RESUMO
Vitamin A and provitamin A carotenoids are involved in the regulation of adipose tissue metabolism and inflammation. We examined the effect of dietary supplementation using all-trans and 9-cis ß-carotene-rich Dunaliella bardawil alga as the sole source of vitamin A on obesity-associated comorbidities and adipose tissue dysfunction in a diet-induced obesity mouse model. Three-week-old male mice (C57BL/6) were randomly allocated into two groups and fed a high-fat, vitamin A-deficient diet supplemented with either vitamin A (HFD) or ß-carotene (BC) (HFD-BC). Vitamin A levels in the liver, WATs, and BAT of the HFD-BC group were 1.5-2.4-fold higher than of the HFD group. BC concentrations were 5-6-fold greater in BAT compared to WAT in the HFD-BC group. The eWAT mRNA levels of the Mcp-1 and Cd68 were 1.6- and 2.1-fold lower, respectively, and the plasma cholesterol and triglyceride concentrations were 30% and 28% lower in the HFD-BC group compared with the HFD group. Dietary BC can be the exclusive vitamin A source in mice fed a high-fat diet, as shown by the vitamin A concentration in the plasma and tissues. Feeding BC rather than vitamin A reduces adipose tissue macrophage recruitment markers and plasma lipid concentrations.
Assuntos
Clorofíceas , beta Caroteno , Tecido Adiposo/metabolismo , Animais , Clorofíceas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Expressão Gênica , Fígado , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Triglicerídeos/metabolismo , Vitamina A/farmacologia , beta Caroteno/metabolismo , beta Caroteno/farmacologiaRESUMO
Maternal docosahexaenoic acid (DHA) is required during pregnancy to supply for normal fetal growth and development. This pilot study aimed to assess the unknown fatty acid (FA) composition in a cohort of non-pregnant and pregnant Israeli women at term and their offspring on a normal diet without n-3 FA supplementation. The fatty acid profile, analyzed using gas chromatography, showed significantly higher plasma monounsaturated (MUFA) and lower n-6 FA percent distribution with similar n-3 index, in pregnant compared to non-pregnant women. RBC exhibited significantly higher MUFA with similar n-3 index, in pregnant compared to non-pregnant women. N-3 FA significantly correlated between neonates' plasma, with higher n-3 index, and pregnant women's DHA. Conclusion: DHA levels in non-pregnant and pregnant Israeli women at term were comparable and the DHA in pregnant women's plasma positively correlated with their neonate's level, suggesting an efficient mother-fetus FA transfer and/or fetal fatty acid metabolism to longer FA products.
Assuntos
Ácidos Graxos Ômega-3/sangue , Ácidos Graxos Ômega-6/sangue , Troca Materno-Fetal , Adulto , Proteínas de Arabidopsis/sangue , Carbono-Oxigênio Ligases/sangue , Estudos de Casos e Controles , Ácidos Docosa-Hexaenoicos/sangue , Ácidos Graxos Essenciais/sangue , Ácidos Graxos Insaturados/sangue , Feminino , Humanos , Recém-Nascido , Israel , Fenômenos Fisiológicos da Nutrição Materna , Projetos Piloto , Gravidez , Triglicerídeos/sangue , Ácido alfa-Linolênico/sangue , Ácido gama-Linolênico/sangueRESUMO
Docosahexaenoic acid (DHA) is critical for normal brain development and function. DHA is in danger of being significantly reduced in the human food supply, and the question of whether its metabolic precursor, the essential n-3 alpha linolenic acid (ALA) during pregnancy, can support fetal brain DHA levels for optimal neurodevelopment, is fundamental. Female mice were fed either ALA-enriched or Control diet during pregnancy and lactation. The direct effect of maternal dietary ALA on lipids was analyzed in liver, red blood cells, brain and brain vasculature, together with genes of fatty acid metabolism and transport in three-week-old offspring. The long-term effect of maternal dietary ALA on brain fatty acids and memory was studied in 19-week-old offspring. Three-week-old ALA offspring showed higher levels of n-3 fatty acids in liver, red blood cell, blood-brain barrier (BBB) vasculature and brain parenchyma, DHA enrichment in brain phospholipids and higher gene and protein expression of the DHA transporter, major facilitator superfamily domain containing 2a, compared to Controls. 19-week-old ALA offspring showed higher brain DHA levels and better memory performance than Controls. The increased brain DHA levels induced by maternal dietary ALA during pregnancy-lactation, together with the up-regulated levels of major facilitator superfamily domain containing 2a, may indicate a mode for greater DHA uptake with long-term impact on better memory in ALA offspring.
