131 results on '"Helena C. F. Oliveira"'
Search Results
52. Pravastatin Provokes Muscle-specific Mitochondrial Dysfunction and Alters Protein Turnover: Protection by CoQ10
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Lais Rosa Viana, Ana Carolina Marques, Anibal E. Vercesi, Maria Cristina Cintra Gomes Marcondes, Helena C. F. Oliveira, and Estela Natacha Brandt Busanello
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medicine.medical_specialty ,Endocrinology ,Chemistry ,Internal medicine ,Internal Medicine ,Protein turnover ,medicine ,General Medicine ,Cardiology and Cardiovascular Medicine ,Pravastatin ,medicine.drug - Published
- 2018
53. Coenzyme Q10 or creatine counteract pravastatin-induced liver redox changes in hypercholesterolemic mice
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Ana Carolina Marques, Anibal E. Vercesi, Estela N. B. Busanello, and Helena C. F. Oliveira
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Coenzyme Q10 ,Antioxidant ,medicine.medical_treatment ,nutritional and metabolic diseases ,Familial hypercholesterolemia ,Pharmacology ,Creatine ,medicine.disease ,Protein oxidation ,Biochemistry ,chemistry.chemical_compound ,chemistry ,Lipid oxidation ,Physiology (medical) ,LDL receptor ,medicine ,lipids (amino acids, peptides, and proteins) ,Pravastatin ,medicine.drug - Abstract
Statins are the preferred therapy to treat hypercholesterolemia and decrease coronary heart disease. However, previous studies have reported mitochondrial dysfunctions of several experimental models submitted to diverse statins treatments. The aim of the present study was to investigate whether treatment with doses of pravastatin during 3 months induces hepatotoxicity in LDL receptor knockout mice (LDLr-/-), a model for human familial hypercholesterolemia. We evaluated liver mitochondrial function parameters, antioxidant enzymes activities and protein and lipid oxidation markers. We observed a higher mitochondrial H2O2 production rate, decreased activity of aconitase and increased MPT. Among several antioxidant enzymes, only G6PD activity was increased in treated mice. The presence of several oxidized lipid species was detected in pravastatin group but protein oxidation markers were not altered. Diet supplementation with the antioxidants CoQ10 or creatine fully reversed all pravastatin effects. Taken together, our results show that pravastatin chronic treatment induced liver mitochondrial redox imbalance that may explain the hepatic side effects reported in a small number of patients, and the co-treatment with safe antioxidants neutralize these side effects.
- Published
- 2018
54. Reactive oxygen species generation in peripheral blood monocytes and oxidized LDL are increased in hyperlipidemic patients
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Lucia Nassi Castilho, Eliana Cotta de Faria, Giovanna R. Degasperi, Edilma Maria de Albuquerque Vasconcelos, Anibal E. Vercesi, and Helena C. F. Oliveira
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Adult ,Male ,medicine.medical_specialty ,Lipoproteins ,medicine.medical_treatment ,Clinical Biochemistry ,Hyperlipidemias ,medicine.disease_cause ,Monocytes ,Flow cytometry ,Internal medicine ,Hyperlipidemia ,medicine ,Humans ,chemistry.chemical_classification ,Reactive oxygen species ,medicine.diagnostic_test ,Chemistry ,Insulin ,Monocyte ,General Medicine ,Middle Aged ,medicine.disease ,In vitro ,Lipoproteins, LDL ,Endocrinology ,medicine.anatomical_structure ,Immunology ,Female ,Reactive Oxygen Species ,Lipid profile ,Oxidative stress - Abstract
Objectives Experimental and in vitro evidences have established that reactive oxygen species (ROS) generated by vascular wall cells play a key role in atherogenesis. Here, we evaluated the rate of ROS generation by resting peripheral monocytes in naive hyperlipidemic subjects. Design and methods Primary hypercholesterolemic, combined hyperlipidemic, and normolipidemic individuals were studied. ROS generation and the mitochondrial electrical transmembrane potential were estimated by flow cytometry. Plasma oxidized (ox) LDL levels and lipid profile were measured by ELISA and enzymatic colorimetric methods. Results Both hyperlipidemic groups presented significantly higher rates of monocyte ROS generation and elevated plasma levels of ox-LDL. Combined hyperlipidemic subjects presented increased levels of small dense LDL and insulin. Significant positive correlations between monocyte ROS generation and ox-LDL concentrations were found in pooled data. Conclusions These data provide evidence that ROS production by circulating monocytes from hyperlipidemic subjects may contribute to the systemic oxidative stress and possibly to atherogenesis.
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- 2009
55. Cholesteryl ester transfer protein (CETP) increases postprandial triglyceridaemia and delays triacylglycerol plasma clearance in transgenic mice
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Alessandro G. Salerno, P.R. Patricio, Helena C. F. Oliveira, and J.A. Berti
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Blood Glucose ,Very low-density lipoprotein ,medicine.medical_specialty ,Cholesterol, VLDL ,Hyperlipidemias ,Mice, Transgenic ,Biochemistry ,Mice ,chemistry.chemical_compound ,High-density lipoprotein ,Internal medicine ,Chylomicrons ,Cholesterylester transfer protein ,medicine ,Animals ,Molecular Biology ,LDL-Receptor Related Proteins ,Triglycerides ,Intermediate-density lipoprotein ,Lipoprotein lipase ,biology ,Fasting ,Organ Size ,Cell Biology ,Postprandial Period ,Dietary Fats ,Cholesterol Ester Transfer Proteins ,carbohydrates (lipids) ,Lipoprotein Lipase ,Endocrinology ,Intestinal Absorption ,Liver ,chemistry ,biology.protein ,Cholesteryl ester ,Emulsions ,Female ,lipids (amino acids, peptides, and proteins) ,Hepatic lipase ,Lipoprotein - Abstract
The CETP (cholesteryl ester transfer protein) is a plasma protein synthesized in several tissues, mainly in the liver; CETP reduces plasma HDL (high-density lipoprotein) cholesterol and increases the risk of atherosclerosis. The effect of CETP levels on postprandial intravascular metabolism of TAGs (triacylglycerols) is an often-overlooked aspect of the relationship between CETP and lipoprotein metabolism. Here, we tested the hypothesis that CETP delays the plasma clearance of TAG-rich lipoprotein by comparing human CETP expressing Tg (transgenic) and non-Tg mice. After an oral fat load, the postprandial triglyceridaemia curve was markedly increased in CETP-Tg compared with non-Tg mice (280±30 versus 190±20 mg/dl per 6 h respectively, P
- Published
- 2009
56. Saturated Fatty Acids Produce an Inflammatory Response Predominantly through the Activation of TLR4 Signaling in Hypothalamus: Implications for the Pathogenesis of Obesity
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Silvana Bordin, José B.C. Carvalheira, Daniela Miti Lemos Tsukumo, Hilton Kenji Takahashi, Licio A. Velloso, Gabriel Forato Anhê, Rui Curi, Dennys E. Cintra, Joseane Morari, Mario J.A. Saad, Giovanna R. Degasperi, Maria Esméria Corezola do Amaral, Marciane Milanski, Raphael G. P. Denis, Helena C. F. Oliveira, and Andressa Coope
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Male ,medicine.medical_specialty ,Indoles ,medicine.medical_treatment ,Hypothalamus ,Biology ,Antibodies ,Mice ,Internal medicine ,medicine ,Animals ,Immunoprecipitation ,Obesity ,RNA, Messenger ,Rats, Wistar ,Receptor ,Mice, Inbred C3H ,Leptin receptor ,General Neuroscience ,Leptin ,Insulin ,Endoplasmic reticulum ,Body Weight ,Fatty Acids ,Articles ,Mice, Mutant Strains ,Toll-Like Receptor 2 ,Rats ,Toll-Like Receptor 4 ,Disease Models, Animal ,Endocrinology ,Gene Expression Regulation ,Mutation ,Cytokines ,Microglia ,Intracellular ,Signal Transduction ,Hormone - Abstract
In animal models of diet-induced obesity, the activation of an inflammatory response in the hypothalamus produces molecular and functional resistance to the anorexigenic hormones insulin and leptin. The primary events triggered by dietary fats that ultimately lead to hypothalamic cytokine expression and inflammatory signaling are unknown. Here, we test the hypothesis that dietary fats act through the activation of toll-like receptors 2/4 and endoplasmic reticulum stress to induce cytokine expression in the hypothalamus of rodents. According to our results, long-chain saturated fatty acids activate predominantly toll-like receptor 4 signaling, which determines not only the induction of local cytokine expression but also promotes endoplasmic reticulum stress. Rats fed on a monounsaturated fat-rich diet do not develop hypothalamic leptin resistance, whereas toll-like receptor 4 loss-of-function mutation and immunopharmacological inhibition of toll-like receptor 4 protects mice from diet-induced obesity. Thus, toll-like receptor 4 acts as a predominant molecular target for saturated fatty acids in the hypothalamus, triggering the intracellular signaling network that induces an inflammatory response, and determines the resistance to anorexigenic signals.
- Published
- 2009
57. Fatty acid synthase inhibition with Orlistat promotes apoptosis and reduces cell growth and lymph node metastasis in a mouse melanoma model
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Helena C. F. Oliveira, Ricardo D. Coletta, Karina G. Zecchin, Fabiana Seguin, Helena Fonseca Raposo, Edgard Graner, Débora Campanella Bastos, Marco Aurélio de Carvalho, Michelle Agostini, Ana Lúcia Carrinho Ayrosa Rangel, Silvio Sanches Veiga, and Massimo Loda
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Cancer Research ,Apoptosis ,Biology ,Metastasis ,Lactones ,Mice ,Cell Line, Tumor ,medicine ,Animals ,Melanoma ,neoplasms ,Peritoneal Neoplasms ,Cell Proliferation ,Orlistat ,Cell growth ,Cancer ,medicine.disease ,Enzyme Activation ,Mice, Inbred C57BL ,Disease Models, Animal ,Fatty acid synthase ,Oncology ,Lymphatic Metastasis ,Mediastinal lymph node ,Immunology ,Cutaneous melanoma ,Saturated fatty acid ,biology.protein ,Cancer research ,Fatty Acid Synthases ,Neoplasm Transplantation - Abstract
Fatty acid synthase (FASN) is the enzyme responsible for the endogenous synthesis of the saturated fatty acid palmitate. In contrast to most normal cells, malignant cells depend on FASN activity for growth and survival. In fact, FASN is overexpressed in a variety of human cancers including cutaneous melanoma, in which its levels of expression are associated with a poor prognosis and depth of invasion. Here, we show that the specific inhibition of FASN activity by the antiobesity drug Orlistat or siRNA is able to significantly reduce proliferation and promote apoptosis in the mouse metastatic melanoma cell line B16-F10. These results prompted us to verify the effect of FASN inhibition on the metastatic process in a model of spontaneous melanoma metastasis, in which B16-F10 cells injected in the peritoneal cavity of C57BL/6 mice metastasize to the mediastinal lymph nodes. We observed that mice treated with Orlistat 48 hr after the inoculation of B16-F10 cells exhibited a 52% reduction in the number of mediastinal lymph node metastases, in comparison with the control animals. These results suggest that FASN activity is essential for B16-F10 melanoma cell proliferation and survival while its inactivation by Orlistat significantly reduces their metastatic spread. The chemical inhibition of FASN activity could have a potential benefit in association with the current chemotherapy for melanoma.
