RESUMEN
Cholesteryl ester transfer protein (CETP) increases the atherosclerosis risk by lowering HDL-cholesterol levels. It also exhibits tissue-specific effects independent of HDL. However, sexual dimorphism of CETP effects remains largely unexplored. Here, we hypothesized that CETP impacts the perivascular adipose tissue (PVAT) phenotype and function in a sex-specific manner. PVAT function, gene and protein expression, and morphology were examined in male and female transgenic mice expressing human or simian CETP and their non-transgenic counterparts (NTg). PVAT exerted its anticontractile effect in aortas from NTg males, NTg females, and CETP females, but not in CETP males. CETP male PVAT had reduced NO levels, decreased eNOS and phospho-eNOS levels, oxidative stress, increased NOX1 and 2, and decreased SOD2 and 3 expressions. In contrast, CETP-expressing female PVAT displayed increased NO and phospho-eNOS levels with unchanged NOX expression. NOX inhibition and the antioxidant tempol restored PVAT anticontractile function in CETP males. Ex vivo estrogen treatment also restored PVAT function in CETP males. Moreover, CETP males, but not female PVAT, show increased inflammatory markers. PVAT lipid content increased in CETP males but decreased in CETP females, while PVAT cholesterol content increased in CETP females. CETP male PVAT exhibited elevated leptin and reduced Prdm16 (brown adipocyte marker) expression. These findings highlight CETP sex-specific impact on PVAT. In males, CETP impaired PVAT anticontractile function, accompanied by oxidative stress, inflammation, and whitening. Conversely, in females, CETP expression increased NO levels, induced an anti-inflammatory phenotype, and preserved the anticontractile function. This study reveals sex-specific vascular dysfunction mediated by CETP.
Asunto(s)
Tejido Adiposo , Proteínas de Transferencia de Ésteres de Colesterol , Ratones Transgénicos , Estrés Oxidativo , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Proteínas de Transferencia de Ésteres de Colesterol/genética , Animales , Masculino , Femenino , Ratones , Tejido Adiposo/metabolismo , Humanos , Caracteres Sexuales , Óxido Nítrico/metabolismoRESUMEN
Beta cell destruction in type 1 diabetes (TID) is associated with cellular oxidative stress and mitochondrial pathway of cell death. The aim of this study was to determine whether oxidative stress and mitochondrial dysfunction are present in T1D model (non-obese diabetic mouse, NOD) and if they are related to the stages of disease development. NOD mice were studied at three stages: non-diabetic, pre-diabetic, and diabetic and compared with age-matched Balb/c mice. Mitochondria respiration rates measured at phosphorylating and resting states in liver and soleus biopsies and in isolated liver mitochondria were similar in NOD and Balb/c mice at the three disease stages. However, NOD liver mitochondria were more susceptible to calcium-induced mitochondrial permeability transition as determined by cyclosporine-A-sensitive swelling and by decreased calcium retention capacity in all three stages of diabetes development. Mitochondria H2O2 production rate was higher in non-diabetic, but unaltered in pre-diabetic and diabetic NOD mice. The global cell reactive oxygen species (ROS), but not specific mitochondria ROS production, was significantly increased in NOD lymphomononuclear and stem cells in all disease stages. In addition, marked elevated rates of 2',7'-dichlorodihydrofluorescein (H2DCF) oxidation were observed in pancreatic islets from non-diabetic NOD mice. Using matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) and lipidomic approach, we identified oxidized lipid markers in NOD liver mitochondria for each disease stage, most of them being derivatives of diacylglycerols and phospholipids. These results suggest that the cellular oxidative stress precedes the establishment of diabetes and may be the cause of mitochondrial dysfunction that is involved in beta cell death.