Assuntos
Encéfalo/metabolismo , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/metabolismo , Ácido alfa-Linolênico/farmacologia , Animais , Animais Recém-Nascidos , Encéfalo/efeitos dos fármacos , Feminino , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , DesmameRESUMO
Vitamin A deficiency (VAD) is a major health problem, especially in developing countries. In this study, we investigated the effect of VAD from weaning to adulthood in apoE-/- mice. Three-week-old male mice were allocated into four diet groups: I. VAD II. VAD+vitamin A (VA), 1500 IU retinyl-palmitate; III. VAD+ß-carotene (BC), 6 g/kg feed, containing 50% all-trans and 50% 9-cis BC. IV. VAD with BC and VA (BC+VA). After 13 weeks, we assessed the size of atherosclerotic plaques and measured VA in tissues and BC in plasma and tissues. VAD resulted in diminished hepatic VA levels and undetectable brain VA levels compared to the other groups. BC completely replenished VA levels in the liver, and BC+VA led to a two-fold elevation of hepatic VA accumulation. In adipose tissue, mice fed BC+VA accumulated only 13% BC compared to mice fed BC alone. Atherosclerotic lesion area of BC group was 73% lower compared to VAD group (p < 0.05). These results suggest that BC can be a sole source for VA and inhibits atherogenesis.
Assuntos
Apolipoproteínas E/deficiência , Aterosclerose/etiologia , Aterosclerose/prevenção & controle , Suplementos Nutricionais , Fitoterapia , Deficiência de Vitamina A/tratamento farmacológico , beta Caroteno/administração & dosagem , Animais , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
BACKGROUND AND AIMS: Fulminant hepatitis failure (FHF) is marked by the sudden loss of hepatic function, with a severe life-threatening course in persons with no prior history of liver disease. Interleukin (IL)-1α and IL-1ß are key inflammatory cytokines but little is known about their role in the development of FHF. The aim of this study was to assess the involvement of IL-1α and IL-1ß in the progression of LPS/GalN-induced FHF. METHODS: WT, IL-1α or IL-1ß deficient mice were injected with LPS/GalN. Blood and liver tissue were collected at different time points, FHF related pathways were examined. RESULTS: After FHF induction the survival of both IL-1α and IL-1ß KO mice was longer than that of WT mice. Lower serum liver enzyme levels, demonstrated reduced hepatic injury in the IL-1α and IL-1ßKO mice. Histologically detected liver injury and apoptotic hepatocytes were significantly reduced in the IL-1αand IL-1ßKO mice compared to WT mice. Reduced hepatic IkB levels and upregulated NFκB activity in WT mice remained inhibited in IL-1α and IL-1ß KO mice. Hepatic expression levels of TNFα and IL-6 were significantly increased in WT mice but not in IL-1α and IL-1ß KO mice. CONCLUSIONS: IL-1α and IL-1ß play a central role in the pathogenesis of LPS/GalN-induced FHF. These interleukins are associated with the activation of NFκB signaling, upregulation of the pro-inflammatory cytokines and liver damage and apoptosis. Since neither IL-1α nor IL-1ß depletions completely rescued the phenotype, we believe that IL-1α and IL-1ß have a similar and probably complementary role in FHF progression.
Assuntos
Interleucina-1alfa/fisiologia , Interleucina-1beta/fisiologia , Falência Hepática Aguda/fisiopatologia , Animais , Western Blotting , Marcação In Situ das Extremidades Cortadas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Cholesterol efflux from macrophages is a key process in reverse cholesterol transport and, therefore, might inhibit atherogenesis. 9-cis-ß-carotene (9-cis-ßc) is a precursor for 9-cis-retinoic-acid (9-cis-RA), which regulates macrophage cholesterol efflux. Our objective was to assess whether 9-cis-ßc increases macrophage cholesterol efflux and induces the expression of cholesterol transporters. Enrichment of a mouse diet with ßc from the alga Dunaliella led to ßc accumulation in peritoneal macrophages. 9-cis-ßc increased the mRNA levels of CYP26B1, an enzyme that regulates RA cellular levels, indicating the formation of RA from ßc in RAW264.7 macrophages. Furthermore, 9-cis-ßc, as well as all-trans-ßc, significantly increased cholesterol efflux to high-density lipoprotein (HDL) by 50% in RAW264.7 macrophages. Likewise, food fortification with 9-cis-ßc augmented cholesterol efflux from macrophages ex vivo. 9-cis-ßc increased both the mRNA and protein levels of ABCA1 and apolipoprotein E (APOE) and the mRNA level of ABCG1. Our study shows, for the first time, that 9-cis-ßc from the diet accumulates in peritoneal macrophages and increases cholesterol efflux to HDL. These effects might be ascribed to transcriptional induction of ABCA1, ABCG1, and APOE. These results highlight the beneficial effect of ßc in inhibition of atherosclerosis by improving cholesterol efflux from macrophages.