- Published
- 2008
58. Adverse effect of the anabolic-androgenic steroid mesterolone on cardiac remodelling and lipoprotein profile is attenuated by aerobicz exercise training
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Maria Alice da Cruz-Höfling, Karina Fontana, Marta Beatriz Leonardo, Helena C. F. Oliveira, and Carlos Alberto Mandarim-de-Lacerda
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medicine.medical_specialty ,medicine.diagnostic_test ,biology ,Triglyceride ,business.industry ,Mesterolone ,Cell Biology ,medicine.disease ,Pathology and Forensic Medicine ,chemistry.chemical_compound ,Blood pressure ,Endocrinology ,chemistry ,Ventricular hypertrophy ,Internal medicine ,LDL receptor ,Cholesterylester transfer protein ,medicine ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Lipid profile ,business ,Molecular Biology ,medicine.drug ,Lipoprotein - Abstract
Abuse of anabolic–androgenic steroids (AAS) for improving physical performance is associated with serious, sometimes fatal, adverse effects. The aim of the present work was to investigate the effects of AAS on the cardiac structure and the plasma lipoprotein profile isolated and in combination with exercise. Transgenic mice with a human lipaemic phenotype (expressing cholesteryl ester transfer protein on the LDL receptor knockout background) were used in this study. Sedentary and exercised mice (treadmill running, five times per week for 6 weeks) were treated with mesterolone (2 μg/g body weight) or vehicle (control-C) in the last 3 weeks. Four groups were compared: (i) exercise + mesterolone (Ex-M), (ii) exercise + vehicle (Ex-C), (iii) sedentary + mesterolone (Sed-M) and (iv) sedentary + vehicle (Sed-C). Arterial blood pressure and body mass increased in all groups along time, but Sed-M reached the highest values and Ex-C the lowest. Treatment with mesterolone increased total cholesterol, triglyceride, low-density lipoprotein cholesterol (LDL-c) and very LDL-c (VLDL-c) plasma levels. However, exercise blunted some of these deleterious effects by increasing high-density lipoprotein cholesterol and decreasing LDL-c, VLDL-c and triglycerides. Exercise training induced beneficial effects, such as physiological cardiomyocyte hypertrophy, increase in myocardial circulation and decrease in cardiac interstitium. However, mesterolone impaired such physiological gains and in addition increased troponin T plasma levels both in sedentary and exercised mice. Thus, while mesterolone induced pro-atherogenic lipoprotein profile and pathogenic cardiac hypertrophy, exercise counteracted these effects and modified favourably both the lipoprotein profile and the cardiac remodelling induced by mesterolone.
- Published
- 2008
59. Oxidative stress in hypercholesterolemic LDL (low-density lipoprotein) receptor knockout mice is associated with low content of mitochondrial NADP-linked substrates and is partially reversed by citrate replacement
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Helena C. F. Oliveira, Jesus A. Velho, Anibal E. Vercesi, Bruno A. Paim, and Roger F. Castilho
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Antioxidant ,medicine.medical_treatment ,Hypercholesterolemia ,Glutathione reductase ,Mitochondria, Liver ,Mitochondrion ,medicine.disease_cause ,Biochemistry ,Citric Acid ,Mice ,chemistry.chemical_compound ,Physiology (medical) ,medicine ,Animals ,Peroxidase ,Mice, Knockout ,chemistry.chemical_classification ,Reactive oxygen species ,Glutathione Disulfide ,Hydrogen Peroxide ,Glutathione ,Oxidative Stress ,Glutathione Reductase ,Receptors, LDL ,chemistry ,LDL receptor ,NAD+ kinase ,NADP ,Oxidative stress - Abstract
We have previously proposed that hypercholesterolemic LDL receptor knockout (k/o) mice mitochondria possess a lower antioxidant capacity due to a large consumption of reducing equivalents from NADPH to sustain high rates of lipogenesis. In this work, we tested the hypothesis that this k/o mice mitochondrial oxidative stress results from the depletion of NADPH-linked substrates. In addition, the oxidative stress was further characterized by showing a lower mitochondrial GSH/GSSG ratio and a higher liver content of protein carbonyls as compared to controls. The activity of the antioxidant enzyme system glutathione reductase/peroxidase did not differ in k/o and control mitochondria. The faster spontaneous oxidation of endogenous NADPH in the k/o mitochondria was prevented by the addition of exogenous catalase, indicating that this oxidation is mediated by mitochondrially generated H2O2. The higher rate of H2O2 production was also prevented by the addition of exogenous isocitrate that maintains NADP fully reduced. The hypothesis that high rates of lipogenesis in the k/o cells decrease mitochondrial NADPH/NADP+ ratio due to consumption of NADPH-linked substrates was supported by two findings: (i) oxygen consumption supported by endogenous NAD(P)H-linked substrates was slower in k/o than in control mitochondria, but was similar in the presence of exogenous isocitrate; (ii) in vivo treatment of k/o mice with sodium citrate/citric acid drinking solution for 2 weeks partially restored both the rate of oxygen consumption supported by NAD(P)H-linked substrates and the mitochondrial capacity to sustain reduced NADPH. In conclusion, the data demonstrate that the mitochondrial oxidative stress in hypercholesterolemic LDL receptor knockout mice is the result of a low content of mitochondrial NADPH-linked substrates in the intact animal that can be, at least in part, replenished by oral administration of citrate.
- Published
- 2008
60. The Absence of Transthyretin does not Impair Regulation of Lipid and Glucose Metabolism
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Joana Almeida Palha, Fernanda Marques, Pedro Oliveira, Helena C. F. Oliveira, João Carlos Sousa, and Universidade do Minho
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Blood Glucose ,Endocrinology, Diabetes and Metabolism ,Medicina Básica [Ciências Médicas] ,Clinical Biochemistry ,Peroxisome proliferator-activated receptor ,White adipose tissue ,Transthyretin ,PPAR ,Biochemistry ,Mice ,0302 clinical medicine ,Endocrinology ,Adipocytes ,Prealbumin ,Receptor ,chemistry.chemical_classification ,0303 health sciences ,Fasting ,General Medicine ,Neuropeptide Y receptor ,Lipids ,3. Good health ,Ciências Médicas::Medicina Básica ,LXR ,medicine.medical_specialty ,RXR ,030209 endocrinology & metabolism ,macromolecular substances ,Biology ,Carbohydrate metabolism ,Retinoids ,03 medical and health sciences ,Internal medicine ,medicine ,Animals ,RNA, Messenger ,Liver X receptor ,030304 developmental biology ,Science & Technology ,Body Weight ,Biochemistry (medical) ,nutritional and metabolic diseases ,Glucose Tolerance Test ,Lipid Metabolism ,nervous system diseases ,Thyroxine ,Glucose ,Gene Expression Regulation ,Nuclear receptor ,chemistry ,biology.protein - Abstract
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., POCTI / NSE / 37315 / 2001 and POCI/SAU-NEU/56618/2004, FEDER from Fundação para a Ciência e Tecnologia (Portugal)
- Published
- 2007
61. Overexpression of apolipoprotein CIII increases and CETP reverses diet-induced obesity in transgenic mice
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E P M S Francesconi, T.R. Silva, Anibal E. Vercesi, Maria Esméria Corezola do Amaral, Maria Lúcia Bonfleur, Alessandro G. Salerno, P.R. Patricio, Antonio C. Boschero, Helena C. F. Oliveira, Luciane C. Alberici, and Dora Maria Grassi-Kassisse
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Leptin ,medicine.medical_specialty ,Apolipoprotein B ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Medicine (miscellaneous) ,Adipose tissue ,Mice, Transgenic ,Mice ,chemistry.chemical_compound ,Internal medicine ,Adipocyte ,medicine ,Animals ,Obesity ,Hypertriglyceridemia ,Apolipoprotein C-III ,Nutrition and Dietetics ,biology ,Triglyceride ,Insulin ,Body Weight ,Fasting ,medicine.disease ,Cholesterol Ester Transfer Proteins ,Mice, Inbred C57BL ,Endocrinology ,chemistry ,Body Composition ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Lipoprotein - Abstract
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.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.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.
- Published
- 2007
62. REGULATION OF HEPATIC CHOLESTEROL METABOLISM IN CETP+/?/LDLr+/?MICE BY CHOLESTEROL FEEDING AND BY DRUGS (CHOLESTYRAMINE AND LOVASTATIN) THAT LOWER PLASMA CHOLESTEROL
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L.M. Harada, Eder Carlos da Rocha Quintão, Alexandre J. F. Carrilho, Helena C. F. Oliveira, and Edna Regina Nakandakare
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medicine.medical_specialty ,Physiology ,Cholestyramine Resin ,Cholesterol 7 alpha-hydroxylase ,Cholesterol, Dietary ,Mice ,chemistry.chemical_compound ,Physiology (medical) ,Internal medicine ,Cholesterylester transfer protein ,medicine ,Animals ,Lovastatin ,RNA, Messenger ,Liver X receptor ,Triglycerides ,Mice, Knockout ,Pharmacology ,Cholestyramine ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Cholesterol ,Anticholesteremic Agents ,Reverse cholesterol transport ,Lipid Metabolism ,Cholesterol Ester Transfer Proteins ,Endocrinology ,Liver ,Receptors, LDL ,chemistry ,HMG-CoA reductase ,Microsomes, Liver ,biology.protein ,lipids (amino acids, peptides, and proteins) ,medicine.drug - Abstract
SUMMARY 1 The hepatic mechanisms involved in the simultaneous regulation of plasma cholesterol concentration and cholesteryl ester transfer protein (CETP) activity were investigated by sharply modifying the hepatic rates of cholesterol synthesis. This was accomplished by cholestyramine, lovastatin and cholesterol feeding in human CETP transgenic mice cross-bred with low-density lipoprotein receptor (LDLr)-knockout mice, generating CETP+/–/LDLr+/– mice, which present a plasma lipoprotein profile resembling that of humans. 2 Analyses of pooled data showed that the plasma CETP activity correlated positively with plasma total cholesterol concentration, hepatic CETP mRNA and the liver microsomal cholesterol content; a negative correlation was found between plasma CETP activity and the liver 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and LDLr mRNA levels. These coordinated events represent an efficient control system that stabilizes the cell cholesterol content. 3 Nonetheless, not all cholesterol metabolism regulatory systems seem to fit into a coherent pattern of responses, suggesting that other unknown cellular mechanisms play roles depending on the type of pharmacological intervention. 4 For example, microsomal cholesterol content was not affected by cholestyramine, but was increased on cholesterol feeding (as predicted), and, surprisingly, on lovastatin treatment. Furthermore, although both plasma cholesterol-lowering drugs increased CYP7A1 mRNA and had no effect on CYP27 mRNA, other metabolic components were differentially modified. Cholestyramine and lovastatin, respectively, did not modify and increased both HMG-CoA and sterol responsive element binding protein 1c mRNA, did not modify and lowered liver X receptor α mRNA, lowered and increased ATP binding cassette A1 mRNA and lowered and did not modify scavenger receptor B1 mRNA. 5 That is, different to unabsorbed cholestyramine, lovastatin, as an absorbed plasma cholesterol-lowering drug, may have modified the activity of other unknown genes that play roles in the interaction of CETP with the metabolism of hepatic cholesterol.
- Published
- 2006
63. Atherosclerosis is enhanced by testosterone deficiency and attenuated by CETP expression in transgenic mice
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Patrícia M. Cazita, J.A. Berti, Daniel F. J. Ketelhuth, Magnus Gidlund, A.C. Casquero, Alessandro G. Salerno, E.J.B. Bighetti, and Helena C. F. Oliveira
- Subjects
Male ,plasma lipoprotein kinetics ,medicine.medical_specialty ,Very low-density lipoprotein ,Apolipoprotein B ,Lipoproteins ,lipoprotein lipase ,Gene Expression ,Mice, Transgenic ,QD415-436 ,Biochemistry ,Mice ,Endocrinology ,Internal medicine ,Cholesterylester transfer protein ,medicine ,Animals ,Humans ,Lipolysis ,Testosterone ,Receptor ,Glycoproteins ,Lipoprotein lipase ,biology ,Chemistry ,Cell Biology ,low density lipoprotein receptor ,Atherosclerosis ,Lipids ,Recombinant Proteins ,Cholesterol Ester Transfer Proteins ,Mice, Inbred C57BL ,aortic atherosclerosis lesion ,LDL receptor ,lipolysis ,biology.protein ,Diet, Atherogenic ,oxidized low density lipoprotein ,lipids (amino acids, peptides, and proteins) ,Hepatic lipase ,Carrier Proteins ,Orchiectomy - Abstract
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.
