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Megalin-mediated reuptake of retinol in the kidneys of mice is essential for vitamin A homeostasis
(2005)
The reuptake of retinol (ROH) and retinol-binding protein (RBP) in the kidneys is mediated by the endocytic receptor megalin, suggesting an important role for this receptor in vitamin A (VA) metabolism. We examined the extent to which megalin deficiency may affect urinary ROH excretion, levels of ROH and RBP in plasma, as well as storage of VA in liver and kidney. For this purpose, mice with a kidney-specific megalin gene defect (megalin(lox/lox):; apoE(Cre)) and control mice (megalin(lox/lox)) were fed either a basal diet containing 4500 retinol equivalents (RE)/kg diet or a diet without VA during experimental periods of 42 and 84 d. Urinary ROH excretion was observed only in megalin(lox/lox); apoE(Cre) mice (P < 0.0001, 2-way ANOVA) and not in the controls. Plasma ROH and RBP differed only by diet (P < 0.05), but not genotype (P = 0.615). A major effect of megalin deficiency, however, was evident in retinyl ester levels in the liver (P < 0.05), which were similar to 37% lower than those in megalin(lox/lox) controls (P < 0.05, Student's t test) during the 84-d period of dietary VA deprivation. Kidney levels of VA were not affected by the receptor gene defect. The findings demonstrate that urinary ROH excretion caused by megalin deficiency requires accelerated mobilization of hepatic VA stores to maintain normal plasma ROH levels, which suggests that megalin plays an essential role in systemic VA homeostasis
Background: Transthyretin (TTR), a traditional biomarker for nutritional and inflammatory status exists in different molecular variants of yet unknown importance. A truncated form of TTR has recently been described to be part of a set of biomarkers for the diagnosis of ovarian cancer. The main aim of the study was therefore to characterize differences in microheterogeneity between ascitic fluid and plasma of women affected with ovarian cancer and to evaluate the tumor site as the possible source of TTR. Methods: Subjects were 48 women with primary invasive epithelial ovarian cancer or recurrent ovarian carcinoma. The control group consisted of 20 postmenopausal women. TTR and retinol-binding protein (RBP) levels were measured by enzyme-linked immunoassay ( ELISA) and C-reactive protein (CRP) levels by a high- sensitivity latex particle turbidimetric assay. The molecular heterogeneity of TTR was analysed using immunoprecipitation and matrix-associated laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Presence of TTR in tumor tissue was determined with indirect peroxidase immunostaining. Results: TTR and RBP (mu g/ml) levels in serum were 148.5 +/- 96.7 and 22.5 +/- 14.8 in affected women compared to 363.3 +/- 105.5 and 55.8 +/- 9.3 in healthy postmenopausal women ( p < 0.01). In ascitic fluid, levels were 1.02 +/- 0.24 and 4.63 +/- 1.57 mu g/ml, respectively. The mean levels of TTR and RBP in serum showed a tendency to decrease with the severity of the disease and were lower in affected women whose CRP levels were > 40 mg/ml ( p = 0.08 for TTR; p < 0.05 for RBP). No differences in TTR microheterogeneity were observed between TTR isolated from serum of affected and healthy women or from ascitic fluid. TTR occurred rather consistently in four variants. Mass signals were at 13758 +/- 7, 13876 +/- 13 ( greatest intensity), 13924 +/- 21 and 14062 +/- 24 Da, representing native, S-cysteinylated, S-cysteinglycinylated and glutathionylated TTR, respectively. Serum of healthy and affected women as well as ascitic fluid contained the truncated fragment of TTR ( 12828 +/- 11 Da). No immunoreactive TTR was observed in the tumor sites. Conclusion: The severity of the cancer associated catabolism as well as the inflammation status affect serum TTR and RBP levels. Neither TTR nor its truncated form originates from tumor tissue and its occurrence in ascites may well reflect the filtration from blood into ascitic fluid