Assuntos
Aterosclerose/prevenção & controle , HDL-Colesterol/metabolismo , Suplementos Nutricionais , Reguladores do Metabolismo de Lipídeos/uso terapêutico , Macrófagos Peritoneais/metabolismo , Regulação para Cima , beta Caroteno/análogos & derivados , Transportador 1 de Cassete de Ligação de ATP/agonistas , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/agonistas , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Apolipoproteínas E/agonistas , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Aterosclerose/imunologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Células Cultivadas , Clorófitas/química , HDL-Colesterol/sangue , Indução Enzimática , Reguladores do Metabolismo de Lipídeos/metabolismo , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fitoplâncton/química , Células RAW 264.7 , Receptores de LDL/genética , Receptores de LDL/metabolismo , Ácido Retinoico 4 Hidroxilase/química , Ácido Retinoico 4 Hidroxilase/genética , Ácido Retinoico 4 Hidroxilase/metabolismo , beta Caroteno/metabolismo , beta Caroteno/uso terapêuticoRESUMO
Vitamin A is involved in regulation of glucose concentrations, lipid metabolism, and inflammation, which are major risk factors for atherogenesis. However, the effect of vitamin A deficiency on atherogenesis has not been investigated. Therefore, the objective of the current study was to examine whether vitamin A deficiency accelerates atherogenesis in apolipoprotein E-deficient mice (apoE(-/-)). ApoE(-/-) mice were allocated into the following groups: control, fed vitamin A-containing chow diet; BC, fed chow diet fortified with Dunaliella powder containing ßc isomers; VAD, fed vitamin A-deficient diet; and VAD-BC group, fed vitamin A-deficient diet fortified with a Dunaliella powder. Following 15 weeks of treatment, liver retinol concentration had decreased significantly in the VAD group to about 30% that of control group. Vitamin A-deficient diet significantly increased both plasma cholesterol concentrations and the atherosclerotic lesion area at the aortic sinus (+61%) compared to the control group. Dietary ßc fortification inhibited the elevation in plasma cholesterol and retarded atherogenesis in mice fed the vitamin A-deficient diet. The results imply that dietary vitamin A deficiency should be examined as a risk factor for atherosclerosis and that dietary ßc, as a sole source of retinoids, can compensate for vitamin A deficiency.
Assuntos
Apolipoproteínas E/deficiência , Aterosclerose/tratamento farmacológico , Aterosclerose/etiologia , Suplementos Nutricionais , Deficiência de Vitamina A/complicações , Vitamina A/metabolismo , beta Caroteno/uso terapêutico , Animais , Aterosclerose/sangue , Aterosclerose/prevenção & controle , Peso Corporal/efeitos dos fármacos , Colesterol/sangue , Regulação da Expressão Gênica/efeitos dos fármacos , Resistência à Insulina , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Vitamina A/sangue , Deficiência de Vitamina A/sangue , Deficiência de Vitamina A/patologiaRESUMO
Phytosterols are sterols found naturally in various oils from plants. Phytosterols compete with cholesterol for a place in the mixed micelles, needed for cholesterol absorption by the small intestine. As a result, cholesterol absorption, either from food or from bile salts is lowered by about 50%, leading to a towering of about 10% of blood cholesterol level, despite an increase in hepatic cholesterol synthesis. This reduction is achieved when phytosterols are given both as monotherapy, and in addition to statin therapy. The average Western diet contains about 400-800 mg of phytosterols per day, while the dose needed for lowering the blood cholesterol level is about 2-3 grams per day. Therefore, for the purpose of reducing blood cholesterol, they should be given either as phytosterol-enriched food or as supplements. The reduction in the level of LDL-choLesterol achieved with phytosterols may reduce the risk of coronary disease by about 25%. Hence, the American Heart Association recommended the consumption of phytosterols, as part of a balanced diet, for towering blood cholesterol levels.
