Model-based compartmental analysis indicates a reduced mobilization of hepatic vitamin A during inflammation in rats

Vitamin A (VA) kinetics was studied in rats with marginal VA stores before, during, and after inflammation. Rats received orally [11,12-(3)H(N)]retinol ([(3)H]VA; day 0), and inflammation was induced on day 21 with lipopolysacchride (LPS) for 3 days (n = 5) or recombinant human interleukin-6 (rhIL-6) for 7 days (n = 5). Both the fraction of [(3)H]VA and retinol concentrations in plasma were reduced significantly by LPS or rhIL-6. Compartmental analysis using the Windows version of Simulation, Analysis, and Modeling software was applied to group mean data, and non-steady-state models were developed. After absorption, VA kinetics was described by a three-compartment model that included plasma, kidney/interstitium, and liver/carcass. Four mechanisms decreasing plasma retinol were investigated: increased urinary excretion, increased irreversible loss, increased movement into interstitium, and decreased hepatic mobilization. Modeling demonstrated that a 79% reduction in hepatic mobilization of retinol (from 4.3 to 0.9 nmol/h) by 15 h after LPS best accounted for the observed changes in plasma VA kinetics (sum of squares = 9.05 x 10(-07)). rhIL-6 caused an earlier reduction (75% by 5.6 h). These models predicted a return to control values by 10 days after inflammation. If prolonged, inflammation-induced hyporetinolemia can render hepatic retinol unavailable to extrahepatic tissues, possibly leading to their impaired function, as observed in VA-deficient children with measles infection.     

A multicompartmental model of vitamin A kinetics in rats with marginal liver vitamin A stores

A linear, first-order, constant-coefficient multicompartmental model is presented which describes the dynamics of [3H]retinol turnover in adult rats with normal plasma retinol concentrations but low liver stores (less than 100 micrograms of retinol equivalents). To fit plasma and tissue (liver, kidney, and rest of carcass) tracer and tracee data, eight physiological compartments were required in the model: two in plasma (proposed to correspond to the retinol transport complex, and retinyl esters in plasma lipoproteins) and two each in liver, kidneys, and other extrahepatic tissues. Extensive recycling of retinol among plasma, liver, and the rest of carcass was also required. The model predicted that 44% of whole body vitamin A (143 micrograms) was in extrahepatic tissues. The vitamin A utilization rate (system disposal rate) was 6.9 micrograms of retinol equivalents/day. The system residence time (mean sojourn time) for vitamin A was 21 days, and the fractional catabolic rate for the system was 5%/day. The mean transit time (turnover time) for vitamin A in its plasma retinol transport complex was 0.078 days (1.9 hr); the residence time was 0.98 day, versus 11 days in the liver, 9 days in carcass, and 0.54 days in kidneys. The model predicted that, of the plasma turnover, 48% recycled to the liver and 52% to extrahepatic tissues. The liver retinol secretion rate was 48 micrograms/day, more than half of which was from recycled plasma retinol. Since the plasma retinol turnover rate (87 micrograms/day) was 13 times the system disposal rate, the data suggest that this is a high response system in which changes in the dynamics of recycling of retinol allow for rapid adjustment in vitamin A distribution in response to changes in nutritional, metabolic, or physiological conditions; and in which plasma retinol levels are controlled homeokinetically by changes in hepatic and extrahepatic recycling of holo retinol-binding protein.     

Utilization of vitamin E

Natural (RRR) or synthetic (all-rac) forms of alpha-tocopherol are available (usually as acetate esters) for use as vitamin E supplements. In animal tests, the natural stereoisomer, RRR-alpha-tocopheryl acetate, is 1.36 times more biologically potent than all-rac-alpha-tocopheryl acetate, an equimolar mixture of eight stereoisomers [8,15,40-43]. The higher biologic activity of natural compared with synthetic vitamin E does not result from differences in antioxidant activity [2,3], but could hypothetically be explained by differences in (1) absorption, (2) plasma transport, (3) delivery to tissues, or (4) metabolism. These possibilities will be considered in this review.     

