RESUMEN
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
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
AIM: Homogeneous assay reagents for the determination of low-density lipoprotein cholesterol (LDL-C) have been available from several manufacturers. However, there has been considerable controversy due to uncertainty regarding their reactivity with intermediate-density lipoprotein (IDL), which is detected at an especially high frequency in patients with type III hyperlipemia. In this study, we examined the reactivity of a homogeneous assay, Cholestest LDL (R) (CT-LDL), with hyperlipemic sera that were classified according to the WHO system. METHODS: Sera from 6 normolipidemic and 22 hyperlipidemic patients classified according to the WHO system were used for this study. All serum specimens were fractionated by the ultracentrifugation method of Hatch and Lees, and subjected to lipid and protein measurements. RESULTS: The percent bias of values measured by CT-LDL relative to those determined by the ultracentrifugation method was calculated and compared to the lipid/protein ratios of each lipoprotein fraction. Consequently, the coefficient of correlation between the bias and the Triglyceride/Total cholesterol (TG/TC) ratio in the IDL fraction was 0.742. There were also correlations with the TG/TC ratio and the apo-lipoprotein B/Total Cholesterol ratio in the LDL fraction and in the LDL+IDL fraction, respectively. CONCLUSION: Further testing will be required in order to know more about the clinical condition of hyperlipidemic patients, since CT-LDL may react differently with some beta lipoproteins having a diverse lipid/protein composition compared to those in normolipidemic specimens.
Asunto(s)
Bioensayo/normas , LDL-Colesterol/sangre , Hiperlipidemias/sangre , Hiperlipidemias/diagnóstico , Colesterol/sangre , Humanos , Lipoproteínas/sangre , Reproducibilidad de los Resultados , Triglicéridos/sangre , UltracentrifugaciónRESUMEN
Plasma high density lipoprotein (HDL)-cholesterol levels are inversely correlated with the incidence of cardiovascular diseases. HDL is mainly assembled in the liver through the ATP-binding cassette transporter (ABCA1) pathway. In humans, plasma HDL-cholesterol levels are positively correlated with plasma adiponectin (APN) concentrations. Recently, we reported that APN enhanced apolipoprotein A-I (apoA-I) secretion and ABCA1 expression in HepG2 cells. In the present study, we investigated HDL assembly in APN-knockout (KO) mice. The apoA-I protein levels in plasma and liver were reduced in APN-KO mice compared with wild-type-mice. The ABCA1 expression in liver was also decreased in APN-KO mice. APN deficiency might cause the impaired HDL assembly by decreasing ABCA1 expression and apoA-I synthesis in the liver.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/metabolismo , Adiponectina/fisiología , Apolipoproteína A-I/metabolismo , Lipoproteínas HDL/metabolismo , Hígado/metabolismo , Transportador 1 de Casete de Unión a ATP , Transportadoras de Casetes de Unión a ATP/genética , Adiponectina/genética , Animales , Apolipoproteína A-I/sangre , Lipoproteínas HDL/sangre , Lipoproteínas VLDL/sangre , Ratones , Ratones NoqueadosRESUMEN
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.
Asunto(s)
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.
Asunto(s)
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.
Asunto(s)
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.
Asunto(s)
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.
Asunto(s)
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.
Asunto(s)
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
Numerous large-scale clinical studies have revealed that the low-density lipoprotein cholesterol (LDL-C)-lowering effect of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) prevents coronary heart disease (CHD). Statins have not only LDL-C-lowering effects but also high-density lipoprotein cholesterol (HDL-C)-elevating effects, which differ among statins. In this article, we discuss the molecular mechanisms of HDL-C elevation by statins and its effect on HDL functions. We summarize the reports to date on the effects of statins on various proteins, enzymes and receptors involved in reverse cholesterol transport (RCT), which is one of the protective systems against atherosclerosis. Since statins increase the synthesis of apolipoprotein A-I (ApoA-I) and HDL neogenesis in the liver, the HDL-C-increasing effect of statins may reflect RCT activation. Moreover, HDL has pleiotropic effects, including anti-inflammatory and anti-oxidative effects, as well as RCT. In the future, it may be necessary to assess the functions of HDL elevated by statins, and select statins based on differences in their effects in clinical practice.
