aorta/patología , Células Cultivadas , Colesterol/metabolismo , Humanos , Inflamación/etiología , Péptidos y Proteínas de Señalización Intercelular/análisis , Macrófagos/química , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , ProgranulinasRESUMEN
AIM: The clustering of dyslipidemia, impaired glucose tolerance and hypertension increases the morbidity and mortality from cardiovascular events. A class B scavenger receptor, CD36, is a receptor for oxidized LDL and a transporter of long-chain fatty acids. Because of the impaired uptake of oxidized LDL in CD36-deficient macrophages and from the results of CD36 knockout mice, CD36 deficiency (CD36-D) was supposed to be associated with reduced risks for coronary artery disease (CAD); however, CD36-D patients are often accompanied by a clustering of coronary risk factors. The current study aimed to investigate the morbidity and severity of cardiovascular diseases in CD36-D patients. METHODS: By screening for CD36 antigen on platelets and monocytes using FACS or the absent myocardial accumulation of 123I-BMIPP by scintigraphy, 40 patients with type I CD36-D were collected, the morbidity of CAD and their features of atherosclerotic cardiovascular diseases were observed. Screening for CD36-D in both CAD patients (n = 319) and healthy subjects (n = 1,239) were underwent. RESULTS: The morbidity of CAD was significantly higher in CD36-D patients than in the general population; 50% of patients (20 out of 40) had CAD identified by BMIPP scintigraphy and 37.5% (3 out of 8) by FACS screening, respectively. Three representative CD36-D cases demonstrated severe CAD and atherosclerosis. The frequency of CD36-D was three times higher in CAD patients than in healthy subjects (0.9% vs 0.3%, p < 0.0001). CONCLUSION: The morbidity of CAD is significantly higher in CD36-D patients suffering from severe atherosclerosis, implying that the status of CD36-D might be atherogenic.
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Aterosclerosis/etiología , Aterosclerosis/metabolismo , Antígenos CD36/deficiencia , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/metabolismo , Anciano , Plaquetas/metabolismo , Estudios de Casos y Controles , Femenino , Citometría de Flujo , Humanos , Masculino , Monocitos/metabolismo , Factores de RiesgoRESUMEN
AIM: High density lipoprotein (HDL) has multi-antiatherogenic effects such as antioxidation and anti-inflammation, in addition to being a key mediator of reverse cholesterol transport. Probucol, known as a lipid lowering drug, is also a potent antioxidant, but it decreases serum HDL cholesterol (HDL-C) levels. To elucidate the effect of probucol on antioxidant properties of HDL, we investigated the function of HDL derived from patients with heterozygous familial hypercholesterolemia (FH) who have been treated with probucol. METHODS AND RESULTS: Probucol-treated FH patients (n=21) showed a 47% reduction of serum HDL-C levels compared to probucol-untreated FH patients (n=15). High performance liquid chromatography (HPLC) analysis revealed that probucol diminished HDL particle size compared to the non-treated group. Antioxidant capacity of HDL was evaluated by its effect to protect reference LDL from oxidation induced in the presence of an oxidizing agent, AAPH. The HDL derived from the probucol-treated group demonstrated a significantly prolonged time to start oxidation by 112%, decreased the maximum oxidation rate by 14%, and lowered the maximum concentration of conjugated dienes formation by 15%. Furthermore, HDL-associated paraoxonase 1 (PON1) activity, but not platelet-activating factor acetyl-hydrolase (PAF-AH) correlated with these measurements of HDL anti-oxidative activity. Treatment with probucol in vitro and inhibition of PON1 activity demonstrated that probucol in HDL particles and increase of PON1 activity might largely contribute to the increase of HDL anti-oxidative activity. CONCLUSION: Probucol reduced HDL-C levels and HDL particle size in patients with heterozygous FH, while it concomitantly enhanced HDL anti-oxidative properties, possibly through increasing PON1 activity.