- Published
- 2006
64. [Untitled]
- Author
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Giovana R. Degaspari, Helena C. F. Oliveira, Eliana Cotta de Faria, E.J.B. Bighetti, Anibal E. Vercesi, Luciane C. Alberici, and Cláudio T. De Souza
- Subjects
chemistry.chemical_classification ,medicine.medical_specialty ,Physiology ,Hypertriglyceridemia ,Fatty acid ,Cell Biology ,Mitochondrion ,Biology ,medicine.disease ,Endocrinology ,chemistry ,Mitochondrial permeability transition pore ,Adenine nucleotide ,Internal medicine ,Respiration ,medicine ,Uncoupling protein ,Ciprofibrate ,medicine.drug - Abstract
High plasma level of triglycerides (TGs) is a common feature in atherosclerosis, obesity, diabetes, alcoholism, stress, and infection. Since mitochondria have been implicated in cell death under a variety of metabolic disorders, we examined liver mitochondrial functions in hypertriglyceridemic transgenic mice. Hypertriglyceridemia increased resting respiration and predisposed to mitochondrial permeability transition (MPT). Ciprofibrate therapy reduced plasma TG levels, normalized respiration, and prevented MPT. The higher resting respiration in transgenic mitochondria remained in the presence of the adenine nucleotide carrier inhibitor, carboxyatractyloside, bovine serum albumin, and the uncoupling proteins (UCPs) inhibitor, GDP. UCP2 content was similar in both control and transgenic mitochondria. We propose that faster resting respiration represents a regulated adaptation to oxidize excess free fatty acid in the transgenic mice.
- Published
- 2003
65. Plasma Glucose Regulation and Insulin Secretion in Hypertriglyceridemic Mice
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Helena C. F. Oliveira, Viviane Delghingaro-Augusto, Elaine Vieira, Antonio C. Boschero, Maria Esméria Corezola do Amaral, J.A. Berti, and Everardo M. Carneiro
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Blood Glucose ,Male ,Genetically modified mouse ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Transgene ,Clinical Biochemistry ,Mice, Transgenic ,Fatty Acids, Nonesterified ,Biochemistry ,Statistics, Nonparametric ,Islets of Langerhans ,Mice ,chemistry.chemical_compound ,Endocrinology ,Insulin resistance ,Internal medicine ,Insulin Secretion ,medicine ,Animals ,Insulin ,Glucose homeostasis ,Apolipoproteins C ,Triglycerides ,Hypertriglyceridemia ,Apolipoprotein C-III ,Glucose tolerance test ,medicine.diagnostic_test ,Heparin ,Cholesterol ,Body Weight ,Biochemistry (medical) ,General Medicine ,Glucose Tolerance Test ,medicine.disease ,chemistry ,Area Under Curve ,Female ,lipids (amino acids, peptides, and proteins) - Abstract
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.
- Published
- 2002
66. The role of cholesteryl ester transfer protein expression on endothelial cells: oxidative stress and vascular dysfunction
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Jeferson Stravinsky, Estela Lorza-Gil, Helena C. F. Oliveira, Gabriel G. Dorighello, Daniela M. Guizoni, Amarylis C. B. A. Wanschel, Adriene Alexandra Paiva, Ana Paula Davel, and Alessandro G. Salerno
- Subjects
chemistry.chemical_classification ,Reactive oxygen species ,medicine.medical_specialty ,biology ,Superoxide ,Cell adhesion molecule ,Glutathione ,medicine.disease ,medicine.disease_cause ,biology.organism_classification ,Biochemistry ,carbohydrates (lipids) ,chemistry.chemical_compound ,Endocrinology ,chemistry ,Enos ,Physiology (medical) ,Internal medicine ,Cholesterylester transfer protein ,medicine ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Endothelial dysfunction ,Oxidative stress - Abstract
High-density lipoprotein cholesterol (HDL-C) levels are inversely correlated with development of atherosclerotic coronary heart disease and studies demonstrate that cholesteryl ester transfer protein (CETP) deficiency is associated with markedly increased HDL levels. HDL may exert atheroprotective activity by preventing endothelial dysfunction, a key step in the development of atherosclerosis. However, the CETP effects per se on endothelial function needs to be clarified. This study evaluates the role of CETP in the setting of early atherosclerosis and its contribution to endothelial dysfunction. In vitro, knockdown of Human Aortic Endothelial Cells (HAECs) with siCETP, prevented expression of adhesion molecules. Notably, eNOS activity was augmented in aortas of CETP-transgenic mice and correlated with decreased levels of inhibitory interaction with caveolin-1. Furthermore, the presence of CETP in aortas coincided with an increase in vascular production of reactive oxygen species evidenced by augmented oxidized to reduced glutathione ratio (GSSG/GSH), increased superoxide and hydrogen peroxide production and a marked decrease in endothelium-dependent vasorelaxation. Together, these findings suggest a role for CETP in promoting endothelial dysfunction and highlight the role in promoting oxidative stress.
- Published
- 2017
67. Oxidative stress and susceptibility to mitochondrial permeability transition precedes the onset of diabetes in autoimmune non-obese diabetic mice
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P. G. La Guardia, Carina Malaguti, Diogo Noin de Oliveira, Ana Catarina Rezende Leite, Rodrigo Ramos Catharino, Anibal E. Vercesi, Helena C. F. Oliveira, and R. L. de Lima Zollner
- Subjects
Programmed cell death ,medicine.medical_specialty ,Nod ,Mitochondrion ,Biology ,medicine.disease_cause ,Biochemistry ,Mitochondrial Membrane Transport Proteins ,Permeability ,Autoimmune Diseases ,Diabetes Mellitus, Experimental ,Mice ,Mice, Inbred NOD ,Internal medicine ,Diabetes mellitus ,medicine ,Animals ,NOD mice ,Type 1 diabetes ,Mice, Inbred BALB C ,Mitochondrial Permeability Transition Pore ,General Medicine ,medicine.disease ,Mitochondria ,Oxidative Stress ,Endocrinology ,Mitochondrial permeability transition pore ,Female ,Reactive Oxygen Species ,Oxidative stress - Abstract
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.
- Published
- 2014
68. Oxidation of LDL enhances the cholesteryl ester transfer protein (CETP)-mediated cholesteryl ester transfer rate to HDL, bringing on a diminished net transfer of cholesteryl ester from HDL to oxidized LDL
- Author
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Antonio Sesso, Lucia Nassi Castilho, Eder Carlos da Rocha Quintão, Patrícia M. Cazita, Admar Costa de Oliveira, and Helena C. F. Oliveira
- Subjects
Clinical Biochemistry ,Biochemistry ,chemistry.chemical_compound ,High-density lipoprotein ,Cholesterylester transfer protein ,Humans ,Glycoproteins ,biology ,Biochemistry (medical) ,Reverse cholesterol transport ,General Medicine ,In vitro ,Cholesterol Ester Transfer Proteins ,Lipoproteins, LDL ,Kinetics ,chemistry ,Acetylation ,Low-density lipoprotein ,Cholesteryl ester ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Cholesterol Esters ,Carrier Proteins ,Lipoproteins, HDL ,Oxidation-Reduction ,Oxidized ldl - Abstract
Cholesteryl ester transfer protein (CETP) plays a controversial role in atherogenesis by contributing to the net transfer of high density lipoprotein (HDL) cholesteryl ester (CE) to the liver via apolipoprotein-B-containing lipoproteins (apoB-LP). We evaluated in vitro the CETP-mediated bidirectional transfer of CE from HDL to the chemically modified pro-atherogenic low density lipoprotein (LDL) particles. Acetylated or oxidized (ox) LDL, either unlabeled or [3H]-CE labeled, were incubated with [14C]-CE-HDL in the presence of the lipoprotein-deficient plasma fraction (d>1.21 g/ml) as the source of CETP. The amount of radioactive CE transferred was determined after dextran sulfate/MgCl2 precipitation of LDL. The results showed a 1.4–2.8-fold lower HDL-CE transfer to acetylated LDL while no effect was observed on the CE transfer to oxidized LDL. However, the reverse transfer rate of [3H]CE-LDL to HDL was 1.4–3.6 times greater when LDL was oxidized than when it was intact. Overall, HDL2 was better than HDL3 as donor of CE to native LDL, probably reflecting the relatively greater CE content of HDL2. Oxidation of LDL enhanced the CETP-mediated cholesteryl ester transfer rate to HDL, bringing on a reduced net transfer rate of cholesteryl ester from HDL to ox LDL. This may diminish the oxLDL particle’s atherogenic effect.
- Published
- 2001
69. Role of Nicotinamide Nucleotide Transhydrogenase (Nnt) in Atherosclerosis: Macrophage Reactive Oxygen Species Generation
- Author
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Amarylis C. B. A. Wanschel, Helena C. F. Oliveira, Anibal E. Vercesi, Estela Lorza-Gil, Carina Malaguti, and Alessandro G. Salerno
- Subjects
Biochemistry ,Nicotinamide Nucleotide Transhydrogenase ,Chemistry ,Physiology (medical) ,Reactive oxygen species generation ,Macrophage - Published
- 2015
70. Cholesteryl ester transfer protein gene mutations in Brazilian hyperalphalipoproteinemia
- Author
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E.C. de Faria, Helena C. F. Oliveira, Roberto Schreiber, R.T. Nakamura, D. Kaplan, J. Tentor, Hildete Prisco Pinheiro, L.M. Harada, and M. L. Y. Cruz
- Subjects
chemistry.chemical_classification ,Mutation ,biology ,Gene mutation ,medicine.disease_cause ,Molecular biology ,chemistry ,Biochemistry ,Carrier protein ,Phospholipid transfer protein ,Cholesterylester transfer protein ,Genetics ,biology.protein ,medicine ,Lipase ,Glycoprotein ,Genetics (clinical) - Published
- 2006
71. Activation of the mitochondrial ATP-sensitive K+ channel reduces apoptosis of spleen mononuclear cells induced by hyperlipidemia
- Author
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Helena C. F. Oliveira, Bruno A. Paim, Luciane C. Alberici, Karina G. Zecchin, Sandra R. Mirandola, Roger F. Castilho, Cezar R. Pestana, and Anibal E. Vercesi
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Programmed cell death ,Potassium Channels ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Apoptosis ,Hyperlipidemias ,Mitochondrion ,medicine.disease_cause ,Peripheral blood mononuclear cell ,chemistry.chemical_compound ,Mice ,Endocrinology ,Adenosine Triphosphate ,Oxygen Consumption ,Superoxides ,medicine ,Animals ,Biochemistry, medical ,chemistry.chemical_classification ,Hypertriglyceridemia ,Reactive oxygen species ,biology ,Superoxide ,Cytochrome c ,Research ,Biochemistry (medical) ,Leukopenia ,Mitochondria uncoupling ,Cell biology ,Mitochondria ,Oxidative Stress ,Biochemistry ,chemistry ,biology.protein ,Leukocytes, Mononuclear ,Cell redox state ,Reactive Oxygen Species ,Oxidative stress ,Spleen - Abstract
Background We have previously demonstrated that increased rates of superoxide generation by extra-mitochondrial enzymes induce the activation of the mitochondrial ATP-sensitive potassium channel (mitoKATP) in the livers of hypertriglyceridemic (HTG) mice. The resulting mild uncoupling mediated by mitoKATP protects mitochondria against oxidative damage. In this study, we investigate whether immune cells from HTG mice also present increased mitoKATP activity and evaluate the influence of this trait on cell redox state and viability. Methods Oxygen consumption (Clark-type electrode), reactive oxygen species production (dihydroethidium and H2-DCF-DA probes) and cell death (annexin V, cytocrome c release and Trypan blue exclusion) were determined in spleen mononuclear cells. Results HTG mice mononuclear cells displayed increased mitoKATP activity, as evidenced by higher resting respiration rates that were sensitive to mitoKATP antagonists. Whole cell superoxide production and apoptosis rates were increased in HTG cells. Inhibition of mitoKATP further increased the production of reactive oxygen species and apoptosis in these cells. Incubation with HTG serum induced apoptosis more strongly in WT cells than in HTG mononuclear cells. Cytochrome c release into the cytosol and caspase 8 activity were both increased in HTG cells, indicating that cell death signaling starts upstream of the mitochondria but does involve this organelle. Accordingly, a reduced number of blood circulating lymphocytes was found in HTG mice. Conclusions These results demonstrate that spleen mononuclear cells from hyperlipidemic mice have more active mitoKATP channels, which downregulate mitochondrial superoxide generation. The increased apoptosis rate observed in these cells is exacerbated by closing the mitoKATP channels. Thus, mitoKATP opening acts as a protective mechanism that reduces cell death induced by hyperlipidemia.