Asunto(s)
Enfermedades Autoinmunes/metabolismo , Diabetes Mellitus Experimental/metabolismo , Mitocondrias/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Estrés Oxidativo , Animales , Femenino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos NOD , Poro de Transición de la Permeabilidad Mitocondrial , Permeabilidad , Especies Reactivas de Oxígeno/metabolismoRESUMEN
AIMS/HYPOTHESIS: Changes in cellular cholesterol level may contribute to beta cell dysfunction. Islets from low density lipoprotein receptor knockout (LDLR(-/-)) mice have higher cholesterol content and secrete less insulin than wild-type (WT) mice. Here, we investigated the association between cholesterol content, insulin secretion and Ca(2+) handling in these islets. METHODS: Isolated islets from both LDLR(-/-) and WT mice were used for measurements of insulin secretion (radioimmunoassay), cholesterol content (fluorimetric assay), cytosolic Ca(2+) level (fura-2AM) and SNARE protein expression (VAMP-2, SNAP-25 and syntaxin-1A). Cholesterol was depleted by incubating the islets with increasing concentrations (0-10mmol/l) of methyl-beta-cyclodextrin (MßCD). RESULTS: The first and second phases of glucose-stimulated insulin secretion (GSIS) were lower in LDLR(-/-) than in WT islets, paralleled by an impairment of Ca(2+) handling in the former. SNAP-25 and VAMP-2, but not syntaxin-1A, were reduced in LDLR(-/-) compared with WT islets. Removal of excess cholesterol from LDLR(-/-) islets normalized glucose- and tolbutamide-induced insulin release. Glucose-stimulated Ca(2+) handling was also normalized in cholesterol-depleted LDLR(-/-) islets. Cholesterol removal from WT islets by 0.1 and 1.0mmol/l MßCD impaired both GSIS and Ca(2+) handling. In addition, at 10mmol/l MßCD WT islet showed a loss of membrane integrity and higher DNA fragmentation. CONCLUSION: Abnormally high (LDLR(-/-) islets) or low cholesterol content (WT islets treated with MßCD) alters both GSIS and Ca(2+) handling. Normalization of cholesterol improves Ca(2+) handling and insulin secretion in LDLR(-/-) islets.
Asunto(s)
Calcio/metabolismo , Colesterol/metabolismo , Glucosa/farmacología , Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Animales , Western Blotting , Técnicas In Vitro , Secreción de Insulina , Islotes Pancreáticos/efectos de los fármacos , Ratones , Ratones Noqueados , Receptores de LDL/genética , Receptores de LDL/metabolismoRESUMEN
We determined the influence of fasting (FAST) and feeding (FED) on cholesteryl ester (CE) flow between high-density lipoproteins (HDL) and plasma apoB-lipoprotein and triacylglycerol (TG)-rich emulsions (EM) prepared with TG-fatty acids (FAs). TG-FAs of varying chain lengths and degrees of unsaturation were tested in the presence of a plasma fraction at d > 1.21 g/mL as the source of CE transfer protein. The transfer of CE from HDL to FED was greater than to FAST TG-rich acceptor lipoproteins, 18% and 14%, respectively. However, percent CE transfer from HDL to apoB-containing lipoproteins was similar for FED and FAST HDL. The CE transfer from HDL to EM depended on the EM TG-FA chain length. Furthermore, the chain length of the monounsaturated TG-containing EM showed a significant positive correlation of the CE transfer from HDL to EM (r = 0.81, P < 0.0001) and a negative correlation from EM to HDL (r = -041, P = 0.0088). Regarding the degree of EM TG-FAs unsaturation, among EMs containing C18, the CE transfer was lower from HDL to C18:2 compared to C18:1 and C18:3, 17.7%, 20.7%, and 20%, respectively. However, the CE transfer from EMs to HDL was higher to C18:2 than to C18:1 and C18:3, 83.7%, 51.2%, and 46.3%, respectively. Thus, the EM FA composition was found to be the rate-limiting factor regulating the transfer of CE from HDL. Consequently, the net transfer of CE between HDL and TG-rich particles depends on the specific arrangement of the TG acyl chains in the lipoprotein particle core.