Asunto(s)
HDL-Colesterol/sangre , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , HDL-Colesterol/fisiología , HumanosRESUMEN
Sitosterolemia is a rare, autosomal recessive inherited sterol storage disease associated with high tissue and serum plant sterol concentrations, caused by mutations in the adenosine triphosphate-bind-ing cassette (ABC) transporter ABCG5 or ABCG8 genes. Markedly increased serum concentration of plant sterols. such as sitosterol and campesterol, cause premature atherosclerosis and massive xanthomas. Hitherto known treatments for sitosterolemia, including a low-sterol diet, bile-salt binding resins, ileal bypass surgery and low density lipoprotein (LDL) apheresis have not yielded sufficient reduction of serum plant sterol levels and many patients show a sustained elevation of plant sterol levels, subsequently developing premature atherosclerotic cardiovascular diseases. Ezetimibe, an inhibitor of intestinal cholesterol absorption through its binding to Niemann-Pick C1-like 1 (NPC1L1), has been widely used for decreasing serum LDL-cholesterol levels in patients with hypercholesterolemia. Ezetimibe also reduces the gastrointestinal absorption of plant sterols, thereby also lowering the serum concentrations of plant sterols. This pharmacological property of ezetimibe shows its potential as a novel effective therapy for sitosterolemia. In the current review, we discuss the current therapy for patients with sitosterolemia and present two Japanese adolescent patients with this disease, one of whom underwent percutaneous coronary intervention for accelerated coronary atherosclerosis. Ezetimibe administration in addition to conventional drug therapy successfully reduced serum sitosterol levels by 51.3% and 48.9%, respectively, in the two patients, demonstrating ezetimibe as a novel and potent treatment agent for sitosterolemia that could work additively with conventional drug therapy.
Asunto(s)
Anticolesterolemiantes/uso terapéutico , Azetidinas/uso terapéutico , Errores Innatos del Metabolismo Lipídico/tratamiento farmacológico , Errores Innatos del Metabolismo Lipídico/metabolismo , Fitosteroles/metabolismo , Sitoesteroles/sangre , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 5 , Transportadoras de Casetes de Unión a ATP/genética , Adolescente , Ácidos y Sales Biliares/metabolismo , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/prevención & control , Ezetimiba , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Íleon/cirugía , Resinas de Intercambio Iónico/uso terapéutico , Errores Innatos del Metabolismo Lipídico/complicaciones , Errores Innatos del Metabolismo Lipídico/terapia , Lipoproteínas/genética , Masculino , Modelos Biológicos , Mutación Missense , Sitoesteroles/uso terapéutico , Adulto JovenRESUMEN
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.
Asunto(s)
Técnicas de Laboratorio Clínico/normas , Lipoproteínas/sangre , Adulto , Anciano , LDL-Colesterol/sangre , Enfermedad Coronaria/sangre , Diabetes Mellitus Tipo 2/sangre , Humanos , Hiperlipoproteinemia Tipo III/sangre , Lipoproteínas IDL/sangre , Lipoproteínas LDL/sangre , Persona de Mediana Edad , Modelos TeóricosRESUMEN
The clustering of risk factors including dyslipidemia, hyperglycemia, and hypertension is highly atherogenic along with the excess of remnants from triglyceride (TG)-rich lipoproteins. CD36 is involved in the uptake of long-chain fatty acids (LCFAs) in muscles and small intestines. Patients with CD36 deficiency (CD36-D) have postprandial hypertriglyceridemia, insulin resistance, and hypertension. To investigate the underlying mechanism of postprandial hypertriglyceridemia in CD36-D, we analyzed lipoprotein profiles of CD36-D patients and CD36-knockout (CD36-KO) mice after oral fat loading (OFL). In CD36-D patients, plasma triglycerides, apolipoprotein B-48 (apoB-48), free fatty acids (FFAs), and free glycerol levels were much higher after OFL than those of controls, along with increases in chylomicron (CM) remnants and small dense low-density lipoprotein (sdLDL) particles. In CD36-KO mice, lipoproteins smaller than CM in size in plasma and intestinal lymph were markedly increased after OFL and mRNA levels of genes involved in FFA biosynthesis, such as fatty acid binding protein (FABP)-1 and FAS, were significantly increased. These results suggest that CD36-D might increase atherosclerotic risk by enhancing plasma level of CM remnants due to the increased synthesis of lipoproteins smaller than CM in size in the intestine.