- Published
- 2013
72. Redox properties of mitochondria from C57BL/6J mice that lack NADP+‐transhydrogenase activity due to spontaneous NNT mutation
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Felipe G. Ravagnani, Anibal E. Vercesi, Tiago R. Figueira, Juliana A. Ronchi, Roger F. Castilho, and Helena C. F. Oliveira
- Subjects
Nicotinamide Nucleotide Transhydrogenase ,Biochemistry ,Chemistry ,Mutation (genetic algorithm) ,Genetics ,Mitochondrion ,C57bl 6j ,Molecular Biology ,Redox ,Biotechnology - Published
- 2013
73. Cholesterol reduction ameliorates glucose-induced calcium handling and insulin secretion in islets from low-density lipoprotein receptor knockout mice
- Author
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C.A. de Oliveira, Helena C. F. Oliveira, Jane Cristina de Souza, Emerielle C. Vanzela, Everardo M. Carneiro, Antonio C. Boschero, Rafaela Antônio de Bastos Ribeiro, and Luiz F. Rezende
- Subjects
endocrine system ,medicine.medical_specialty ,endocrine system diseases ,medicine.medical_treatment ,Blotting, Western ,Biology ,In Vitro Techniques ,chemistry.chemical_compound ,Islets of Langerhans ,Mice ,Internal medicine ,Insulin Secretion ,medicine ,Animals ,Insulin ,Secretion ,Receptor ,Molecular Biology ,Calcium metabolism ,Mice, Knockout ,geography ,geography.geographical_feature_category ,Cholesterol ,Radioimmunoassay ,Cell Biology ,Islet ,Endocrinology ,Glucose ,chemistry ,Receptors, LDL ,LDL receptor ,lipids (amino acids, peptides, and proteins) ,Calcium - Abstract
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 Ca2 + 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 Ca2 + level (fura-2AM) and SNARE protein expression (VAMP-2, SNAP-25 and syntaxin-1A). Cholesterol was depleted by incubating the islets with increasing concentrations (0–10 mmol/l) of methyl-beta-cyclodextrin (MβCD). 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 Ca2 + 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 Ca2 + handling was also normalized in cholesterol-depleted LDLR−/− islets. Cholesterol removal from WT islets by 0.1 and 1.0 mmol/l MβCD impaired both GSIS and Ca2 + handling. In addition, at 10 mmol/l MβCD 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 MβCD) alters both GSIS and Ca2 + handling. Normalization of cholesterol improves Ca2 + handling and insulin secretion in LDLR−/− islets.
- Published
- 2012
74. The role of dyslipidemia on ocular surface, lacrimal and meibomian gland structure and function
- Author
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Italo Cade Jorge, Elisio Bueno Machado Filho, Jane Cristina de Souza, Silvana S. Meyrelles, Eduardo Rocha, Leonardo Tannus Malki, Carolina Maria Módulo, Ana Carolina Ribeiro Dias, Isabele B S Gomes, and Helena C. F. Oliveira
- Subjects
Genetically modified mouse ,Apolipoprotein E ,Male ,medicine.medical_specialty ,Apolipoprotein B ,Meibomian gland ,Blood lipids ,Mice, Transgenic ,Lacrimal gland ,Cornea ,Cellular and Molecular Neuroscience ,Mice ,LIPOPROTEÍNAS ,Risk Factors ,Internal medicine ,medicine ,Animals ,Dyslipidemias ,biology ,Lacrimal Apparatus ,Meibomian Glands ,medicine.disease ,Sensory Systems ,Lipoproteins, LDL ,Mice, Inbred C57BL ,Ophthalmology ,Disease Models, Animal ,Endocrinology ,medicine.anatomical_structure ,Tears ,LDL receptor ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Dry Eye Syndromes ,Female ,Dyslipidemia ,Follow-Up Studies - Abstract
Dyslipidemia is characterized by high lipid blood levels that are risk factors for cardiovascular diseases, which are leading causes of death. However, it is unclear whether dyslipidemia is a cause of the dry eye syndrome (DES). Therefore we determined in transgenic mice models of dyslipidemia, whether there is an association with DES development.Dyslipidemic models included male and female adult mice overexpressing apolipoprotein CIII (Apo CIII), LDL receptor knockout (LDLR-KO) and ApoE knockout (ApoE-KO). They were compared with age- and gender-matched C57BL/6 mice. Ocular health was evaluated based on corneal slit lamp assessment, phenol red thread test (PRT) and impression cytology. Blood lipid profiles and histology of meibomian and lacrimal glands were also evaluated. Effects of high-fat diet and aging were observed in LDLR-KO and ApoCIII strains, respectively.Body weight and lacrimal gland weight were significantly higher in male mice compared to females of the same strain (P 0.05). Body weight was significantly lower in LDLRKO mice receiving high lipid diet compared to their controls (P = 0.0043). ApoE-KO were hypercholesterolemic and ApoCIII hypertriglyceridemic while LDLR-KO showed increases in both parameters. The PRT test was lower in male LDLR-KO mice with high-fat diet than control mice with standard diet (P = 0.0273). Aging did not affect lacrimal structural or functional parameters of ApoCIII strain.DES development is not solely dependent on dyslipidemia in relevant mice models promoting this condition. On the other hand, lacrimal gland structure and function are differentially impacted by lipid profile changes in male and female mice. This dissociation suggests that other factors beside dyslipidemia impact on tear film dysfunction and DES development.
- Published
- 2012
75. Nagase analbuminemic rats have faster plasma triacylglycerol and VLDL synthesis rates
- Author
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Eder Carlos da Rocha Quintão, Helena C. F. Oliveira, Edna Regina Nakandakare, J.C. Rocha, and Sergio Catanozzi
- Subjects
medicine.medical_specialty ,Very low-density lipoprotein ,Biophysics ,Serum albumin ,Blood lipids ,Lipoproteins, VLDL ,Hematocrit ,Biochemistry ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Endocrinology ,Species Specificity ,Internal medicine ,medicine ,Animals ,Bovine serum albumin ,Serum Albumin ,Triglycerides ,medicine.diagnostic_test ,biology ,Triglyceride ,Chemistry ,Albumin ,Metabolism ,Rats ,Kinetics ,biology.protein ,lipids (amino acids, peptides, and proteins) - Abstract
Serum triacylglycerol (TG) concentration is markedly elevated in Nagase analbuminemic rats (NAR) as compared to Sprague-Dawley rats (SDR) and reflects a high level of mainly VLDL. Hepatic production of triacylglycerol, as measured by the Triton-WR1339 infusion technique of impairing TG removal from blood, and plasma metabolic rate of pulse-infused [125I]apo VLDL, were higher in NAR. However, contrary to previous reports, this elevated TG production could not be controlled by previous treatment of NAR with (i) bovine albumin infused intra-arterially or into the peritoneal cavity, or with (ii) dextran (Mol.wt. 73,500) injected intraperitoneally. Albumin administration expanded the plasma volume and could explain the apparent reduction of blood lipids found by others. Nonetheless, intraperitoneal dextran, as compared to saline, reduced the plasma cholesterol concentration regardless of the variation in the hematocrit level and thus, by raising the osmotic pressure of blood might regulate the metabolism of cholesterol-rich lipoproteins such as LDL and HDL in NAR.
- Published
- 1994
76. Enhanced insulin secretion and glucose tolerance in rats exhibiting low plasma free fatty acid levels and hypertriglyceridaemia due to congenital albumin deficiency
- Author
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Tiago R, Figueira, Rosane A, Ribeiro, Letícia M, Ignacio-Souza, Anibal E, Vercesi, Everardo M, Carneiro, and Helena C F, Oliveira
- Subjects
Blood Glucose ,Hypertriglyceridemia ,Rats, Sprague-Dawley ,Islets of Langerhans ,Insulin Secretion ,Animals ,Insulin ,Female ,Fatty Acids, Nonesterified ,Glucose Tolerance Test ,Deficiency Diseases ,Serum Albumin ,Rats - Abstract
Congenitally analbuminaemic individuals and rats (NARs) exhibit several metabolic abnormalities, including hypertriglyceridaemia and plasma free fatty acid deficiency. Our aim was to study glucose homeostasis and insulin secretion in NARs. Plasma concentrations of lipids, glucose and insulin and secretion of insulin from the pancreatic islets were measured in female NARs and control animals (Sprague-Dawley rats; SDRs). Glucose homeostasis tests were also performed. Plasma glucose levels were similar between NARs and SDRs, irrespective of feeding status. However, fed insulinaemia was ∼37% higher (P 0.05) in NARs than in SDRs. The NARs displayed a markedly increased glucose tolerance, i.e. the integrated glycaemic response was one-third that of the control animals. Enhanced glucose tolerance was associated with threefold higher insulinaemia at peak glycaemia after a glucose load than in the control animals. Similar peripheral insulin sensitivity was observed between groups. Isolated pancreatic islets from NARs secreted significantly more insulin than islets from SDRs in response to a wide range of glucose concentrations (2.8-33.3 mm). Despite having similar liver glycogen contents in the fully fed state, NARs had ∼40% (P 0.05) lower glycogen contents than SDRs after 6 h fasting. The injection of a gluconeogenic substrate, pyruvate, elicited a faster rise in glycaemia in NARs compared with SDRs. Overall, NARs displayed enhanced glucose tolerance, insulin secretion and gluconeogenic flux. The higher glucose tolerance in NARs compared with SDRs is attributed to enhanced islet responsiveness to secretagogues, while peripheral insulin sensitivity seems not to be involved in this alteration. We propose that the enhanced glucose metabolism is a chronic compensatory adaptation to decreased free fatty acid availability in NARs.
- Published
- 2011
77. The higher susceptibility of congenital analbuminemic rats to Ca2+-induced mitochondrial permeability transition is associated with the increased expression of cyclophilin D and nitrosothiol depletion
- Author
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Helena C. F. Oliveira, Tiago R. Figueira, Angela Saito, Roger F. Castilho, and Anibal E. Vercesi
- Subjects
Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,chemistry.chemical_element ,Gene Expression ,Mitochondrion ,Calcium ,medicine.disease_cause ,Biochemistry ,Permeability ,Congenital Abnormalities ,Rats, Sprague-Dawley ,Cyclophilins ,Endocrinology ,Internal medicine ,Blood plasma ,Genetics ,medicine ,Animals ,Molecular Biology ,Serum Albumin ,Membrane Potential, Mitochondrial ,S-Nitrosothiols ,Chemistry ,Congenital analbuminemia ,Brain ,Mitochondria ,Rats ,Oxidative Stress ,Mitochondrial permeability transition pore ,Liver ,Mitochondrial Membrane Protein ,Female ,NAD+ kinase ,Mitochondrial Swelling ,Reactive Oxygen Species ,Oxidative stress ,Cyclophilin D - Abstract
Congenital analbuminemia is a rare autosomal recessive disorder characterized by a trace level of albumin in blood plasma and mild clinical symptoms. Analbuminemic patients generally present associated abnormalities, among which dyslipidemia is a hallmark. In this study, we show that mitochondria isolated from different tissues (liver, heart and brain) from 3-month-old analbuminemic rats (NAR) present a higher susceptibility to Ca 2+ -induced mitochondrial permeability transition (MPT), as assessed by either Ca 2+ -induced mitochondrial swelling, dissipation of membrane potential or mitochondrial Ca 2+ release. The Ca 2+ retention capacity of the liver mitochondria isolated from 3-month-old NAR was about 50% that of the control. Interestingly, the assessment of this variable in 21-day-old NAR indicated that the mitochondrial Ca 2+ retention capacity was preserved at this age, as compared to age-matched controls, which indicates that a reduced capacity for mitochondrial Ca 2+ retention is not a constitutive feature. The search for putative mediators of MPT sensitization in NAR revealed a 20% decrease in mitochondrial nitrosothiol content and a 30% increase in cyclophilin D expression. However, the evaluation of other variables related to mitochondrial redox status showed similar results between the controls and NAR, i.e. , namely the contents of reduced mitochondrial membrane protein thiol groups and total glutathione, H 2 O 2 release rate, and NAD(P)H reduced state. We conclude that the higher expression of cyclophilin D, a major component of the MPT pore, and decreased nitrosothiol content in NAR mitochondria may underlie MPT sensitization in these animals.