Asunto(s)
Ésteres del Colesterol/metabolismo , Grasas de la Dieta/metabolismo , Ayuno/sangre , Lipoproteínas HDL/metabolismo , Triglicéridos/metabolismo , Proteínas Portadoras/sangre , Grasas de la Dieta/administración & dosificación , Humanos , MasculinoRESUMEN
We determined the influence of fasting (FAST) and feeding (FED) on cholesteryl ester (CE) flow between high-density lipoproteins (HDL) and plasma apoB-lipoprotein and triacylglycerol (TG)-rich emulsions (EM) prepared with TG-fatty acids (FAs). TG-FAs of varying chain lengths and degrees of unsaturation were tested in the presence of a plasma fraction at d > 1.21 g/mL as the source of CE transfer protein. The transfer of CE from HDL to FED was greater than to FAST TG-rich acceptor lipoproteins, 18 percent and 14 percent, respectively. However, percent CE transfer from HDL to apoB-containing lipoproteins was similar for FED and FAST HDL. The CE transfer from HDL to EM depended on the EM TG-FA chain length. Furthermore, the chain length of the monounsaturated TG-containing EM showed a significant positive correlation of the CE transfer from HDL to EM (r = 0.81, P < 0.0001) and a negative correlation from EM to HDL (r = -041, P = 0.0088). Regarding the degree of EM TG-FAs unsaturation, among EMs containing C18, the CE transfer was lower from HDL to C18:2 compared to C18:1 and C18:3, 17.7 percent, 20.7 percent, and 20 percent, respectively. However, the CE transfer from EMs to HDL was higher to C18:2 than to C18:1 and C18:3, 83.7 percent, 51.2 percent, and 46.3 percent, respectively. Thus, the EM FA composition was found to be the rate-limiting factor regulating the transfer of CE from HDL. Consequently, the net transfer of CE between HDL and TG-rich particles depends on the specific arrangement of the TG acyl chains in the lipoprotein particle core.
Asunto(s)
Humanos , Masculino , Ésteres del Colesterol/metabolismo , Grasas de la Dieta/metabolismo , Ayuno/sangre , Lipoproteínas HDL/metabolismo , Triglicéridos/metabolismo , Proteínas Portadoras/sangre , Grasas de la Dieta/administración & dosificaciónAsunto(s)
Colesterol/metabolismo , Islotes Pancreáticos/metabolismo , Receptores de LDL/metabolismo , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Animales , Línea Celular Tumoral , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatología , Hipercolesterolemia/genética , Hipercolesterolemia/metabolismo , Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/metabolismo , Masculino , Ratones , Ratones Noqueados , Receptores de LDL/genéticaRESUMEN
Increased levels of neuropeptide Y have been reported in transthyretin-null mice. This effect might be related to transthyretin ligands (retinol and thyroxine) since, through binding to nuclear receptors, they modulate the expression of genes that control cellular metabolism. The retinoic X receptors form obligatory heterodimers with peroxisome proliferator-activated receptors and liver X receptors - potent regulators of fat, glucose and cholesterol homeostasis. We used transthyretin-null mice to investigate whether the absence of transthyretin influences metabolism. Transthyretin-null mice do not differ from controls in body weight and white adipose tissue morphology, nor in basal or fast-induced circulating levels of glucose, lipids, and leptin. Glucose tolerance tests show that transthyretin-null mice have normal capacity to remove and metabolize energy substrates. Expression of genes encoding lipid transporters and nuclear receptors are also similar in transthyretin-null and control mice. Therefore, the absence of transthyretin does not seem to influence the regulation of lipid and glucose metabolism.
Asunto(s)
Glucosa/metabolismo , Metabolismo de los Lípidos , Prealbúmina/deficiencia , Adipocitos/citología , Animales , Glucemia/análisis , Peso Corporal , Ayuno , Regulación de la Expresión Génica , Prueba de Tolerancia a la Glucosa , Metabolismo de los Lípidos/genética , Lípidos/sangre , Ratones , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
OBJECTIVE: We recently described that hypertriglyceridemic apolipoprotein (apo) CIII transgenic mice show increased whole body metabolic rate. In this study, we used these apo CIII-expressing mice, combined or not with the expression of the natural promoter-driven CETP gene, to test the hypothesis that both proteins modulate diet-induced obesity. MEASUREMENTS AND RESULTS: Mice expressing apo CIII, CIII/CETP, CETP and nontransgenic (NonTg) mice were maintained on a high-fat diet (14% fat by weight) during 20 weeks after weaning. At the end of this period, all groups exhibited the expected lipemic phenotype. Fasting glucose levels were neither affected by the high-fat diet nor by the distinct genotypes. However, apo CIII mice showed significantly higher glycemia ( approximately 35%) and lower insulin levels ( approximately 45%) in the fed state, compared with the NonTg mice. The apo CIII mice presented significantly increased body weight, lipid content of the carcass ( approximately 25%), visceral adipose tissue mass (about twofold) and adipocyte size ( approximately 25%) compared with the CETP and NonTg mice. The CETP expression in the apo CIII background normalized the subcutaneous adipose depot and visceral adipocyte size to the levels of NonTg mice. Plasma leptin levels were lower in CETP groups (25-50%) and higher in the apo CIII mice. Similar core body temperature in all groups and similar liver mitochondrial resting respiration rates in CIII and NonTg mice indicate no differences in basal energy expenditure rates among these mice fed a high-fat diet. CONCLUSION: The elevation of plasma apo CIII levels aggravates diet-induced obesity and the expression of physiological levels of circulating CETP reverses this adipogenic effect, indicating a novel role for CETP in modulating adiposity.