Asunto(s)
Antígenos CD36/deficiencia , Quilomicrones/metabolismo , Periodo Posprandial , Anciano , Animales , Antígenos CD36/genética , Quilomicrones/química , Grasas de la Dieta , Ayuno , Femenino , Regulación de la Expresión Génica , Humanos , Mucosa Intestinal/química , Mucosa Intestinal/citología , Mucosa Intestinal/fisiología , Metabolismo de los Lípidos , Lipoproteínas/química , Lipoproteínas/metabolismo , Masculino , Síndrome Metabólico/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Tamaño de la PartículaRESUMEN
AIM: Tangier disease (TD), caused by deficiency of ATP-binding cassette transporter A1, is characterized by the absence of high density lipoprotein and the accumulation of cholesteryl esters in many tissues. Recently, it has been reported that ABCA1 is expressed in pancreatic beta cells and mice with specific inactivation of ABCA1 in beta cells showed markedly impaired insulin secretion, suggesting that ABCA1 deficiency may be involved in diabetes. The aim of the current study was to confirm these findings by the oral glucose tolerance test (OGTT) in human subjects with ABCA1 deficiency. METHODS AND RESULTS: Four Japanese patients with TD were investigated by OGTT with 75 g glucose. In all TD patients, the plasma glucose concentration after 30 min progressively increased, indicating a type 2 diabetic pattern; however the plasma insulin concentration did not respond well to glucose increase. The calculated insulinogenic index was significantly lower in TD patients than in non-diabetic controls (0.055+/-0.034 vs 0.775+/-0.538, mean+/-SD, p<0.05, respectively). CONCLUSIONS: Although the number of TD patients was very small in the current study, these observations indicated a possible mechanism that glucose-stimulated insulin secretion might be impaired in human TD patients with ABCA1 mutations. Taken together, ABCA1 may be involved in insulin secretion from pancreatic beta-cells.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Insulina/metabolismo , Mutación , Enfermedad de Tangier/genética , Transportador 1 de Casete de Unión a ATP , Anciano , Glucemia , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Glucosa/farmacología , Prueba de Tolerancia a la Glucosa , Humanos , Secreción de Insulina , Japón , Masculino , Persona de Mediana Edad , Enfermedad de Tangier/sangreRESUMEN
Tangier disease (TD) is characterized by a deficiency of high density lipoprotein (HDL) in plasma and patients with TD have an increased risk for coronary artery disease (CAD). Recently, we reported that fibroblasts from TD exhibited large and flattened morphology, which is often observed in senescent cells. On the other hand, data have accumulated to show the relationship between cellular senescence and development of atherosclerotic CAD. The aim of the present study was to investigate whether TD fibroblasts exhibited cellular senescence. The proliferation of TD fibroblasts was gradually decreased at population doubling level (PDL) approximately 10 compared with control cells. TD cells practically ceased proliferation at PDL approximately 30. DNA synthesis was markedly decreased in TD fibroblasts. TD cells exhibited a higher positive rate for senescence-associated beta-galactosidase (SA-beta-gal), which is one of the biomarkers of cellular senescence in vitro. These data showed that TD cells reached cellular senescence at an earlier PDL compared with controls. Although, there was no difference in the telomere length of fibroblasts between TD and controls at the earlier passage (PDL 6), the telomere length of TD cells was shorter than that of controls at the late passage (PDL 25). Taken together, the current study demonstrates that the late-passaged TD fibroblasts showed senescent phenotype in vitro, which might be related to the increased cardiovascular manifestations in TD patients.