- Published
- 2011
78. Cholesteryl ester transfer protein: the controversial relation to atherosclerosis and emerging new biological roles
- Author
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Helena C. F. Oliveira and Eliana Cotta de Faria
- Subjects
medicine.medical_specialty ,Lipoproteins ,Clinical Biochemistry ,Inflammation ,Disease ,Biochemistry ,Alzheimer Disease ,Internal medicine ,Cholesterylester transfer protein ,Genetics ,medicine ,Animals ,Humans ,Cholesterol metabolism ,Obesity ,Molecular Biology ,Cardiovascular mortality ,Clinical Trials as Topic ,Adipogenesis ,biology ,business.industry ,Oxidation reduction ,Cell Biology ,medicine.disease ,Atherosclerosis ,Cholesterol Ester Transfer Proteins ,carbohydrates (lipids) ,Endocrinology ,Cholesterol ,Mutation ,biology.protein ,lipids (amino acids, peptides, and proteins) ,medicine.symptom ,Alzheimer's disease ,business ,Oxidation-Reduction ,Lipoprotein - Abstract
Cholesteryl ester transfer protein (CETP) exerts a profound impact on high-density lipoprotein (HDL) metabolism and, consequently, on the risk of atherosclerosis development and cardiovascular mortality. Here, we review the complex relationship between CETP and atherosclerosis based upon the experimental, clinical, and epidemiological studies. In addition, we discuss the recent findings that expand the functions of CETP to new areas of interest such as Alzheimer's disease, inflammation, and obesity.
- Published
- 2011
79. Lack of plasma albumin enhances glucose tolerance and insulin secretion
- Author
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Everardo M. Carneiro, Helena C. F. Oliveira, Anibal E. Vercesi, Rosane Aparecida Ribeiro, Tiago R. Figueira, and Letícia M. Ignacio-Souza
- Subjects
medicine.medical_specialty ,Endocrinology ,Chemistry ,Internal medicine ,Genetics ,medicine ,Plasma Albumin ,Insulin secretion ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2011
80. Distinct hepatic lipid profile of hypertriglyceridemic mice determined by easy ambient sonic-spray ionization mass spectrometry
- Author
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Helena C. F. Oliveira, Luciane C. Alberici, Rodrigo Ramos Catharino, Rosana M. Alberici, Anibal E. Vercesi, and Marcos N. Eberlin
- Subjects
Spectrometry, Mass, Electrospray Ionization ,Mice, Transgenic ,Mass spectrometry ,Biochemistry ,Analytical Chemistry ,chemistry.chemical_compound ,Mice ,Phosphatidylcholine ,Animals ,Humans ,Phosphatidylinositol ,Triglycerides ,Ambient ionization ,chemistry.chemical_classification ,Hypertriglyceridemia ,Chromatography ,Fatty acid ,Lipid Metabolism ,Lipids ,Mice, Inbred C57BL ,Oleic acid ,chemistry ,Liver ,Arachidonic acid ,Ex vivo - Abstract
Easy ambient sonic-spray ionization mass spectrometry (EASI-MS) was used to interrogate the hepatic lipid profiles of hypertriglyceridemic and control normotriglyceridemic mice. The analyses of ex vivo complex lipid mixtures were made directly with EASI-MS without accompanying separation steps. Intense ions for phosphatidylcholines and triacylglycerols were observed in the positive ion mode whereas the spectra in the negative ion mode provided profiles of phosphatidylethanolamines and phosphatidylinositol. EASI-MS was coupled to high-performance thin-layer chromatography for analysis of free fatty acids. Fourier transform–ion cyclotron resonance–mass spectrometry was also employed to confirm the identity of the detected lipids. We demonstrated higher incorporation of oleic acid in phosphatidylcholine and triacylglycerol composition, higher relative abundance of arachidonic acid containing phosphatidylinositol, and overall distinct free fatty acid profile in the livers of genetic hypertriglyceridemic mice. We propose that these alterations in liver lipid composition are related to the higher tissue and body metabolic rates described in these hypertriglyceridemic mice.
- Published
- 2011
81. Mitochondrial energy metabolism and redox responses to hypertriglyceridemia
- Author
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Luciane C. Alberici, Anibal E. Vercesi, and Helena C. F. Oliveira
- Subjects
medicine.medical_specialty ,Lipid Metabolism Disorder ,Bioenergetics ,Physiology ,Cell Respiration ,Oxidative phosphorylation ,Mitochondrion ,Biology ,medicine.disease_cause ,Mice ,Insulin resistance ,KATP Channels ,Internal medicine ,medicine ,Animals ,Beta oxidation ,Hypertriglyceridemia ,Fatty liver ,Cell Biology ,medicine.disease ,Adaptation, Physiological ,Mitochondria ,Endocrinology ,Liver ,Energy Metabolism ,Oxidation-Reduction ,Oxidative stress - Abstract
In this work we review recent findings that explain how mitochondrial bioenergetic functions and redox state respond to a hyperlipidemic in vivo environment and may contribute to the maintenance of a normal metabolic phenotype. The experimental model utilized to evidence these adaptive mechanisms is especially useful for these studies since it exhibits genetic hypertriglyceridemia and avoids complications introduced by high fat diets. Liver from hypertrigliceridemic (HTG) mice have a greater content of glycerolipids together with increased mitochondrial free fatty acid oxidation. HTG liver mitochondria have a higher resting respiration rate but normal oxidative phosphorylation efficiency. This is achieved by higher activity of the mitochondrial potassium channel sensitive to ATP (mitoK(ATP)). The mild uncoupling mediated by mitoK(ATP) accelerates respiration rates and reduces reactive oxygen species generation. Although this response is not sufficient to inhibit lipid induced extra-mitochondrial oxidative stress in whole liver cells it avoids amplification of this redox imbalance. Furthermore, higher mitoK(ATP) activity increases liver, brain and whole body metabolic rates. These mitochondrial adaptations may explain why these HTG mice do not develop insulin resistance and obesity even under a severe hyperlipidemic state. On the contrary, when long term high fat diets are employed, insulin resistance, fatty liver and obesity develop and mitochondrial adaptations are inefficient to counteract energy and redox imbalances.
- Published
- 2011
82. Cholesteryl esters in lymph chylomicrons: contribution from high density lipoprotein transferred from plasma into intestinal lymph
- Author
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Eder Carlos da Rocha Quintão, Helena C. F. Oliveira, H Meinertz, and K Nilausen
- Subjects
medicine.medical_specialty ,Chyle ,biology ,Cholesterol ,Reverse cholesterol transport ,digestive, oral, and skin physiology ,Cell Biology ,QD415-436 ,Biochemistry ,chemistry.chemical_compound ,Endocrinology ,High-density lipoprotein ,chemistry ,Internal medicine ,Cholesterylester transfer protein ,Cholesteryl ester ,medicine ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Lymph ,Chylomicron - Abstract
Most of the cholesterol in intestinal chyle and chylomicrons is derived from plasma. Our aim was to determine how much plasma low density (LDL) and high density (HDL) lipoproteins contribute to the cholesterol in chyle and chylomicrons, and to examine how plasma cholesterol becomes associated with lymph chylomicrons. Intravenous injection of radioiodinated plasma lipoproteins into two chyluric patients showed that 82% of the HDL plasma pool transferred daily to intestinal chyle, corresponding to 58% of lymph cholesterol; LDL contributed 18% of its plasma pool, corresponding to 18% of lymph cholesterol. When plasma HDL radiolabeled in both the protein and cholesteryl ester moieties was injected, the isotope ratios of plasma HDL and lymph lipoproteins were identical; 85% of the HDL cholesteryl esters transferred to triglyceride-rich lipoproteins, while the apolipoproteins remained largely (70%) in the higher density lipoproteins of the chyle. Incubations of similarly labeled plasma HDL showed preferential transfer of cholesteryl esters to artificial chylomicrons mediated by a factor present in lipoprotein-free plasma. Thus, a sizable portion of plasma HDL enters intestinal lymphatics probably as intact HDL, and then transfers part of their cholesteryl esters to chylomicrons, possibly mediated by transfer proteins. Reverse cholesterol transport may therefore include an extravascular loop via lymph chylomicrons and chylomicron remnants to the liver.
- Published
- 1993
83. Inhibition of nitric oxide synthase protects hypercholesterolemic mice mitochondria against permeability transition
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Ana Catarina Rezende Leite, Adriana Cassina, Rafael Garcia, Helena C. F. Oliveira, Anibal E. Vercesi, Tiago F. Rezende, Rafael Radi, Roger F. Castilho, and Fabiane Leonel Utino
- Subjects
Nitric oxide synthase ,biology ,Chemistry ,Biophysics ,biology.protein ,Cell Biology ,Mitochondrion ,Biochemistry - Published
- 2010
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84. Reduction of endoplasmic reticulum stress--a novel mechanism of action of statins in the protection against atherosclerosis
- Author
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Daniela S. Razolli, Gabriel G. Dorighello, Licio A. Velloso, Andressa Coope, Marciane Milanski, Ana Paula Arruda, Helena C. F. Oliveira, and Ikaro Breder
- Subjects
medicine.medical_specialty ,Simvastatin ,Eukaryotic Initiation Factor-2 ,Inflammation ,Regulatory Factor X Transcription Factors ,Pharmacology ,Endoplasmic Reticulum ,Cell Line ,Mice ,eIF-2 Kinase ,Stress, Physiological ,Internal medicine ,medicine ,Macrophage ,Animals ,Humans ,Phosphorylation ,Endoplasmic Reticulum Chaperone BiP ,Heat-Shock Proteins ,Pravastatin ,Mice, Knockout ,biology ,Endoplasmic reticulum ,Macrophages ,Fatty Acids ,Atherosclerosis ,Antigens, Differentiation ,DNA-Binding Proteins ,Disease Models, Animal ,Endocrinology ,Mechanism of action ,Receptors, LDL ,Knockout mouse ,HMG-CoA reductase ,LDL receptor ,biology.protein ,lipids (amino acids, peptides, and proteins) ,medicine.symptom ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Cardiology and Cardiovascular Medicine ,medicine.drug ,Transcription Factors - Abstract
Fatty-acid-induced endoplasmic reticulum stress has been recently described as a novel mechanism involved in the genesis of atherosclerosis. Here we show that statins, a class of drug widely employed in the clinical management of hypercholesterolemia, reduces lipid-induced macrophage endoplasmic reticulum stress in an isolated cell system and in LDL receptor knockout mice. Given the importance of endoplasmic reticulum stress as an inducer of inflammation, we suspect that the novel mechanism of action herein described for statins may play a major role on its beneficial effects in the prevention of cardiovascular disease.
