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1.
J Lipid Res ; 55(8): 1738-49, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24914038

RESUMO

Little is known about the contribution of different tissues to whole-body vitamin A (VA) kinetics in neonates. Here, we have used model-based compartmental analysis of tissue tracer kinetic data from unsupplemented (control) and VA-retinoic acid (VARA)-supplemented neonatal rats to determine VA kinetics in specific tissues under control and supplemented conditions. First, compartmental models for retinol kinetics were developed for individual tissues, and then an integrated compartmental model incorporating all tissues was developed for both groups. The models predicted that 52% of chylomicron (CM) retinyl ester was cleared by liver in control pups versus 22% in VARA-treated pups, whereas about 51% of VA was predicted to be extrahepatic in 4- to 6-day-old unsupplemented neonatal rats. VARA increased CM retinyl ester uptake by lung, carcass, and intestine; decreased the release into plasma of retinol that had been cleared by liver and lung as CM retinyl esters; stimulated the uptake of retinol from plasma holo-retinol binding protein into carcass; and decreased the retinol turnover out of the liver. Overall, neonatal VA trafficking differed from that previously described for adult animals, with a larger contribution of extrahepatic tissues to CM clearance, especially after VA supplementation, and a significant amount of VA distributed in extrahepatic tissues.


Assuntos
Suplementos Nutricionais , Modelos Biológicos , Tretinoína/farmacologia , Tretinoína/farmacocinética , Vitamina A/farmacologia , Vitamina A/farmacocinética , Animais , Animais Recém-Nascidos , Feminino , Ratos , Ratos Sprague-Dawley
2.
J Lipid Res ; 55(6): 1077-86, 2014 06.
Artigo em Inglês | MEDLINE | ID: mdl-24711633

RESUMO

Vitamin A (VA) metabolism in neonates is virtually uncharacterized. Our objective was to develop a compartmental model of VA metabolism in unsupplemented and VA-supplemented neonatal rats. On postnatal day 4, pups (n = 3/time) received 11,12-[(3)H]retinol orally, in either oil (control) or VA combined with retinoic acid (VARA) [VA (∼6 mg/kg body weight) + 10% retinoic acid]. Plasma and tissues were collected at 14 time points up to 14 days after dose administration. VARA supplementation rapidly, but transiently, increased total retinol mass in plasma, liver, and lung. It decreased the peak fraction of the dose in plasma. A multi-compartmental model developed to fit plasma [(3)H]retinol data predicted more extensive recycling of retinol between plasma and tissues in neonates compared with that reported in adults (144 vs. 12-13 times). In VARA pups, the recycling number for retinol between plasma and tissues (100 times) and the time that retinol spent in plasma were both lower compared with controls; VARA also stimulated the uptake of plasma VA into extravascular tissues. A VARA perturbation model indicated that the effect of VARA in stimulating VA uptake into tissues in neonates is both dramatic and transient.


Assuntos
Suplementos Nutricionais , Modelos Biológicos , Tretinoína/farmacologia , Tretinoína/farmacocinética , Vitamina A/farmacologia , Vitamina A/farmacocinética , Animais , Feminino , Masculino , Ratos , Ratos Sprague-Dawley
3.
J Nutr ; 143(3): 253-9, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23325918

RESUMO

The accumulation of hepatic TG and development of hepatic steatosis (HS) is a serious complication of the use of parenteral nutrition (PN) formulas containing a high percentage of dextrose. But whether fat emulsions or other nutrients can ameliorate the induction of HS by high-carbohydrate diets is still uncertain. We hypothesized that administration of a lipid emulsion (LE; Intralipid) and/or the vitamin A metabolite retinal (RAL) will reduce hepatic TG accumulation and attenuate indicators of inflammation. C57BL/6 male mice were fed PN formula as their only source of hydration and nutrition for 4-5 wk. In Expt. 1, mice were fed PN only or PN plus treatment with RAL (1 µg/g orally), LE (200 µL i.v.), or both LE and RAL. In Expt. 2, LE was orally administered at 4 and 13.5% of energy to PN-fed mice. All PN mice developed HS compared with mice fed normal chow (NC) and HS was reduced by LE. The liver TG mass was lower in the PN+LE and PN+RAL+LE groups compared with the PN and PN+RAL groups (P < 0.01) and in the 4% and 13.5% PN+LE groups compared with PN alone. Hepatic total retinol was higher in the RAL-fed mice (P < 0.0001), but RAL did not alter TG mass. mRNA transcripts for fatty acid synthase (Fasn) and sterol regulatory element-binding protein-1c (Srebpf1) were higher in the PN compared with the NC mice, but FAS protein and Srebpf1 mRNA were lower in the PN+LE groups compared with PN alone. The inflammation marker serum amyloid P component was also reduced. In summary, LE given either i.v. or orally may be sufficient to reduce the steatotic potential of orally fed high-dextrose formulas and may suppress the early development of HS during PN therapy.