Asunto(s)
Apolipoproteína C-III/fisiología , Proteínas de Transferencia de Ésteres de Colesterol/fisiología , Ayuno/metabolismo , Hipertrigliceridemia/metabolismo , Leptina/metabolismo , Animales , Composición Corporal/fisiología , Peso Corporal/fisiología , Ayuno/sangre , Hipertrigliceridemia/sangre , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , ObesidadRESUMEN
The metabolic effects of carbohydrate supplementation in mice have not been extensively studied. In rats, glucose- and fructose-rich diets induce hypertriacylglycerolemia. In the present study, we compared the metabolic responses to two monosaccharide supplementations in two murine models. Adult male Wistar rats (N = 80) and C57BL/6 mice (N = 60), after 3 weeks on a standardized diet, were submitted to dietary supplementation by gavage with glucose (G) or fructose (F) solutions (500 g/L), 8 g/kg body weight for 21 days. Glycemia was significantly higher in rats after fructose treatment (F: 7.9 vs 9.3 mM) and in mice (G: 6.5 vs 10 and F: 6.6 vs 8.9 mM) after both carbohydrate treatments. Triacylglycerolemia increased significantly 1.5 times in rats after G or F supplementation. Total cholesterol did not change with G treatment in rats, but did decrease after F supplementation (1.5 vs 1.4 mM, P < 0.05). Both supplementations in rats induced insulin resistance, as suggested by the higher Homeostasis Model Assessment Index. In contrast, mice showed significant decreases in triacylglycerol (G: 1.8 vs 1.4 and F: 1.9 vs 1.4 mM, P < 0.01) and total cholesterol levels (G and F: 2.7 vs 2.5 mM, P < 0.05) after both monosaccharide supplementations. Wistar rats and C57BL/6 mice, although belonging to the same family (Muridae), presented opposite responses to glucose and fructose supplementation regarding serum triacylglycerol, free fatty acids, and insulin levels after monosaccharide treatment. Thus, while Wistar rats developed features of plurimetabolic syndrome, C57BL/6 mice presented changes in serum biochemical profile considered to be healthier for the cardiovascular system.
Asunto(s)
Carbohidratos de la Dieta/efectos adversos , Fructosa/administración & dosificación , Glucosa/administración & dosificación , Hipertrigliceridemia/etiología , Resistencia a la Insulina , Animales , Colesterol/sangre , Suplementos Dietéticos/efectos adversos , Modelos Animales de Enfermedad , Fructosa/efectos adversos , Glucosa/efectos adversos , Hipertrigliceridemia/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratas , Ratas Wistar , Triglicéridos/sangreRESUMEN
The metabolic effects of carbohydrate supplementation in mice have not been extensively studied. In rats, glucose- and fructose-rich diets induce hypertriacylglycerolemia. In the present study, we compared the metabolic responses to two monosaccharide supplementations in two murine models. Adult male Wistar rats (N = 80) and C57BL/6 mice (N = 60), after 3 weeks on a standardized diet, were submitted to dietary supplementation by gavage with glucose (G) or fructose (F) solutions (500 g/L), 8 g/kg body weight for 21 days. Glycemia was significantly higher in rats after fructose treatment (F: 7.9 vs 9.3 mM) and in mice (G: 6.5 vs 10 and F: 6.6 vs 8.9 mM) after both carbohydrate treatments. Triacylglycerolemia increased significantly 1.5 times in rats after G or F supplementation. Total cholesterol did not change with G treatment in rats, but did decrease after F supplementation (1.5 vs 1.4 mM, P < 0.05). Both supplementations in rats induced insulin resistance, as suggested by the higher Homeostasis Model Assessment Index. In contrast, mice showed significant decreases in triacylglycerol (G: 1.8 vs 1.4 and F: 1.9 vs 1.4 mM, P < 0.01) and total cholesterol levels (G and F: 2.7 vs 2.5 mM, P < 0.05) after both monosaccharide supplementations. Wistar rats and C57BL/6 mice, although belonging to the same family (Muridae), presented opposite responses to glucose and fructose supplementation regarding serum triacylglycerol, free fatty acids, and insulin levels after monosaccharide treatment. Thus, while Wistar rats developed features of plurimetabolic syndrome, C57BL/6 mice presented changes in serum biochemical profile considered to be healthier for the cardiovascular system.
