RESUMO
Vitamin B12 deficiency is a risk factor for bone disorders via mechanisms not fully understood. In this study, an increase in serum inorganic phosphorus (Pi) concentrations was associated with a vitamin B12 deficiency. Napi2a, a renal cotransporter for Pi reabsorption, accumulated on plasma membranes in a vitamin B12 deficiency suggests that vitamin B12 plays an important role in Pi homeostasis.
Assuntos
Reabsorção Óssea , Rim/metabolismo , Osteoclastos/patologia , Fosfatos/metabolismo , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIa/fisiologia , Deficiência de Vitamina B 12/fisiopatologia , Animais , Homeostase , RatosRESUMO
Megalin is a scavenger receptor that serves in the endocytosis of a highly diverse group of ligands that includes Vitamin B12. We found an accumulation of megalin closed to apical region in renal proximal tubule cells of Vitamin B12-deficient rats. Interestingly, Vitamin B12 levels also controlled resorption of renal retinol binding protein. Using L2 yolk sac cells, megalin localized to the submembrane compartment by methylmalonic acid (MMA), which accumulates during vitamin B12 deficiency. In addition, MMA inhibited megalin-mediated endocytosis via YWTD repeats motif in an ectodomain of megalin. Therefore, megalin endocytosis may be regulated by MMA.
Assuntos
Endocitose , Túbulos Renais Proximais/metabolismo , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Ácido Metilmalônico/urina , Deficiência de Vitamina B 12/metabolismo , Vitamina B 12/metabolismo , Animais , Animais Lactentes , Linhagem Celular , Regulação da Expressão Gênica , Células HEK293 , Humanos , Túbulos Renais Proximais/fisiopatologia , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Ácido Metilmalônico/farmacologia , Ratos , Ratos Wistar , Proteínas de Ligação ao Retinol/genética , Proteínas de Ligação ao Retinol/metabolismo , Transdução de Sinais , Deficiência de Vitamina B 12/genética , Deficiência de Vitamina B 12/fisiopatologia , Saco Vitelino/citologia , Saco Vitelino/efeitos dos fármacos , Saco Vitelino/metabolismoRESUMO
We have previously reported that rats fed on a vitamin B12 (B12)-deficient diet containing 180 g soybean protein per kg diet showed marked histologic damage in their testes. In this paper, we report the effect of B12-deficiency on B12-dependent methionine synthase in the rats' testes and the effect of methionine supplementation of the diet on testicular damage. Rats were fed the soybean protein-based B12-deficient diet for 120 d. We confirmed that those rats were in serious B12-deficiency by measuring urinary methylmalonic acid excretion and B12 content in tissues. Methionine synthase activity in the testis of the B12-deficient rats was less than 2% of that in B12-supplemented (control) rats. To complement disrupted methionine biosynthesis, methionine was supplied in the diet. A supplement of 5 g D,L-methionine per kg diet to the B12-deficient diet did not affect urinary methylmalonic acid excretion of B12-deficient rats. The testicular histology of rats fed the methionine-supplemented B12-deficient diet was almost indistinguishable from that of control rats. Thus, we conclude that the lowered testicular methionine synthase activity is the primary cause of the histologic damage due to B12-deficiency and that methionine supplementation to the diet can reduce the damage. These findings would indicate the importance of the methionine synthase activity, especially for testicular function.
Assuntos
Suplementos Nutricionais , Metionina/uso terapêutico , Proteínas de Soja/administração & dosagem , Doenças Testiculares/prevenção & controle , Testículo/efeitos dos fármacos , Deficiência de Vitamina B 12/dietoterapia , 5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/biossíntese , 5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/efeitos dos fármacos , Análise de Variância , Animais , Peso Corporal/efeitos dos fármacos , Dieta/métodos , Modelos Animais de Doenças , Feminino , Masculino , Ácido Metilmalônico/urina , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Wistar , Doenças Testiculares/complicações , Doenças Testiculares/patologia , Testículo/fisiopatologia , Testículo/ultraestrutura , Deficiência de Vitamina B 12/complicações , Deficiência de Vitamina B 12/urinaRESUMO
Newborn mice weaned from mice fed on a B12-deficient diet during pregnancy and lactation were fed on a B12-deficient diet for 90 days after weaning, and the state of B12 deficiency was evaluated. The effect of B12 deficiency on the testicular tissue was also examined. The body weight of the mice fed on a B12-deficient diet for 90 days was slightly lower than that of the control mice administrated CN-B12, and the urinary excretion of methylmalonic acid (MMA) was increased. The B12 concentrations in the liver and testes were markedly depressed by B12 deficiency, being about 13 and 10 pmol/g, respectively, on day 90. The testes weight was clearly reduced by B12 deficiency. The testes weight/100 g body weight was also lowered. Clear morphological changes were observed in the testicular tissue of the B12-deficient mice. These results showed that mice in a severely B12-deficient state could be produced by dietary B12 deprivation. These B12-deficient mice could be useful as model animals not only for elucidating the functions of B12 in vivo, but also for biochemical studies.