Asunto(s)
Anticolesterolemiantes/uso terapéutico , Antioxidantes/farmacología , Arildialquilfosfatasa/metabolismo , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Hiperlipoproteinemia Tipo II/metabolismo , Lipoproteínas HDL/efectos de los fármacos , Lipoproteínas HDL/metabolismo , Probucol/uso terapéutico , Femenino , Heterocigoto , Humanos , Hiperlipoproteinemia Tipo II/genética , Lipoproteínas HDL/química , Masculino , Persona de Mediana Edad , Oxidación-ReducciónRESUMEN
AIM: Remnant lipoproteins are atherogenic and are accumulated in patients with type III hyperlipidemia (HL). Although type III HL is diagnosed by phenotyping apolipoprotein (apo) E, this procedure is time-consuming and inconvenient for routine clinical use. Clinical indices for screening type III HL in untreated HL patients have been proposed; however, in clinical settings, HL patients are promptly treated with lipid-lowering agents without diagnosing the underlying cause. We investigated whether existing clinical indices for screening type III HL as well as the apo B-48/triglyceride (TG) ratio, which was suggested to be related to the accumulation of small chylomicron (CM) remnants, are useful after the initiation of lipid-lowering therapies. METHODS: In 25 normolipidemic subjects and 191 treated HL patients (type I, n =6; IIa, 62; IIb, 66; III, 12; IV, 22; and V, 23) from Osaka University Hospital and related hospitals, fasting low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), TG, and apolipoproteins were measured and clinical indices were evaluated statistically. RESULTS: Apo B-48 levels were significantly higher in patients with type I, III, and V HL, and TG levels were significantly higher in patients with type I and V HL. The apo B-48/TG ratio was significantly higher only in patients with type III HL compared with other types of HL (p<0.001), and was statistically significant among the other clinical indices (AUC-ROC value, 0.895; cut-off value, 0.110). CONCLUSION: The apo B-48/TG ratio is a novel and useful marker for detecting type III HL even after the initiation of lipid-lowering interventions.
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Apolipoproteína B-48/sangre , Hiperlipidemias/diagnóstico , Hipolipemiantes/uso terapéutico , Lipoproteínas/sangre , Triglicéridos/sangre , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Hiperlipidemias/sangre , Hiperlipidemias/tratamiento farmacológico , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
OBJECTIVE: Adiponectin (APN) improves insulin resistance and prevents atherosclerosis, and HDL removes cholesterol from atherosclerotic lesions. We have demonstrated that serum HDL-cholesterol (HDL-C) and APN concentrations are positively correlated and that APN accelerates reverse cholesterol transport (RCT) by increasing HDL synthesis in the liver and cholesterol efflux from macrophages. We previously reported that APN reduced apolipoprotein (apo) B secretion from the liver. It is well-known that insulin resistance influences the lipoprotein profile. In this study, we investigated the clinical significance of APN levels and insulin resistance in lipoprotein metabolism. MATERIAL/METHOD: We investigated the correlation between serum APN concentration, HOMA-R, the lipid concentrations and lipoprotein particle size by high-performance liquid chromatography (HPLC) in 245 Japanese men during an annual health checkup. RESULTS: Serum APN level was positively correlated with the cholesterol content in large LDL and HDL particles, but inversely correlated with the cholesterol content in large VLDL and small LDL particles. HOMA-R was negatively correlated with the cholesterol content in large LDL and HDL particles and positively correlated with the cholesterol content in large VLDL and small LDL particles. By multivariate analysis, APN was correlated with the particle size of LDL-C and HDL-C independently of age, BMI and HOMA-R. CONCLUSIONS: APN may be associated with the formation of both HDL and LDL particles, reflecting the enhancement of RCT and the improvement in TG-rich lipoprotein metabolism and insulin resistance.