Assuntos
Emulsões Gordurosas Intravenosas/uso terapêutico , Fígado Gorduroso/prevenção & controle , Mediadores da Inflamação/sangue , Inflamação/prevenção & controle , Fígado/efeitos dos fármacos , Nutrição Parenteral/efeitos adversos , Triglicerídeos/metabolismo , Administração Oral , Animais , Gorduras na Dieta/farmacologia , Gorduras na Dieta/uso terapêutico , Emulsões Gordurosas Intravenosas/farmacologia , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Glucose/efeitos adversos , Inflamação/sangue , Inflamação/etiologia , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/metabolismo , Retinaldeído/farmacologia , Retinaldeído/uso terapêutico , Componente Amiloide P Sérico/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Vitamina A/sangue
4.
J Nutr ; 142(8): 1590-5, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22739370

RESUMO

Coadministration of retinoic acid (RA) and polyinosinic acid:polycytidylic acid (PIC) has been shown to cooperatively enhance the anti-tetanus toxoid (anti-TT) vaccine response in adult mice. Germinal center formation in the spleen is critical for a normal antibody response. Recent studies have identified Stimulated by Retinoic Acid-6 (Stra6) as the cell membrane receptor for retinol-binding protein (RBP) in many organs, including spleen. The objectives of the present studies were to test whether orally administered vitamin A (VA) itself, either alone or combined with RA, and/or treatment with PIC regulates Stra6 gene expression in mouse spleen and, concomitantly, antibody production. Eight-week-old C57BL/6 mice were immunized with TT. In an initial kinetic study, oral VA (6 mg/kg) increased anti-TT IgM and IgG production as well as splenic Stra6 mRNA expression. In treatment studies that were analyzed 9 d postimmunization, retinoids including VA, RA, VA and RA combined, and PIC significantly increased plasma anti-TT IgM and IgG (P < 0.05) and splenic Stra6 mRNA (P < 0.05). Treatments that included PIC elevated plasma anti-TT IgM and IgG concentrations >20-fold (P < 0.01). Immunohistochemistry of STRA6 protein in mouse spleen confirmed its increase after immunization and retinoid treatment. In conclusion, retinoid treatments that included VA, RA, VA and RA combined, and the combination of retinoid and PIC stimulated the expression of Stra6 in spleen, which potentially could increase the local uptake of retinol. Concomitantly, these treatments increased the systemic antigen-specific antibody response. The ability of oral retinoids to stimulate systemic immunity has implications for public health and therapeutic use of VA.


Assuntos
Anticorpos Antibacterianos/sangue , Proteínas de Membrana/metabolismo , Baço/metabolismo , Toxoide Tetânico/imunologia , Tretinoína/farmacologia , Vitamina A/farmacologia , Administração Oral , Animais , Quimioterapia Combinada , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Poli I-C/administração & dosagem , Poli I-C/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Distribuição Aleatória , Tretinoína/administração & dosagem , Vitamina A/administração & dosagem
5.
J Nutr ; 142(4): 649-54, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22357747