Asunto(s)
Animales , Masculino , Ratones , Ratas , Carbohidratos de la Dieta/efectos adversos , Fructosa/administración & dosificación , Glucosa/administración & dosificación , Hipertrigliceridemia/etiología , Resistencia a la Insulina , Colesterol/sangre , Modelos Animales de Enfermedad , Suplementos Dietéticos/efectos adversos , Fructosa/efectos adversos , Glucosa/efectos adversos , Hipertrigliceridemia/metabolismo , Ratas Wistar , Triglicéridos/sangreAsunto(s)
Proteínas Portadoras/genética , Glicoproteínas/genética , Hiperlipoproteinemias/genética , Mutación , Adulto , Anciano , Brasil/etnología , Enfermedades de las Arterias Carótidas/diagnóstico , Enfermedades de las Arterias Carótidas/genética , Proteínas Portadoras/sangre , Proteínas de Transferencia de Ésteres de Colesterol , Femenino , Glicoproteínas/sangre , Humanos , Hiperlipoproteinemias/diagnóstico , Hiperlipoproteinemias/epidemiología , Lipasa/sangre , Lipoproteínas/metabolismo , Masculino , Persona de Mediana Edad , Proteínas de Transferencia de Fosfolípidos/sangreRESUMEN
In this work, we investigated the impact of testosterone deficiency and cholesteryl ester transfer protein (CETP) expression on lipoprotein metabolism and diet-induced atherosclerosis. CETP transgenic mice and nontransgenic (nTg) littermates were studied 4 weeks after bilateral orchidectomy or sham operation. Castrated mice had an increase in the LDL fraction (+36% for CETP and +79% for nTg mice), whereas the HDL fraction was reduced (-30% for CETP and -11% for nTg mice). Castrated mice presented 1.7-fold higher titers of anti-oxidized LDL (Ox-LDL) antibodies than sham-operated controls. Plasma levels of CETP, lipoprotein lipase, and hepatic lipase were not changed by castration. Kinetic studies showed no differences in VLDL secretion rate, VLDL-LDL conversion rate, or number of LDL and HDL receptors. Competition experiments showed lower affinity of LDL from castrated mice for tissue receptors. Diet-induced atherosclerosis studies showed that testosterone deficiency increased by 100%, and CETP expression reduced by 44%, the size of aortic lesion area in castrated mice. In summary, testosterone deficiency increased plasma levels of apolipoprotein B-containing lipoproteins (apoB-LPs) and anti-OxLDL antibodies, decreased LDL receptor affinity, and doubled the size of diet-induced atherosclerotic lesions. The expression of CETP led to a milder increase of apoB-LPs and reduced atherosclerotic lesion size in testosterone-deficient mice.