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Adiponectina/sangre , Pueblo Asiatico/estadística & datos numéricos , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Cromatografía Líquida de Alta Presión , Resistencia a la Insulina , Tamaño de la Partícula , Adulto , Anciano , Apolipoproteínas/sangre , Biomarcadores/sangre , Glucemia/metabolismo , Grosor Intima-Media Carotídeo , VLDL-Colesterol/sangre , Estudios Transversales , Humanos , Japón , Masculino , Persona de Mediana Edad , Análisis MultivarianteRESUMEN
BACKGROUND: Apolipoprotein B-48 (apoB-48) is a constituent of chylomicron remnants synthesized in the small intestines. The serum concentration of apoB-48 at fasting has been reported to be a marker of postprandial hyperlipidemia, a presumed risk factor for atherosclerosis. METHODS: We evaluated the basal performance of a recently developed chemiluminescent enzyme immunoassay (CLEIA). We also examined the correlations between serum apoB-48 concentrations and other lipid concentrations or life style patterns, including smoking and drinking. We analyzed the data of 273 clinical samples by multiple regression analysis to examine the influence of other serum lipid values, age, sex, smoking, drinking status and BMI on serum apoB-48 values. RESULTS: Within-run and between-run precision was obtained with 1.7-2.7% and 1.2-7.3%, respectively. The correlativity of enzyme-linked immunosorbent assay was correlation coefficient r=0.953, and regression y=1.02×-1.59. Serum apoB-48 concentrations were higher in males than in females, and were correlated with the status of smoking as well as with remnant-like particle-cholesterol (RLP-C) concentrations. Patients with the metabolic syndrome showed higher values of serum apoB-48 compared with control subjects. CONCLUSION: Serum apoB-48 measurement by CLEIA was satisfactory for clinical use to assess abnormalities in the chylomicron remnant metabolism.
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Apolipoproteína B-48/sangre , Quilomicrones/metabolismo , Técnicas para Inmunoenzimas/métodos , Femenino , Humanos , Límite de Detección , Luminiscencia , Masculino , Síndrome Metabólico/sangre , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: Postprandial hyperlipidemia (PPHL) is an independent risk factor for coronary heart disease (CHD) which is based on the accumulation of chylomicrons (CM) and CM remnants containing apolipoprotein B-48 (apoB-48). Since atherosclerotic cardiovascular diseases are frequently observed even in subjects with normal serum triglyceride (TG) level, the correlation between fasting apoB-48 containing lipoproteins and carotid intima-media thickness (IMT) was analyzed in subjects with normal TG levels. METHODS: From subjects who took their annual health check at the Osaka Police Hospital (n=245, male), one-hundred and sixty-four male subjects were selected to take part in this study; the excluding factors were: systolic blood pressure ≥ 140 mmHg, intake of antihypertensive or antihyperlipidemic drugs, or age >65 years. The association between biochemical markers and IMT was analyzed and independent predictors of max-IMT were determined by multiple regression analysis in all subjects and in groups N-1 (TG<100mg/dl, n=58), N-2 (100 ≤ TG<150 mg/dl, n=53) and H (150 ≤ TG mg/dl, n=53), respectively. RESULTS: Fasting total cholesterol, LDL-cholesterol, HDL-cholesterol, apoB-100 and lnRemL-C (remnant lipoprotein-cholesterol) levels were not correlated with max-IMT, but lnTG and lnapoB-48 were significantly correlated with max-IMT in all subjects. LnapoB-48 and apoB-48/TG ratio were significantly correlated with max-IMT in group N-2. By multiple regression analysis, age and lnapoB-48 were independent variables associated with max-IMT in group N-2. CONCLUSION: Serum apoB-48 level might be a good marker for the detection of early atherosclerosis in middle-aged subjects with normal-range levels of blood pressure and TG.