RESUMO

Vitamin A (VA) and its active form, retinoic acid (RA), are regulators of skeletal development. In the present study, we investigated if maternal VA intake during pregnancy and lactation, as well as direct oral supplementation of neonates with VA + RA (VARA) in early life, alters neonatal bone formation and chondrocyte gene expression. Offspring of dams fed 3 levels of VA (marginal, adequate, and supplemented) for 10 wk were studied at birth (P0) and postnatal day 7 (P7). One-half of the newborns received an oral supplement of VARA on P1, P4, and P7. Tissues were collected on P0 and 6 h after the last dose on P7. Pup plasma and liver retinol concentrations were increased by both maternal VA intake and VARA (P < 0.01). Although maternal VA did not affect bone mineralization as assessed by von Kossa staining, newborn femur length was increased with maternal VA (P < 0.05). VARA supplementation of neonates increased the length of the hypertrophic zone only in VA-marginal pups, close to that in neonates from VA-adequate dams, suggesting VARA caused a catching up of growth that was limited by low maternal VA intake. Maternal diet did not alter type X nor type II collagen mRNA. However, VARA-treated pups from VA-supplemented dams had reduced mRNA for aggrecan, a major component of cartilage matrix, and increased mRNA for matrix metalloproteinase (MMP)13, which catalyzes the degradation of aggrecan and collagens. These results suggest that moderately high maternal VA intake combined with neonatal VARA supplementation can reduce the ratio of aggrecan:MMP, which may unfavorably alter early bone development.


Assuntos
Agrecanas/metabolismo , Fêmur/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Metaloproteinase 13 da Matriz/metabolismo , Osteogênese , Deficiência de Vitamina A/dietoterapia , Vitamina A/efeitos adversos , Agrecanas/genética , Animais , Animais Recém-Nascidos , Condrócitos/metabolismo , Suplementos Nutricionais/efeitos adversos , Feminino , Fêmur/patologia , Lâmina de Crescimento/patologia , Lactação , Fígado/metabolismo , Fenômenos Fisiológicos da Nutrição Materna , Metaloproteinase 13 da Matriz/genética , Gravidez , Ratos , Ratos Sprague-Dawley , Tretinoína/efeitos adversos , Tretinoína/uso terapêutico , Vitamina A/sangue , Vitamina A/metabolismo , Vitamina A/uso terapêutico , Deficiência de Vitamina A/congênito , Deficiência de Vitamina A/metabolismo , Deficiência de Vitamina A/patologia , Desmame
6.
J Nutr ; 141(4): 660-6, 2011 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-21310867

RESUMO

High vitamin A (VA) intakes have been correlated with increased risk of bone fracture. Over 50% of the U.S. adult population reports use of dietary supplements, which can result in VA intakes > 200% of the RDA. In this study, 2 experiments were designed to determine the effect of dietary VA on cortical and trabecular bone properties and resistance to ex vivo fracture. In Expt. 1, we investigated whether orally administered VA accumulates in bone. Seven-week-old rats were treated daily with VA (6 mg/d for 14 d). Total retinol increased in both the tibia and femur (P < 0.01). In Expt. 2, we conducted a longitudinal study in which rats were fed 1 of 3 levels of dietary VA (marginal, adequate, and supplemented, equal to 0.35, 4, and 50 µg retinol/g diet, respectively) from weaning until the ages of 2-3 mo (young), 8-10 mo (middle-age), and 18-20 mo (old). Tibial trabecular and cortical bone structure, bone mineral density, and resistance to fracture were measured using micro-computed tomography and material testing system analysis, respectively. The VA-marginal diet affected measures of cortical bone dimension, suggesting bone remodeling was altered. VA supplementation increased medullary area and decreased cortical thickness in young rats (P < 0.05), but these changes were not present during aging. VA supplementation did not affect resistance to fracture or bone mineral content in old rats. From these results, we conclude that VA-marginal status affects trabecular bone more than cortical bone, and VA supplementation at a moderate level over the lifetime is unlikely to increase the risk of age-related bone fracture in rats.


Assuntos
Envelhecimento/metabolismo , Densidade Óssea , Fraturas Ósseas/prevenção & controle , Vitamina A/administração & dosagem , Animais , Remodelação Óssea , Suplementos Nutricionais , Feminino , Fêmur/metabolismo , Fraturas Ósseas/etiologia , Masculino , Ratos , Ratos Sprague-Dawley , Tíbia/metabolismo , Vitamina A/metabolismo
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