Assuntos
Anticolesterolemiantes/administração & dosagem , LDL-Colesterol/sangue , Fitosteróis/administração & dosagem , American Heart Association , Anticolesterolemiantes/farmacologia , Doença das Coronárias/prevenção & controle , Suplementos Nutricionais , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Fitosteróis/farmacologia , Estados UnidosRESUMO
PURPOSE: The aim of the current study was to evaluate the therapeutic effects of omega-3 plant sterol esters (n-3-PSE) on lipid profile and other coronary heart disease risk factors in subjects with mixed hyperlipidemia. METHODS: Ninety-one patients with mixed hyperlipidemia were randomized in a double blind fashion to receive either placebo (corn oil) or n-3-PSE. Twenty four patients dropped out or were excluded from the efficacy analysis due to protocol violation. The primary efficacy endpoint was mean change in plasma low-density lipoprotein cholesterol (LDL-C) levels after 12 weeks of treatment. Other efficacy measures included plasma lipids, lipoproteins, and high-sensitivity C-reactive protein (hsCRP) levels. Participants who completed the double-blind study were given the option to continue into an open-label, 12-weeks follow up phase. RESULTS: n-3-PSE treatment did not result in a significant change in LDL-C levels. Triglyceride levels were reduced significantly by 19% (51 mg/dL, p < 0.0001) in the n-3-PSE group in comparison with the placebo group (p = 0.025). Diastolic blood pressure and hsCRP were reduced by 7% (5.9 mmHg) and 7.8% (0.6 mg/L), respectively, and were significantly different from the placebo group (p = 0.036 and p = 0.018, respectively). CONCLUSIONS: In patients with mixed hyperlipidemia, n-3-PSE treatment may offer a safe and effective therapy for triglyceride level reduction while avoiding the typical increase in LDL-C levels associated with n-3 fatty acid treatment. The observed reduction in blood pressure and inflammation markers warrants further evaluation. The positive effect of n-3-PSE treatment was preserved at the end of the follow up phase.
Assuntos
Ácidos Graxos Ômega-3/uso terapêutico , Hipercolesterolemia/sangue , Hipercolesterolemia/tratamento farmacológico , Fitosteróis/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Proteína C-Reativa/metabolismo , LDL-Colesterol/sangue , Método Duplo-Cego , Ésteres/efeitos adversos , Ésteres/uso terapêutico , Ácidos Graxos Ômega-3/efeitos adversos , Feminino , Humanos , Hipercolesterolemia/fisiopatologia , Lipídeos/sangue , Lipoproteínas/sangue , Masculino , Pessoa de Meia-Idade , Fitosteróis/efeitos adversos , Placebos , Triglicerídeos/sangueRESUMO
BACKGROUND Fundus albipunctatus is a retinal dystrophy caused by a mutation in the gene encoding 11-cis-retinol dehydrogenase which delays the recovery of rod photoreceptor cells from light stimulation leading to night blindness. A recent study of a mouse model of fundus albipunctatus treated with 9-cis-retinal showed an improvement in visual function and structure. METHODS Seven patients with fundus albipunctatus were given a daily food supplement of four capsules containing high-dose 9-cis-beta-carotene for 90 days. The subjects were tested before and after treatment by visual field and electroretinogram in both eyes. This non-randomised prospective phase I study was registered at http://www.clinicaltrials.gov (NCT00478530). RESULTS All patients showed significant improvements in peripheral visual field (mean deviation improved from -4.77+/-2.0 to -3.28+/-2.28, p=0.009, t test) and a highly significant improvement in rod recovery rates measured electroretinographically (maximal scotopic b-wave amplitude responses, improved from 197+/-49 muV to 292+/-48 muV, p<0.001, t test). No complications or side effects were observed. CONCLUSION Oral treatment with 9-cis-beta-carotene led to reversal of a human retinal dystrophy. This potential therapy is readily available and should be evaluated in retinal dystrophies of similar mechanisms such as various types of retinitis pigmentosa.