Asunto(s)
Aterosclerosis/etiología , Aterosclerosis/prevención & control , Proteínas Portadoras/genética , Glicoproteínas/genética , Testosterona/deficiencia , Animales , Aterosclerosis/genética , Aterosclerosis/metabolismo , Proteínas Portadoras/metabolismo , Proteínas de Transferencia de Ésteres de Colesterol , Dieta Aterogénica , Expresión Génica , Glicoproteínas/metabolismo , Humanos , Lípidos/sangre , Lipoproteínas/sangre , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Orquiectomía , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMEN
We determined whether over-expression of one of the three genes involved in reverse cholesterol transport, apolipoprotein (apo) AI, lecithin-cholesterol acyl transferase (LCAT) and cholesteryl ester transfer protein (CETP), or of their combinations influenced the development of diet-induced atherosclerosis. Eight genotypic groups of mice were studied (AI, LCAT, CETP, LCAT/AI, CETP/AI, LCAT/CETP, LCAT/AI/CETP, and non-transgenic) after four months on an atherogenic diet. The extent of atherosclerosis was assessed by morphometric analysis of lipid-stained areas in the aortic roots. The relative influence (R2) of genotype, sex, total cholesterol, and its main sub-fraction levels on atherosclerotic lesion size was determined by multiple linear regression analysis. Whereas apo AI (R2 = 0.22, P < 0.001) and CETP (R2 = 0.13, P < 0.01) expression reduced lesion size, the LCAT (R2 = 0.16, P < 0.005) and LCAT/AI (R2 = 0.13, P < 0.003) genotypes had the opposite effect. Logistic regression analysis revealed that the risk of developing atherosclerotic lesions greater than the 50th percentile was 4.3-fold lower for the apo AI transgenic mice than for non-transgenic mice, and was 3.0-fold lower for male than for female mice. These results show that apo AI overexpression decreased the risk of developing large atherosclerotic lesions but was not sufficient to reduce the atherogenic effect of LCAT when both transgenes were co-expressed. On the other hand, CETP expression was sufficient to eliminate the deleterious effect of LCAT and LCAT/AI overexpression. Therefore, increasing each step of the reverse cholesterol transport per se does not necessarily imply protection against atherosclerosis while CETP expression can change specific atherogenic scenarios.
Asunto(s)
Apolipoproteína A-I/genética , Aterosclerosis/genética , Proteínas de Transferencia de Ésteres de Colesterol/genética , Dieta Aterogénica , Fosfatidilcolina-Esterol O-Aciltransferasa/genética , Animales , Apolipoproteína A-I/metabolismo , Aterosclerosis/metabolismo , Transporte Biológico/genética , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Modelos Animales de Enfermedad , Genotipo , Modelos Lineales , Masculino , Ratones , Ratones Transgénicos , Fosfatidilcolina-Esterol O-Aciltransferasa/metabolismo , Índice de Severidad de la EnfermedadRESUMEN
We determined whether over-expression of one of the three genes involved in reverse cholesterol transport, apolipoprotein (apo) AI, lecithin-cholesterol acyl transferase (LCAT) and cholesteryl ester transfer protein (CETP), or of their combinations influenced the development of diet-induced atherosclerosis. Eight genotypic groups of mice were studied (AI, LCAT, CETP, LCAT/AI, CETP/AI, LCAT/CETP, LCAT/AI/CETP, and non-transgenic) after four months on an atherogenic diet. The extent of atherosclerosis was assessed by morphometric analysis of lipid-stained areas in the aortic roots. The relative influence (R²) of genotype, sex, total cholesterol, and its main sub-fraction levels on atherosclerotic lesion size was determined by multiple linear regression analysis. Whereas apo AI (R² = 0.22, P < 0.001) and CETP (R² = 0.13, P < 0.01) expression reduced lesion size, the LCAT (R² = 0.16, P < 0.005) and LCAT/AI (R² = 0.13, P < 0.003) genotypes had the opposite effect. Logistic regression analysis revealed that the risk of developing atherosclerotic lesions greater than the 50th percentile was 4.3-fold lower for the apo AI transgenic mice than for non-transgenic mice, and was 3.0-fold lower for male than for female mice. These results show that apo AI overexpression decreased the risk of developing large atherosclerotic lesions but was not sufficient to reduce the atherogenic effect of LCAT when both transgenes were co-expressed. On the other hand, CETP expression was sufficient to eliminate the deleterious effect of LCAT and LCAT/AI overexpression. Therefore, increasing each step of the reverse cholesterol transport per se does not necessarily imply protection against atherosclerosis while CETP expression can change specific athero genic scenarios.