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Apolipoproteína B-48/sangre , Grosor Intima-Media Carotídeo , Triglicéridos/sangre , Aterosclerosis/sangre , Biomarcadores , Presión Sanguínea , Colesterol/sangre , Quilomicrones/sangre , Humanos , Lipoproteínas/sangre , Masculino , Persona de Mediana Edad , Tamaño de la Partícula , Periodo Posprandial , Análisis de Regresión , Factores de RiesgoRESUMEN
AIM: Postprandial hyperlipidemia (PH) is thought to be caused by the impaired postprandial metabolism of triglycerides (TG)-rich lipoproteins in both endogenous and exogenous pathways; however, there is no consensus. It is difficult to estimate the presence of PH without performing a time-consuming oral fat loading (OFL) test, so postprandial lipoprotein metabolism was analyzed by measuring the postprandial levels of apolipoprotein (apo) B-48 and apo B-100, and the correlation between postprandial TG increase and fasting apoB-48 levels was assessed to establish a good marker of PH without performing an OFL test. METHODS: Ten male normolipidemic subjects were loaded with a high-fat (HF, 1045 kcal) or standard (ST, 566 kcal) meal, and the lipids, apolipoproteins and lipoprotein profiles were analyzed after each meal. RESULTS: TG, apo B-48, remnant-like particles (RLP)-cholesterol and RLP-TG levels were increased and their levels were significantly higher after intake of the HF meal than the ST meal; however, there was no postprandial increase in apo B-100 and LDL-C levels. Postprandial increases in TG levels of CM, VLDL, LDL and HDL were significantly higher after intake of the HF meal than the ST meal. Fasting apo B-48 levels were strongly correlated with the incremental area under the curve of TG after intake of the HF meal, but not the ST meal. CONCLUSION: Postprandial TG increase was mainly due to increased CM and CM-R, but not VLDL. Measurement of fasting serum apo B-48 may be a simple and useful method for assessment of the existence of PH.
Asunto(s)
Apolipoproteína B-48/sangre , Biomarcadores/sangre , Ayuno , Hiperlipidemias/sangre , Periodo Posprandial , Humanos , MasculinoRESUMEN
AIM: Metabolic syndrome (MetS) and postprandial hypertriglyceridemia (PHTG) are closely related and both are associated with coronary heart disease. We have demonstrated that CD36 deficiency is prevalent in the genetic background of MetS and is accompanied by PHTG concomitantly with an increase in remnants and a decrease in high density lipoprotein cholesterol. These findings make CD36 knockout mice (CD36KO) an interesting model for evaluating PHTG in MetS. Fenofibrate was reported to reduce fasting and postprandial triglyceride (TG) levels in hypertriglyceridemic subjects with MetS. To define its mechanism, we investigated the effect of fenofibrate on PHTG in CD36KO. METHODS: Wild-type (WT) and CD36KO mice were fed chow diet and fenofibrate for two weeks. TG concentrations and lipoprotein profiles were assessed during fasting and in the postprandial state in plasma; intestinal mucosa and lymph were collected after oral fat loading for both treatment groups. RESULTS: Fenofibrate treatment markedly suppressed the postprandial TG response in CD36KO along with decreased apoB-48 levels in plasma. HPLC analysis depicted the decrease of TG content in chylomicrons (CM) and CM remnant-sized lipoproteins contributed to this suppression, suggesting that CM and CM remnant production in the intestines might be attenuated by fenofibrate. ApoB-48 and TG levels in intestinal lymph were markedly reduced after treatment. Intestinal mRNA expression of apoB was also reduced in the postprandial state after fenofibrate administration without affecting any other genes related to CM assembly and production. CONCLUSION: Fenofibrate reduces PHTG in CD36KO partially through attenuating intestinal CM production.