- Published
- 2010
85. Ciprofibrate increases cholesteryl ester transfer protein gene expression and the indirect reverse cholesterol transport to the liver
- Author
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E.J.B. Bighetti, P.R. Patricio, J.A. Berti, A.C. Casquero, and Helena C. F. Oliveira
- Subjects
medicine.medical_specialty ,Apolipoprotein B ,medicine.drug_class ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Gene Expression ,Fibrate ,chemistry.chemical_compound ,Clofibric Acid ,Mice ,Endocrinology ,Internal medicine ,Cholesterylester transfer protein ,medicine ,Animals ,PPAR alpha ,lcsh:RC620-627 ,Biochemistry, medical ,Hypertriglyceridemia ,Apolipoprotein C-III ,Fenofibrate ,biology ,Chemistry ,Cholesterol ,Research ,Biochemistry (medical) ,Reverse cholesterol transport ,Fibric Acids ,Biological Transport ,medicine.disease ,Cholesterol Ester Transfer Proteins ,carbohydrates (lipids) ,lcsh:Nutritional diseases. Deficiency diseases ,Liver ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Ciprofibrate ,medicine.drug - Abstract
Background CETP is a plasma protein that modulates atherosclerosis risk through its HDL-cholesterol reducing action. The aim of this work was to examine the effect of the PPARα agonist, ciprofibrate, on the CETP gene expression, in the presence and absence of apolipoprotein (apo) CIII induced hypertriglyceridemia, and its impact on the HDL metabolism. Results Mice expressing apo CIII and/or CETP and non-transgenic littermates (CIII, CIII/CETP, CETP, non-Tg) were treated with ciprofibrate during 3 weeks. Drug treatment reduced plasma triglycerides (30-43%) and non-esterified fatty acids (19-47%) levels. Cholesterol (chol) distribution in plasma lipoprotein responses to ciprofibrate treatment was dependent on the genotypes. Treated CIII expressing mice presented elevation in VLDL-chol and reduction in HDL-chol. Treated CETP expressing mice responded with reduction in LDL-chol whereas in non-Tg mice the LDL-chol increased. In addition, ciprofibrate increased plasma post heparin lipoprotein lipase activity (1.3-2.1 fold) in all groups but hepatic lipase activity decreased in treated CETP and non-Tg mice. Plasma CETP activity and liver CETP mRNA levels were significantly increased in treated CIII/CETP and CETP mice (30-100%). Kinetic studies with 3H-cholesteryl ether (CEt) labelled HDL showed a 50% reduction in the 3H-CEt found in the LDL fraction in ciprofibrate treated compared to non-treated CETP mice. This means that 3H-CEt transferred from HDL to LDL was more efficiently removed from the plasma in the fibrate treated mice. Accordingly, the amount of 3H-CEt recovered in the liver 6 hours after HDL injection was increased by 35%. Conclusion Together these data showed that the PPARα agonist ciprofibrate stimulates CETP gene expression and changes the cholesterol flow through the reverse cholesterol transport, increasing plasma cholesterol removal through LDL.
- Published
- 2009
86. Mitochondrial ATP-sensitive K(+) channels as redox signals to liver mitochondria in response to hypertriglyceridemia
- Author
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Camila Campos Mantello, Bruno A. Paim, Karina G. Zecchin, Helena C. F. Oliveira, Alicia J. Kowaltowski, Amanda C. Augusto, Anibal E. Vercesi, Sonia A. Gurgueira, and Luciane C. Alberici
- Subjects
Male ,medicine.medical_specialty ,Potassium Channels ,Mice, Transgenic ,Mitochondria, Liver ,Oxidative phosphorylation ,Mitochondrion ,Biochemistry ,chemistry.chemical_compound ,Mice ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,Xanthine oxidase ,chemistry.chemical_classification ,Hypertriglyceridemia ,Reactive oxygen species ,NADPH oxidase ,biology ,Glutathione ,Disease Models, Animal ,Enzyme ,Endocrinology ,chemistry ,Mitochondrial matrix ,biology.protein ,Female ,Reactive Oxygen Species ,Oxidation-Reduction - Abstract
We have recently demonstrated that hypertriglyceridemic (HTG) mice present both elevated body metabolic rates and mild mitochondrial uncoupling in the liver owing to stimulated activity of the ATP-sensitive potassium channel (mitoK ATP ). Because lipid excess normally leads to cell redox imbalance, we examined the hepatic oxidative status in this model. Cell redox imbalance was evidenced by increased total levels of carbonylated proteins, malondialdehydes, and GSSG/GSH ratios in HTG livers compared to wild type. In addition, the activities of the extramitochondrial enzymes NADPH oxidase and xanthine oxidase were elevated in HTG livers. In contrast, Mn-superoxide dismutase activity and content, a mitochondrial matrix marker, were significantly decreased in HTG livers. Isolated HTG liver mitochondria presented lower rates of H 2 O 2 production, which were reversed by mitoK ATP antagonists. In vivo antioxidant treatment with N -acetylcysteine decreased both mitoK ATP activity and metabolic rates in HTG mice. These data indicate that high levels of triglycerides increase reactive oxygen generation by extramitochondrial enzymes that promote mitoK ATP activation. The mild uncoupling mediated by mitoK ATP increases metabolic rates and protects mitochondria against oxidative damage. Therefore, a biological role for mitoK ATP as a redox sensor is shown here for the first time in an in vivo model of systemic and cellular lipid excess.
- Published
- 2009
87. Independent regulation of chylomicron lipolysis and particle removal rates: Effects of insulin and thyroid hormones on the metabolism of artificial chylomicrons
- Author
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Helena C. F. Oliveira, Eder Carlos da Rocha Quintão, Celina V. Zerbinatti, and Sergio Wechesler
- Subjects
Male ,Thyroid Hormones ,medicine.medical_specialty ,Lipolysis ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Biology ,Hyperthyroidism ,Diabetes Mellitus, Experimental ,Endocrinology ,Hypothyroidism ,Internal medicine ,Chylomicrons ,Blood plasma ,medicine ,Animals ,Insulin ,Pancreatic hormone ,Lipoprotein lipase ,Heparin ,Rats, Inbred Strains ,Rats ,Cholesterol Esters ,Propylthiouracil ,Triolein ,Chylomicron ,medicine.drug ,Hormone - Abstract
The processes of chylomicron lipolysis and removal from plasma were investigated by the intra-arterial infusion of doubly labeled artificial chylomicrons in rats. The rate of lipolysis was measured as a delipidation index (DI), which is the glyceryl-tri 9,10( N )- 3 H oleate ( 3 H-TO) fraction removed from the particle as fatty acids, whereas the cholesteryl(1- 14 C) oleate ( 14 C-CO) plasma disappearance rate measures the splanchnic organ particle uptake. In the alloxan-diabetic rats, despite a normal DI, the 14 C-CO plasma residence time (RT) was longer than in control animals and remained longer after stimulation of the lipoprotein lipase by heparin. DI and 14 C-CO removal rate were not significantly altered by insulin administration to glucose-supplemented control rats. Lipolysis was remarkable in propylthiouracil (PTU)-induced hypothyroidism, and yet the 14 C-CO removal rate was retarded. In hypothyroidism, heparin enhanced the 14 C-CO removal more than in the control group; however, after heparin, the 14 C-CO RT still remained higher in the hypotyroid animals as compared with the control group. Hyperthyroidism lowered the DI; nevertheless, the 14 C-CO disappearance rate was faster than in controls. In summary, lack or excess of thyroid hormone influences both the chylomicron lipolysis and removal systems, whereas lack of insulin impairs mostly the particle removal from plasma, and excess of insulin has no effect on the chylomicron metabolism.
- Published
- 1991
88. Hepatocyte nuclear phenotype: the cross-talk between anabolic androgenic steroids and exercise in transgenic mice
- Author
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Karina, Fontana, Marcela, Aldrovani, Flávia, de Paoli, Helena C F, Oliveira, Benedicto, de Campos Vidal, and Maria Alice, da Cruz-Höfling
- Subjects
Cell Nucleus ,Male ,Staining and Labeling ,Physical Exertion ,Apoptosis ,Mice, Transgenic ,Signal Processing, Computer-Assisted ,DNA Fragmentation ,CD13 Antigens ,Chromatin Assembly and Disassembly ,Cholesterol Ester Transfer Proteins ,Polyploidy ,Mice ,Anabolic Agents ,Phenotype ,Receptors, LDL ,Mesterolone ,Androgens ,Hepatocytes ,In Situ Nick-End Labeling ,Rosaniline Dyes ,Animals ,Humans ,Aspartate Aminotransferases ,Coloring Agents - Abstract
The growing and indiscriminate use of high doses of anabolic androgenic steroid (AAS) among youth and athletes has raised serious concerns about its hepatotoxic effects. Herein, the influence of AAS in the nuclear phenotype of hepatocytes was investigated in sedentary and trained mice heterozygous for the human CETP (cholesteryl ester transfer protein) transgene and for LDL-receptor null allele (CETP+/-LDLr+/-) by image analysis. Five groups were assayed comprising treadmill exercised (Ex) and sedentary (Sed) mice, administered mesterolone (AAS) or gum arabic (GA) and a sedentary blank control: G1(SedAAS), G2(SedGA), G3(ExAAS), G4(ExGA), and G5(SedBL). To assess nuclear phenotypes, the state of chromatin supraorganization, DNA content and fragmentation (TUNEL assay), area and perimeter of hepatocytes were determined in Feulgen-stained liver imprints. In addition, the activity of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) hepatic transaminases were measured. SedAAS-G1 showed the lowest chromatin condensation and highest Feulgen-DNA content, polyploid nuclei frequency, nuclear area and perimeter, suggesting gene activation. Contrarily, ExAAS-G3 showed a highest chromatin condensation, and a significant decrease of Feulgen-DNA content and decreased frequency of polyploid nuclei, which suggest gene silencing. Image analysis of the nuclear phenotype offered a coherent descriptive picture of the changing patterns of chromatin organization, which were shown to be congruent with the levels of Feulgen-DNA content, geometric nuclear parameters and hepatocyte activity. In this study, the image analysis permitted the monitoring of the nuclear response to mesterolone and physical exercise action in liver cells, the molecular mechanism of which is in prospect.
- Published
- 2008
89. Effects of simvastatin, bezafibrate and gemfibrozil on the quantity and composition of plasma lipoproteins
- Author
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Eder Carlos da Rocha Quintão, Helena C. F. Oliveira, Edna Regina Nakandakare, Giuseppe Sperotto, J.C. Rocha, and R C Garcia
- Subjects
Adult ,Male ,Simvastatin ,medicine.medical_specialty ,Very low-density lipoprotein ,Lipoproteins ,Cholesterol, VLDL ,Hyperlipidemias ,chemistry.chemical_compound ,High-density lipoprotein ,Internal medicine ,medicine ,Humans ,Gemfibrozil ,Lovastatin ,Aged ,Hypolipidemic Agents ,Bezafibrate ,Triglyceride ,Cholesterol ,Cholesterol, HDL ,nutritional and metabolic diseases ,Cholesterol, LDL ,Middle Aged ,Apolipoproteins ,Endocrinology ,chemistry ,Low-density lipoprotein ,Female ,Hydroxymethylglutaryl CoA Reductases ,lipids (amino acids, peptides, and proteins) ,Cardiology and Cardiovascular Medicine ,medicine.drug - Abstract
Simvastatin, 10–40 mg/d ( n = 11), bezafibrate, 600 mg/d ( n = 6), and gemfibrozil, 1200 mg/d ( n = 5) were administered for 12 weeks after a 4-week placebo period to subjects with initial plasma levels (mg/100 ml, mean ± SD) of cholesterol (346 ± 77), and of triglycerides (180 ± 54). Total LDL-C plasma concentration was lowered 32% by simvastatin and 35% by bezafibrate, but only bezafibrate diminished the triglyceride (41%) and increased HDL-C plasma levels (35%). Plasma lipoprotein fractions obtained by discontinuous gradient ultracentrifugation, namely, VLDL, lighter LDL (LDL-1), heavier LDL (LDL-2) and bulk HDL were chemically analyzed. Simvastatin and bezafibrate significantly diminished the quantity of VLDL and LDL-1 particles, although barely modifying their composition. Neither drug influenced the LDL-2 plasma concentration. Bezafibrate increased the total plasma HDL level little interfering with its chemical composition. Gemfibrozil was the least effective of all drugs but decreased the lipid and protein contents and their ratios in VLDL and LDL-2.