The term proteinuria is taken to mean abnormally high protein excretion in the urine. Proteinuria is the consequence of glomerular filtration of plasma proteins, their subsequent reabsorption by the proximal tubular cells and secretion of protein by the tubular cells and distal urinary tract. In physiological conditions, the structural integry of the glomerular filtration barrier prevents the abnormal passage of albumin (molecular mass 66 kDa) and high-molecular- weight proteins (> 66 kDa),whereas the passage of low-molecular-weight proteins (< 66 kDa) is almost completely unrestricted. Proteins that arrive the tubular lumen are reabsorbed by endocytosis after binding to the megalin-cubilin complex. An increased load of proteins in the tubular lumen leads to the saturation of the reabsorptive mechanism and higher urinary protein excretion. Proteinuria can originate from prerenal, renal and postrenal causes. Elevated tubular protein concentrations have been recognized to be toxic to tubular cells and associated with the progression of chronic renal disease. Therefore, the quantitative and qualitative evaluation of proteinuria is important for the diagnosis of renal disease
An imbalance between formation and detoxification of oxygen radicals leads to oxidant stress that may increase in more intense oxidative metabolism caused by a high intake of metabolizable energy to provide metabolic intermediates for the milk synthesis and secretion. This hypothesis was tested using dairy cows and the concentration of hydroperoxides in lipids (LHP) extracted from circulative lipoprotein particles of low and very low density (LDL and VLDL/chylomicrons) as oxidant stress indicator. The particles were prepared by ultracentrifugation of serum obtained by coccygeal bleeding (13 cows, 1. parity, n=8 and 2. parity, n=5, lactation stage, 53 +/- 1.4 days post partum) and purified by precipitation. Concentrations of LHP-LDL/mg Lipoprotein correlated significantly with daily milk yield (r = 0.73, P = 0.004) or daily milk energy output (r = 0.77, P = 0.003) in contrast to LHP of VLDL/chylomicron particles. Thus, some evidence was obtained for an almost linear, positive relationship between milk productivity and oxidant stress occurring in LDL
Background: Vitamin A (VA) and its derivates (retinoids) are important nutritional substances, which mediate their biological activity mainly via nuclear retinoid receptors. Maternal VA intake during lactation influences the VA content in milk and the VA status of the progeny. We investigated the effects of maternal supplementation during lactation and direct supplementation to the pups after weaning on the retinoid concentration in serum and liver of neonatal mice using high doses of VA. Methods: Dams were fed a basal (4,500 retinol equivalents/ kg diet) or a VA- supplemented (324,000 retinol equivalents/ kg diet) diet during lactation. Pups kept receiving the same diet after weaning. Serum and liver samples of the pups were collected during lactation at days 1, 3, 5, 7, and 14 and post-weaning at days 21 and 65 after birth. Samples were analysed for retinoids by high-performance liquid chromatography. Results: Maternal VA supplementation resulted in significantly higher concentrations of retinol, retinyl palmitate and retinyl stearate in serum of mice neonates at days 5, 7, 14, 21 and 65 after birth in comparison to the basal diet, whereas significantly higher concentrations were observed in liver at days 5, 14, 21 and 65 after birth. At day 7 after birth, a decrease in the liver retinoid concentrations occurred in the VA-supplemented diet. Conclusion: Our results show for the first time that supplementation with high doses of VA during the lactation period in mice can affect serum retinol concentrations in the neonates and report that day 7 after birth is a critical time in the tissue distribution of retinoids during postnatal development. Copyright (C) 2005 S. Karger AG, Basel
Androgens and estrogens are transported bound to the sex hormone binding globulin (SHBG). SHBG is believed to keep sex steroids inactive and to control the amount of free hormones that enter cells by passive diffusion. Contrary to the free hormone hypothesis, we demonstrate that megalin, an endocytic receptor in reproductive tissues, acts as a pathway for cellular uptake of biologically active androgens and estrogens bound to SHBG. In line with this function, lack of receptor expression in megalin knockout mice results in impaired descent of the testes into the scrotum in males and blockade of vagina opening in females. Both processes are critically dependent on sex-steroid signaling, and similar defects are seen in animals treated with androgen- or estrogen-receptor antagonists. Thus, our findings uncover the existence of endocytic pathways for protein bound androgens and estrogens and their crucial role in development of the reproductive organs