Asunto(s)
Antígenos CD36/deficiencia , Fenofibrato/farmacología , Hipertrigliceridemia/tratamiento farmacológico , Animales , Quilomicrones/biosíntesis , Hipertrigliceridemia/prevención & control , Mucosa Intestinal/metabolismo , Síndrome Metabólico , Ratones , Ratones Noqueados , Periodo PosprandialRESUMEN
AIM: Postprandial hypertriglyceridemia (PHTG) has been shown repeatedly to be associated with metabolic syndrome and atherosclerotic cardiovascular diseases. We have recently reported that ezetimibe inhibits PHTG in patients with type IIb hyperlipidemia. Ezetimibe was also reported to atten-uate PHTG in combination with low-dose statins in patients with obesity or metabolic syndrome. We reported CD36-deficient (CD36KO) mice as a new model for PHTG, in which the synthesis of chylomicron (CM) in the small intestines is enhanced. In the current study, we investigated the effect of ezetimibe on PHTG in this mouse model of metabolic syndrome. METHODS: Wild-type (WT) mice fed a western diet, and CD36KO mice fed a normal chow diet, respectively, were treated for 3 weeks with and without ezetimibe, followed by an evaluation of triglyceride (TG) concentrations by enzymatic method and by high performance liquid chromatogra-phy (HPLC) as well as those of and apolipoprotein (Apo) B-48 in plasma and intestinal lymph after oral fat loading with olive oil. Intestinal mucosa was also harvested to evaluate the transcriptional regulation of the genes involved in the intestinal production of ApoB-containing lipoproteins. RESULTS: Ezetimibe dramatically reduced PHTG in both WT and CD36KO mice. HPLC analysis of plasma showed that the decrease in TG content in CM and CM remnants-sized particles contributed to this suppression, suggesting that CM production in the small intestines might be reduced after ezetimibe treatment. Intestinal lymph was collected after oral fat loading in ezetimibe-treated and non-treated mice. Both TG content and ApoB-48 mass were decreased in ezetimibe-treated mice. The quantitative RT-PCR of intestinal mucosa showed down-regulation of the mRNA expression of FATP4 and ApoB in both groups along with FABP2, DGAT1, DGAT2 and SCD1 in WT mice at postprandial state after ezetimibe treatment. CONCLUSION: Ezetimibe alone reduces PHTG by blocking both the absorption of cholesterol and the intracellular trafficking and metabolism of long-chain fatty acids in enterocytes, resulting in the reduction of the formation of ApoB-48 which is necessary for the ApoB48-containing lipoprotein production in the small intestines.
Asunto(s)
Anticolesterolemiantes/farmacología , Azetidinas/farmacología , Hipertrigliceridemia/tratamiento farmacológico , Animales , Apolipoproteína B-48/metabolismo , Secuencia de Bases , Antígenos CD36/deficiencia , Antígenos CD36/genética , Quilomicrones/sangre , Cartilla de ADN/genética , Modelos Animales de Enfermedad , Ezetimiba , Proteínas de Transporte de Ácidos Grasos/genética , Proteínas de Unión a Ácidos Grasos/genética , Hipertrigliceridemia/sangre , Hipertrigliceridemia/genética , Hipertrigliceridemia/fisiopatología , Absorción Intestinal/efectos de los fármacos , Lipoproteínas VLDL/sangre , Linfa/metabolismo , Masculino , Síndrome Metabólico/sangre , Síndrome Metabólico/tratamiento farmacológico , Síndrome Metabólico/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Periodo Posprandial , ARN Mensajero/genética , ARN Mensajero/metabolismo , Triglicéridos/sangre , Triglicéridos/metabolismo , Trioleína/metabolismoRESUMEN
BACKGROUND: In routine clinical laboratory testing and numerous epidemiological studies, LDL-cholesterol (LDL-C) has been estimated commonly using the Friedewald equation. We investigated the relationship between the Friedewald equation and 4 homogeneous assays for LDL-C. METHODS: LDL-C was determined by 4 homogeneous assays [liquid selective detergent method: LDL-C (L), selective solubilization method: LDL-C (S), elimination method: LDL-C (E), and enzyme selective protecting method: LDL-C (P)]. Samples with discrepancies between the Friedewald equation and the 4 homogeneous assays for LDL-C were subjected to polyacrylamide gel electrophoresis and the beta-quantification method. RESULTS: The correlations between the Friedewald equation and the 4 homogeneous LDL-C assays were as follows: LDL-C (L) (r=0.962), LDL-C (S) (r=0.986), LDL-C (E) (r=0.946) and LDL-C (P) (r=0.963). Discrepancies were observed in sera from type III hyperlipoproteinemia patients and in sera containing large amounts of midband and small dense LDL on polyacrylamide gel electrophoresis. LDL-C (S) was most strongly correlated with the beta-quantification method even in sera from patients with type III hyperlipoproteinemia. CONCLUSIONS: Of the 4 homogeneous assays for LDL-C, LDL-C (S) exhibited the closest correlation with the Friedewald equation and the beta-quantification method, thus reflecting the current clinical databases for coronary heart disease.