- Published
- 1990
90. Mitochondrial energy metabolism and redox state in dyslipidemias
- Author
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Helena C. F. Oliveira, Alicia J. Kowaltowski, Roger F. Castilho, and Anibal E. Vercesi
- Subjects
Clinical Biochemistry ,Hypercholesterolemia ,Energy metabolism ,Mitochondrion ,Biology ,medicine.disease_cause ,Biochemistry ,Redox ,KATP Channels ,Hyperlipidemia ,Genetics ,medicine ,skin and connective tissue diseases ,Molecular Biology ,Ion transporter ,Hypertriglyceridemia ,Cell Biology ,medicine.disease ,Mitochondria ,Mitochondrial permeability transition pore ,sense organs ,Energy Metabolism ,Oxidation-Reduction ,Oxidative stress ,NADP - Abstract
Changes in mitochondrial function are intimately associated with metabolic diseases. Here, we review recent evidence relating alterations in mitochondrial energy metabolism, ion transport and redox state in hypercholesterolemia and hypertriglyceridemia. We focus mainly on changes in mitochondrial respiration, K(+) and Ca(2+) transport, reactive oxygen species generation and susceptibility to mitochondrial permeability transition.
- Published
- 2007
91. CETP expression enhances liver HDL-cholesteryl ester uptake but does not alter VLDL and biliary lipid secretion
- Author
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Attilio Rigotti, Ludwig Amigo, Eder Carlos da Rocha Quintão, Alessandro G. Salerno, Patrícia M. Cazita, L.M. Harada, and Helena C. F. Oliveira
- Subjects
Male ,medicine.medical_specialty ,Very low-density lipoprotein ,Time Factors ,medicine.drug_class ,Cholesterol, VLDL ,Mice, Transgenic ,Lipoproteins, VLDL ,Bile Acids and Salts ,Feces ,Mice ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,Bile ,Humans ,Triglycerides ,biology ,Bile acid ,Triglyceride ,Cholesterol ,Reverse cholesterol transport ,VESÍCULA BILIAR (SECREÇÃO) ,Cholesterol Ester Transfer Proteins ,Mice, Inbred C57BL ,carbohydrates (lipids) ,Endocrinology ,Liver ,chemistry ,HMG-CoA reductase ,LDL receptor ,biology.protein ,Cholesteryl ester ,Female ,lipids (amino acids, peptides, and proteins) ,Cholesterol Esters ,Lipoproteins, HDL ,Cardiology and Cardiovascular Medicine - Abstract
The aim of this work was to study how CETP expression affects whole body cholesterol homeostasis. Thus, tissue uptake and plasma removal rates of labeled HDL-cholesteryl ester (CE), VLDL secretion rates, and biliary lipid secretion and fecal bile acid content were compared between human CETP transgenic (Tg) and non-transgenic (nTg) mice fed with a standard diet. CETP Tg mice exhibited increased HDL-CE plasma fractional catabolic rate and uptake by the liver, adrenals, adipose tissue and spleen. HDL fractions from both CETP Tg and from nTg mice were removed faster from the plasma of CETP expressing than from nTg mice, suggesting a direct role of CETP in accelerating tissue CE uptake. However, neither hepatic output of VLDL cholesterol and triglycerides nor biliary lipid and fecal bile acid excretion were changed in CETP Tg compared to nTg mice. CETP Tg mice also showed enhanced hepatic cholesterol content. Steady state cholesterol homeostasis was probably preserved through the downregulation of hepatic HMG-CoA reductase and LDL receptor expression. In conclusion, although CETP expression facilitates cholesteryl ester tissue uptake, it does not alter biliary lipid and fecal bile acid excretion, the mandatory final step of the reverse cholesterol transport.
- Published
- 2007
92. Opposite lipemic response of Wistar rats and C57BL/6 mice to dietary glucose or fructose supplementation
- Author
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Eliana Cotta de Faria, C.R. Barbosa, E.M.V. Albuquerque, Helena C. F. Oliveira, and Lucia Nassi Castilho
- Subjects
Male ,medicine.medical_specialty ,Physiology ,medicine.medical_treatment ,Immunology ,Biophysics ,Fructose ,Biochemistry ,chemistry.chemical_compound ,Mice ,Insulin resistance ,Internal medicine ,medicine ,Dietary Carbohydrates ,Monosaccharide ,Animals ,General Pharmacology, Toxicology and Pharmaceutics ,Rats, Wistar ,Triglycerides ,Muridae ,chemistry.chemical_classification ,Hypertriglyceridemia ,biology ,Cholesterol ,General Neuroscience ,Insulin ,Cell Biology ,General Medicine ,Carbohydrate ,medicine.disease ,biology.organism_classification ,Rats ,Mice, Inbred C57BL ,Disease Models, Animal ,Endocrinology ,Glucose ,chemistry ,Dietary Supplements ,Insulin Resistance - Abstract
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.
- Published
- 2006
93. Hyperlipidemic mice present enhanced catabolism and higher mitochondrial ATP-sensitive K+ channel activity
- Author
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P.R. Patricio, Helena C. F. Oliveira, Luciane C. Alberici, Anibal E. Vercesi, and Alicia J. Kowaltowski
- Subjects
medicine.medical_specialty ,Potassium Channels ,Cell Respiration ,Hyperlipidemias ,Mice, Transgenic ,Mitochondria, Liver ,Mitochondrion ,Biology ,Body Temperature ,chemistry.chemical_compound ,Eating ,Mice ,Internal medicine ,Respiration ,medicine ,Diazoxide ,Uncoupling protein ,Animals ,Humans ,Apolipoprotein C-III ,Hepatology ,Catabolism ,Fatty Acids ,Gastroenterology ,Metabolism ,Protein Structure, Tertiary ,EGTA ,Endocrinology ,chemistry ,Energy Metabolism ,Mitochondrial Swelling ,Adenosine triphosphate ,medicine.drug - Abstract
Background & Aims: Changes in mitochondrial energy metabolism promoted by uncoupling proteins (UCPs) are often found in metabolic disorders. We have recently shown that hypertriglyceridemic (HTG) mice present higher mitochondrial resting respiration unrelated to UCPs. Here, we disclose the underlying mechanism and consequences, in tissue and whole body metabolism, of this mitochondrial response to hyperlipidemia. Methods: Oxidative metabolism and its response to mitochondrial adenosine triphosphate (ATP)-sensitive K + channel (mitoK ATP ) agonists and antagonists were measured in isolated mitochondria, livers, and mice. Results: Mitochondria isolated from the livers of HTG mice presented enhanced respiratory rates compared with those from wild-type mice. Changes in oxygen consumption were sensitive to adenosine triphosphate (ATP), diazoxide, and 5-hydroxydecanoate, indicating they are attributable to mitochondrial ATP-sensitive K + channel (mitoK ATP ) activity. Indeed, mitochondria from HTG mice presented enhanced swelling in the presence of K + ions, sensitive to mitoK ATP agonists and antagonists. Furthermore, mitochondrial binding to fluorescent glibenclamide indicates that HTG mice expressed higher quantities of mitoK ATP . The higher content and activity of liver mitoK ATP resulted in a faster metabolic state, as evidenced by increased liver oxygen consumption and higher body co 2 release and temperature in these mice. In agreement with higher metabolic rates, food ingestion was significantly larger in HTG mice, without enhanced weight gain. Conclusions: These results show that primary hyperlipidemia leads to an elevation in liver mitoK ATP activity, which may represent a regulated adaptation to oxidize excess fatty acids in HTG mice. Furthermore, our data indicate that mitoK ATP , in addition to UCPs, may be involved in the control of energy metabolism and body weight.
- Published
- 2006
94. Statins induce calcium-dependent mitochondrial permeability transition
- Author
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Jesus A. Velho, Luciane C. Alberici, Márcio Y. Matsumoto, Giovanna R. Degasperi, Ricardo G. Cosso, Anibal E. Vercesi, Heitor Okanobo, and Helena C. F. Oliveira
- Subjects
Statin ,Membrane permeability ,medicine.drug_class ,Mitochondria, Liver ,Pharmacology ,In Vitro Techniques ,Toxicology ,Permeability ,Mice ,Adenine nucleotide ,Cyclosporin a ,polycyclic compounds ,medicine ,Animals ,Lovastatin ,Sulfhydryl Compounds ,Egtazic Acid ,Chelating Agents ,Mice, Knockout ,Chemistry ,Sulfhydryl Reagents ,nutritional and metabolic diseases ,Proteins ,Catalase ,Hindlimb ,Mitochondria, Muscle ,Adenosine Diphosphate ,Electrophysiology ,Dithiothreitol ,Cholesterol ,Biochemistry ,Mitochondrial permeability transition pore ,Receptors, LDL ,Simvastatin ,Phenazines ,lipids (amino acids, peptides, and proteins) ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Mitochondrial Swelling ,Pravastatin ,medicine.drug - Abstract
Statins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) are used in the treatment of hypercholesterolemic patients to reduce risk of cardiovascular diseases because of their cholesterol lowering action. Other lipid independent protective actions of statins have been reported. However, some adverse side effects have, also, been described. We report, here, that liver mitochondria isolated from hypercholesterolemic LDL receptor knockout mice treated during 15 days with therapeutic doses (100 mg/kg, p.o.) of lovastatin presented a higher susceptibility to develop membrane permeability transition (MPT). In experiments in vitro, lovastatin-induced MPT in a dose-dependent manner (10-80 microM) by a mechanism sensitive to cyclosporin A (cyclophilin sequestrant), dithiothreitol (reducing agent), adenine nucleotide carrier inhibitor (ADP), catalase (H2O2 reductant) and EGTA (calcium chelator). In agreement with the inhibition of the mitochondrial swelling by dithiothreitol, lovastatin, also, decreased the content of total mitochondrial membrane protein thiol groups. Simvastatin had similar effects on mitochondria; however, pravastatin, a hydrophilic statin, had a weaker effect in inducing MPT. In conclusion, statins can act directly on mitochondria either in vivo or in vitro inducing permeability transition, which is a process involved in cell death.
- Published
- 2005
95. Atherosclerosis in aged mice over-expressing the reverse cholesterol transport genes
- Author
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E.C. de Faria, J.A. Berti, and Helena C. F. Oliveira
- Subjects
Genetically modified mouse ,Male ,medicine.medical_specialty ,Apolipoprotein B ,Genotype ,Physiology ,Transgene ,Immunology ,Biophysics ,Mice, Transgenic ,Biochemistry ,Severity of Illness Index ,Lesion ,Phosphatidylcholine-Sterol O-Acyltransferase ,Mice ,Diabetes mellitus ,Internal medicine ,Cholesterylester transfer protein ,medicine ,Transgenic mice ,Animals ,General Pharmacology, Toxicology and Pharmaceutics ,lcsh:QH301-705.5 ,lcsh:R5-920 ,Apolipoprotein AI ,biology ,Apolipoprotein A-I ,General Neuroscience ,Reverse cholesterol transport ,Biological Transport ,Cell Biology ,General Medicine ,medicine.disease ,Atherosclerosis ,Cholesteryl ester transfer protein ,Cholesterol Ester Transfer Proteins ,Disease Models, Animal ,Endocrinology ,lcsh:Biology (General) ,biology.protein ,Lecithin-cholesterol acyl transferase ,Linear Models ,Diet, Atherogenic ,lipids (amino acids, peptides, and proteins) ,medicine.symptom ,lcsh:Medicine (General) - Abstract
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.