Assuntos
Modelos Animais de Doenças , Deficiência de Vitamina B 12/metabolismo , Animais , Peso Corporal , Dieta , Fígado/metabolismo , Fígado/patologia , Masculino , Fenômenos Fisiológicos da Nutrição Materna/fisiologia , Ácido Metilmalônico/urina , Camundongos , Camundongos Endogâmicos BALB C , Tamanho do Órgão , Índice de Gravidade de Doença , Testículo/metabolismo , Testículo/patologia , Fatores de Tempo , Vitamina B 12/metabolismo , Deficiência de Vitamina B 12/patologia , Deficiência de Vitamina B 12/urinaRESUMO
The influence of maternal vitamin B12 malnutrition on testicular development of offspring was examined using soy protein-based B12-deficient diets with or without 0.5% DL-methionine supplementation. Dams were fed the B12-deficient diet throughout gestation and lactation, whereas dams in a control group were fed a control diet which contained cyanocobalamin in the B12-deficient diet without methionine. Offspring born to dams fed the B12-deficient diet without methionine showed poor testicular development, e.g. decreased numbers of seminiferous tubules containing healthy spermatocytes and a high ratio of apoptotic cells per all germ cells. The abnormality was rarely observed in the group fed the B12-deficient diet with methionine. It was likely that the testicular abnormality of offspring was caused by B12-deficiency post partum and was prevented by the methionine supplementation. These observations suggested that maternal B12 nutritional status during the pre-weaning period is quite important for spermatogenesis of male offspring and that the requirement of B12 for testicular development is to produce active B12-dependent methionine synthase.
Assuntos
5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/metabolismo , Lactação , Fenômenos Fisiológicos da Nutrição Materna , Metionina/uso terapêutico , Testículo/crescimento & desenvolvimento , Deficiência de Vitamina B 12/complicações , Vitamina B 12/administração & dosagem , Animais , Animais Recém-Nascidos , Dieta , Suplementos Nutricionais , Feminino , Masculino , Metionina/farmacologia , Estado Nutricional , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Fenômenos Fisiológicos da Nutrição Pré-Natal , Ratos , Ratos Wistar , Espermatogênese , Doenças Testiculares/enzimologia , Doenças Testiculares/etiologia , Doenças Testiculares/prevenção & controle , Testículo/anormalidades , Testículo/efeitos dos fármacos , Deficiência de Vitamina B 12/tratamento farmacológico , Complexo Vitamínico B/administração & dosagemRESUMO
BACKGROUND/AIMS: Vitamin B12 (B-12) is an essential cofactor for methionine synthase, and methionine is critical for the methylation of various biological molecules including DNA. Whether changes in B-12 levels can alter specific gene expression through DNA methylation and whether dietary methionine has any effect on general DNA methylation status still remains controversial. METHODS: We raised severely B-12-deficient rats as well severely-B-12 deficient rats but supplemented with 5% methionine. mRNA levels of methionine cycle-related enzymes were analyzed. RESULTS: Gene expression patterns changed under B-12-deficient conditions but were recovered by dietary methionine supplementation to B-12-deficient rats. However, cystathionine beta-synthase mRNA levels, which had decreased under B-12-deficient conditions, did not recover with supplementary dietary methionine. The CpG island of the cystathionine beta-synthase promoter was hypomethylated in B-12-deficient rats, and showed no recovery after methionine addition. CONCLUSIONS: Dietary B-12 can affect epigenetic machinery by regulating DNA methylation status and dietary methionine may have small effects on DNA methylation.