Asunto(s)
Animales , Masculino , Ratones , Apolipoproteína A-I/genética , Aterosclerosis/genética , Proteínas de Transferencia de Ésteres de Colesterol/genética , Dieta Aterogénica , Fosfatidilcolina-Esterol O-Aciltransferasa/genética , Apolipoproteína A-I/metabolismo , Aterosclerosis/metabolismo , Transporte Biológico/genética , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Modelos Animales de Enfermedad , Genotipo , Modelos Lineales , Ratones Transgénicos , Fosfatidilcolina-Esterol O-Aciltransferasa/metabolismo , Índice de Severidad de la EnfermedadRESUMEN
Cholesteryl ester transfer protein (CETP) mediates cholesteryl ester (CE) and triglyceride redistribution among plasma lipoproteins. In this work, we investigated whether varying levels of insulin regulate the CETP expression in vivo. Insulin deficiency [streptozotocin (STZ) injection], and hyperinsulinemia (insulin injections, 14 days) were induced in transgenic mice expressing a human CETP minigene flanked by its natural regulatory sequences. Glucose supplementation was provided to the hyperinsulinemic group (INS+GLUC) and to an extra group of mice (GLUC). In the STZ group, endogenous CE transfer rate, plasma CETP, and hepatic CETP mRNA levels were enhanced 3.0-, 1.5-, and 2.5-fold, respectively, as compared with controls. Insulin replacement in STZ mice normalized their glycemia and liver mRNA levels. Higher plasma CETP levels were observed in GLUC mice, which were decreased in INS+GLUC mice. Hepatic CETP mRNA was not altered in GLUC mice and was reduced by one-third in INS+GLUC mice. These results show that: 1) STZ treatment increases CETP plasma levels and liver mRNA expression; 2) diet glucose supplementation increases plasma CETP levels but does not change liver mRNA abundance; and 3) daily insulin injections blunt the glucose-stimulated CETP expression by reducing its liver mRNA levels. These data suggest that insulin down-regulates CETP gene expression.
Asunto(s)
Proteínas Portadoras/metabolismo , Glicoproteínas/metabolismo , Hiperinsulinismo/metabolismo , Animales , Composición Corporal , Proteínas Portadoras/sangre , Proteínas Portadoras/genética , Proteínas de Transferencia de Ésteres de Colesterol , Ésteres del Colesterol/sangre , Ésteres del Colesterol/metabolismo , Regulación hacia Abajo , Regulación de la Expresión Génica , Glucosa/metabolismo , Glicoproteínas/sangre , Glicoproteínas/genética , Humanos , Hiperinsulinismo/sangre , Hiperinsulinismo/genética , Insulina/administración & dosificación , Insulina/farmacología , Lipoproteínas/genética , Lipoproteínas/metabolismo , Hígado/metabolismo , Ratones , Ratones Transgénicos , ARN Mensajero/metabolismoRESUMEN
In this study, we examined glucose homeostasis and insulin secretion in transgenic mice overexpressing the human apolipoprotein CIII gene (apo CIII tg). These mice have elevated plasma levels of triglycerides, FFA and cholesterol compared to control mice. The body weight, plasma glucose, and insulin levels, glucose disappearance rates, areas under the ipGTT curve for adult (4 - 8 mo. old) and aged (20 - 24 mo. old) apo CIII tg mice and the determination of insulin during the ipGTT were not different from those of control mice. However, an additional elevation of plasma FFA by treatment with heparin for 2 - 4 h impaired the ipGTT responses in apo CIII tg mice compared to saline-treated mice. The glucose disappearance rate in heparin-treated transgenic mice was slightly lower than in heparin-treated controls. Glucose (22.2 mmol/l) stimulated insulin secretion in isolated islets to the same extent in saline-treated control and apo CIII tg mice. In islets from heparin-treated apo CIII tg mice, the insulin secretion at 2.8 and 22.2 mmol glucose/l was lower than in heparin-treated control mice. In conclusion, hypertriglyceridemia per se or a mild elevation in FFA did not affect insulin secretion or insulin resistance in adult or aged apo CIII tg mice. Nonetheless, an additional elevation of FFA induced by heparin in hypertriglyceridemic mice impaired the ipGTT by reducing insulin secretion.