Assuntos
Suplementos Nutricionais , Oftalmopatias Hereditárias/tratamento farmacológico , Degeneração Retiniana/tratamento farmacológico , Vitaminas/uso terapêutico , beta Caroteno/uso terapêutico , Administração Oral , Adolescente , Adulto , Eletrorretinografia , Oftalmopatias Hereditárias/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Degeneração Retiniana/fisiopatologia , Resultado do Tratamento , Acuidade Visual/efeitos dos fármacos , Campos Visuais/efeitos dos fármacos , Adulto JovemAssuntos
HDL-Colesterol/sangue , Complicações do Diabetes/sangue , Angiopatias Diabéticas/sangue , Triglicerídeos/sangue , Aterosclerose/sangue , Aterosclerose/epidemiologia , Aterosclerose/mortalidade , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/mortalidade , Doença das Coronárias/sangue , Doença das Coronárias/epidemiologia , Doença das Coronárias/mortalidade , Complicações do Diabetes/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/mortalidade , Angiopatias Diabéticas/tratamento farmacológico , Dislipidemias/sangue , Ácidos Graxos Ômega-3/uso terapêutico , Humanos , Niacina/uso terapêutico , PPAR alfa/agonistas , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/mortalidadeRESUMO
BACKGROUND: Fatty acid bile acid conjugates (FABACs) are novel synthetic molecules that solubilize cholesterol, prevent cholesterol crystal and gallstone formation, and dissolve pre-existing gallstones in mice. They are thus potential agents for gallstone prevention and treatment. The available knowledge concerning their biliary, systemic or possible toxic effects is, however, incomplete. AIM: To obtain information regarding biliary and systemic effects of FABACs. METHODS: Hamsters, rats and mice were administered C20-FABAC intragastrically, and serum and bile chemistries, organ histology, animal wellbeing, and survival were monitored. RESULTS: FABAC feeding (150 mg/kg/day) caused no adverse effects in any of the animal species studied. FABAC did not influence biliary cholesterol, phospholipid, or bile-salt concentrations in mice. In hamsters, biliary cholesterol concentration decreased slightly, but effects on phospholipids and bile salts were inconsistent. In some mouse strains, FABAC supplementation increased transaminases slightly. In hamsters and rats, transaminases were mainly unaffected or even decreased. Serum alkaline phosphatase, creatinine, albumin and glucose were generally unaffected by FABAC feeding. No gross or histopathological differences between controls and FABAC-fed animals were noted in any of the organs investigated. CONCLUSIONS: C20-FABAC given at a pharmacological dose is safe and devoid of any significant toxic effects in three different animal species.
Assuntos
Bile/efeitos dos fármacos , Ácido Cólico/toxicidade , Ácidos Graxos/toxicidade , Animais , Bile/metabolismo , Glicemia/efeitos dos fármacos , Colesterol/metabolismo , Creatinina/sangue , Cricetinae , Avaliação Pré-Clínica de Medicamentos , Metabolismo dos Lipídeos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Mesocricetus , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Wistar , Albumina Sérica/efeitos dos fármacos , Especificidade da EspécieRESUMO
Magnesium (Mg) modulates blood lipid levels, atherogenesis, and atherosclerosis in rabbits, when supplemented to diet. We have recently reported that a high concentration (50 g/L) of Mg sulfate fortification of drinking water attenuates atherogenesis in male and female LDL-receptor-deficient mice fed a high-cholesterol diet. The aims of the current study were to examine whether lower concentrations and another Mg salt could also have such an antiatherogenic effect. Thirty male LDL-receptor-deficient mice were divided into three groups (n=10 in each group). The mice received either distilled water or water fortified with 0.83 g or with 8.3 g Mg-chloride per liter. In the first (27 wk) and second (5 wk) stages of the experiment, the mice received normal chow and Western-type diet, respectively. Blood was drawn for determination of plasma Mg, calcium, and lipid levels. The extent of atherosclerotic lesions was determined at the aortic sinus. Magnesium-chloride fortification of drinking water did not result in higher plasma Mg concentrations, whereas a trend toward lower plasma calcium concentrations did not reach statistical significance. Even though plasma lipid levels were similar at the beginning and the end of the study, there were decreased plasma cholesterol and triglyceride levels in the Mg groups after stage I. The atherosclerosis extent at the aortic sinus was significantly decreased in the 8.3-g Mg-chloride/L group (23,437 +/- 10,083 micron2) compared with the control group (65,937 +/- 31,761 microm2). There was also a trend toward lower atherosclerosis extent at the aortic sinus in the 0.83-g Mg-chloride/L group. An additional Mg salt (Mg-chloride) fortification of drinking water is capable of inhibiting atherogenesis in male LDL-receptor-deficient mice. That is done in a lower concentration of Mg than previously reported.