- Published
- 2005
96. Effects of diabetes and CETP expression on diet-induced atherosclerosis in LDL receptor-deficient mice
- Author
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J.A. Berti, A.C. Casquero, E.J.B. Bighetti, Helena C. F. Oliveira, Alessandro G. Salerno, and Antonio C. Boschero
- Subjects
Microbiology (medical) ,Blood Glucose ,medicine.medical_specialty ,Ratón ,Arteriosclerosis ,Pathology and Forensic Medicine ,Diabetes Mellitus, Experimental ,Lesion ,Mice ,Diabetes mellitus ,Internal medicine ,Cholesterylester transfer protein ,medicine ,Immunology and Allergy ,Animals ,Risk factor ,Receptor ,Glycoproteins ,biology ,business.industry ,General Medicine ,medicine.disease ,Streptozotocin ,Lipids ,Cholesterol Ester Transfer Proteins ,carbohydrates (lipids) ,Endocrinology ,Receptors, LDL ,LDL receptor ,biology.protein ,Diet, Atherogenic ,Regression Analysis ,lipids (amino acids, peptides, and proteins) ,medicine.symptom ,business ,Carrier Proteins ,Diabetic Angiopathies ,medicine.drug - Abstract
The role of CETP expression and diabetes in atherogenesis was investigated in mice with heterozygous disruption of the LDL receptor gene (LDLR1). LDLR1 mice with and without CETP expression were treated with streptozotocin (STZ) and maintained on a standard diet for one month before switching to an atherogenic diet for an additional month. STZ-sensitive mice had approximately 2.5-fold higher glycemia and 7.5- to 8.0-fold higher cholesterolemia. Factorial analysis of variance showed no significant effect of diabetes, CETP or diabetes-CETP interaction on the size of the atherosclerotic lesions. CETP expression in non-diabetic mice resulted in a 50% reduction in the area of the atherosclerotic lesions. Multiple regression analysis showed a positive and independent atherogenic effect of triglyceridemia in LDLR1 mice and of cholesterolemia in diabetic mice. Logistic analysis showed that elevated plasma cholesterol level significantly increased the risk of developing large lesion size (>75th percentile). In conclusion, CETP expression did not alter the lesion formation in response to diabetes, although it may be protective in the euglycemic state; the triglyceride level was an independent risk factor for LDL receptor-deficient mice but not for CETP-expressing mice; and elevated plasma cholesterol levels increased the risk of developing large atherosclerotic lesions, independently of CETP and diabetes.
- Published
- 2005
97. Oxidative stress in atherosclerosis-prone mouse is due to low antioxidant capacity of mitochondria
- Author
-
Evelise N. Maciel, Luciane C. Alberici, Gabriel G. Dorighello, Anibal E. Vercesi, Alessandro G. Salerno, Helena C. F. Oliveira, Eliana Cotta de Faria, Jesus A. Velho, and Ricardo G. Cosso
- Subjects
Male ,Programmed cell death ,Membrane permeability ,Arteriosclerosis ,Hypercholesterolemia ,Mitochondria, Liver ,Oxidative phosphorylation ,Mitochondrion ,Biology ,medicine.disease_cause ,Biochemistry ,Mitochondrial Membrane Transport Proteins ,Antioxidants ,Ion Channels ,Mice ,Genetics ,medicine ,Animals ,Molecular Biology ,chemistry.chemical_classification ,Mice, Knockout ,Reactive oxygen species ,Mitochondrial Permeability Transition Pore ,Myocardium ,Brain ,Cell biology ,Mitochondria ,Oxidative Stress ,chemistry ,Receptors, LDL ,Knockout mouse ,LDL receptor ,Leukocytes, Mononuclear ,Female ,Reactive Oxygen Species ,Oxidative stress ,Spleen ,Biotechnology - Abstract
Atherosclerotic disease remains a leading cause of death in westernized societies, and reactive oxygen species (ROS) play a pivotal role in atherogenesis. Mitochondria are the main intracellular sites of ROS generation and are also targets for oxidative damage. Here, we show that mitochondria from atherosclerosis-prone, hypercholesterolemic low-density lipoprotein (LDL) receptor knockout mice have oxidative phosphorylation efficiency similar to that from control mice but have a higher net production of ROS and susceptibility to develop membrane permeability transition. Increased ROS production was observed in mitochondria isolated from several tissues, including liver, heart, and brain, and in intact mononuclear cells from spleen. In contrast to control mitochondria, knockout mouse mitochondria did not sustain a reduced state of matrix NADPH, the main source of antioxidant defense against ROS. Experiments in vivo showed faster liver secretion rates and de novo synthesis of triglycerides and cholesterol in knockout than in control mice, suggesting that increased lipogenesis depleted the reducing equivalents from NADPH and generated a state of oxidative stress in hypercholesterolemic knockout mice. These data provide the first evidence of how oxidative stress is generated in LDL receptor defective cells and could explain the increased LDL oxidation, cell death, and atherogenesis seen in familiar hypercholesterolemia.
- Published
- 2004
98. Chronic treatment with bark infusion from Croton cajucara lowers plasma triglyceride levels in genetic hyperlipidemic mice
- Author
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Eliana Cotta de Faria, E.J.B. Bighetti, Helena C. F. Oliveira, and Alba R.M Souza-Brito
- Subjects
Physiology ,Hyperlipidemias ,Mice, Transgenic ,Pharmacology ,law.invention ,chemistry.chemical_compound ,Mice ,law ,Plasma triglyceride ,Physiology (medical) ,Animals ,Croton cajucara ,Essential oil ,Triglycerides ,Mice, Knockout ,Triglyceride ,Chemistry ,Cholesterol ,Plant Extracts ,General Medicine ,Genetically modified organism ,Receptors, LDL ,visual_art ,visual_art.visual_art_medium ,Dehydrocrotonin ,Plant Bark ,lipids (amino acids, peptides, and proteins) ,Bark ,Croton - Abstract
Aqueous infusion and preparations containing dehydrocrotonin (DHC) and essential oil from Croton cajucara bark were tested for plasma lipid-lowering effects in genetically modified hyperlipidemic mice. Two mouse models were tested: 1) primary hypercholesterolemia resulting from the LDL-receptor gene knockout, and 2) combined hyperlipidemia resulting from crosses of LDL-receptor knockout mice with transgenic mice overexpressing apolipo protein (apo) CIII and cholesteryl ester-transfer protein. Mice treated with bark infusion, DHC, essential oil, or placebos for 25 days showed no signals of toxicity as judged by biochemical tests for liver and kidney functions. The bark infusion reduced triglyceride plasma levels by 40%, while essential oil and DHC had no significant effects on plasma lipid levels. The bark infusion treatment promoted a redistribution of cholesterol among the lipoprotein fractions in combined hyperlipidemic mice. There was a marked reduction in the VLDL fraction and an increase in the HDL fraction, in such a way that the (VLDL + LDL)/HDL ratio was reduced by half. The bark infusion treatment did not modify cholesterol distribution in hypercholesterolemic mice. In conclusion, C. cajucara bark infusion reduced plasma triglycerides levels and promoted a redistribution of cholesterol among lipoproteins in genetically combined hyperlipidemic mice. These changes modify risk factors for the development of atherosclerotic diseases.Key words: hyperlipidemia, transgenic mice, Croton cajucara, dehydrocrotonin, cholesterol.
- Published
- 2004
99. Hypertriglyceridemia increases mitochondrial resting respiration and susceptibility to permeability transition
- Author
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Luciane C, Alberici, Helena C F, Oliveira, Eliete J B, Bighetti, Eliana C, de Faria, Giovana R, Degaspari, Claudio T, Souza, and Anibal E, Vercesi
- Subjects
Hypertriglyceridemia ,Cell Respiration ,Fibric Acids ,Membrane Transport Proteins ,Mice, Transgenic ,Serum Albumin, Bovine ,Atractyloside ,Guanosine Diphosphate ,Ion Channels ,Membrane Potentials ,Mitochondria ,Mitochondrial Proteins ,Clofibric Acid ,Mice ,Liver ,Animals ,Uncoupling Protein 2 ,Triglycerides ,Hypolipidemic Agents - Abstract
High plasma level of triglycerides (TGs) is a common feature in atherosclerosis, obesity, diabetes, alcoholism, stress, and infection. Since mitochondria have been implicated in cell death under a variety of metabolic disorders, we examined liver mitochondrial functions in hypertriglyceridemic transgenic mice. Hypertriglyceridemia increased resting respiration and predisposed to mitochondrial permeability transition (MPT). Ciprofibrate therapy reduced plasma TG levels, normalized respiration, and prevented MPT. The higher resting respiration in transgenic mitochondria remained in the presence of the adenine nucleotide carrier inhibitor, carboxyatractyloside, bovine serum albumin, and the uncoupling proteins (UCPs) inhibitor, GDP. UCP2 content was similar in both control and transgenic mitochondria. We propose that faster resting respiration represents a regulated adaptation to oxidize excess free fatty acid in the transgenic mice.
- Published
- 2004
100. Moderate hyperalphalipoproteinaemia in a Brazilian population is related to lipoprotein lipase activity, apolipoprotein A-I concentration, age and body mass index
- Author
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D. Kaplan, Eliana Cotta de Faria, Samira Borges Kauss Alarcon, L.M. Harada, Valéria S. Nunes, Helena C. F. Oliveira, and Eder Carlos da Rocha Quintão
- Subjects
Adult ,Male ,medicine.medical_specialty ,Population ,Hypercholesterolemia ,Body Mass Index ,chemistry.chemical_compound ,Risk Factors ,Phospholipid transfer protein ,Internal medicine ,Cholesterylester transfer protein ,Medicine ,Humans ,education ,Aged ,education.field_of_study ,Lipoprotein lipase ,biology ,Apolipoprotein A-I ,business.industry ,Cholesterol ,Reverse cholesterol transport ,Cholesterol, HDL ,Age Factors ,General Medicine ,Lipase ,Middle Aged ,Lipids ,Lipoprotein Lipase ,Endocrinology ,chemistry ,Cardiovascular Diseases ,biology.protein ,Linear Models ,lipids (amino acids, peptides, and proteins) ,Female ,Hepatic lipase ,business ,Carrier Proteins ,Lipoprotein - Abstract
We investigated 95 Brazilian adults, aged 21–79 years, who were divided into two groups defined as having high-density lipoprotein (HDL)-cholesterol concentrations above [hyperalphalipoproteinaemia (HALP); n=48] or below (controls; n=47) the 90th percentile of a local population. The activities of lipid transfer proteins and enzymes involved in the plasma reverse cholesterol transport and the prevalence of factors that modulate HDL metabolism (alcohol consumption, ponderosity, physical exercise, menopause and use of hormone replacement treatment in women and smoking) were measured, as well as the prevalence of cardiovascular disease and of its various risk factors. The two groups showed no differences in their frequencies of cardiovascular disease. The HDL2/HDL3-cholesterol and triacylglycerol (triglyceride) ratios and the activities of the phospholipid transfer protein (PLTP) and cholesteryl ester transfer protein (CETP) were similar in both groups. Lipoprotein lipase (LPL) and hepatic lipase (HL) activities were 35% higher (P=0.0002) and 40% lower (P=0.0006) respectively, in HALP compared with control subjects. In a multivariate analysis, HDL-cholesterol and its subfractions were influenced by LPL, apolipoprotein A-I, age (negative relationship) and body mass index (negative relationship). Use of alcohol and ponderosity, as well as the interaction of these factors, explained the LPL activity. HL activity was modulated by smoking, and hormone-replacement therapy influenced the apolipoprotein A-I concentration. CETP activity was influenced by race and PLTP by age. The unique phenotype found in this Brazilian HALP population, namely low HL and high LPL activities, could be determined mostly by genetic components, on which future work will focus.
- Published
- 2003
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