维生素D3对自发性高血压大鼠靶器官炎症的影响

目的探索维生素D3与高血压和炎症的关系。方法自发性高血压大鼠20只,随机分为对照组和实验组,各10只。实验组大鼠腹腔注射维生索D3制剂3μg／kg（溶于20％丙二醇0．5mL中）,每周2次;对照组仅腹腔注射丙二醇0．5mL,两组均干预12周。实验过程中监测大鼠血压变化。干预前后,酶联免疫法检测血清25（OH）D3、钙、白细胞介素-6（IL-6）、基质金属蛋白酶-9（MMP-9）的浓度;计算肾脏-体重比和心脏-体重比;HE染色观察两组大鼠肾脏、心脏、主动脉、小动脉组织病理改变。结果实验组和对照组在干预前血压无差异显著性（P〉0．05）;干预后,实验组和对照组大鼠平均收缩压分别为（157±9）mmHg和（173±8）mmHg（P〈0．05）。实验组的血清25（OH）D3、血钙水平比对照组高（P〈0．05）,IL-6、MMP-9水平实验组比对照组低（P〈0．05）。实验组的心脏-体重比小于对照组（P〈0．05）。实验组的肾脏、心脏和小动脉高血压、炎性损害明显轻于对照组。结论规律的维生素D3用药能够抑制炎症因子IL-6、MMP-9的产生,抑制机体炎症反应,调节控制血压。     

The immune responses to diabetes in BB rats supplemented with vitamin A

A substantial amount of evidence suggests that in type I diabetes, vitamin A and zinc status could be of concern because of their impaired metabolic availability. Because both vitamin A and zinc play important roles in the regulation of immune function, the present study was undertaken to examine the immune responses to vitamin A and zinc supplements in diabetic-prone Bio-Breed rats (BBdp), and if the supplements increase the incidence of diabetes. Weanling BBdp rats were fed a NIH-07 diet supplemented with vitamin A either alone or in combination with zinc up to 120 days of age. A greater percentage of rats developing diabetes was found in rats that had supplements of vitamin A and zinc (67%) than those on the basal diet (55%) or with vitamin A supplementation alone (50%). The B cells and macrophages were all markedly increased, whereas CD(4)(+) and CD(8)(+) T cells were decreased at the onset of diabetes. However, this immune status was not changed by vitamin A and zinc supplements. The plasma vitamin A levels were significantly decreased in the presence of diabetes and the vitamin A status did not improve when the rats were given vitamin A and zinc supplements. The Natural Killer cell cytotoxicity on a per-cell basis was significantly decreased in the presence of diabetes, irrespective of supplements with vitamin A and zinc. Overall, results indicated that vitamin A and immune status are both affected by type I diabetes; these effects, however, are not responsive to supplemental intakes of vitamin A either alone or in combination with zinc.     

Studies on metabolism of vitamin A. Absorption of retinal (vitamin A aldehyde) in rats

1. Young rats with low reserves of vitamin A were dosed with retinal in groundnut oil, and the stomach, the contents, mucosa and muscles of small intestine, the blood and the liver were analysed at periods up to 24hr. after dosing. 2. Up to 6hr. after the dose, retinal was present in high concentrations in the contents, mucosa and muscles of the intestine. Small but significant amounts were present in blood and liver at all times. 3. The intestinal mucosa and muscles always contained small amounts of retinol and its esters. 4. A study of the distribution of the three forms of the vitamin within the mucosal cell showed that most of the mucosal retinal enters the cell unchanged. 5. When protein-depleted rats were similarly given retinal, the rate of reduction of the aldehyde, and the consequent deposition in the liver of retinol and its esters, progressively decreased with reduced protein intake.     

The deficit in folate and vitamin B12 triggers liver macrovesicular steatosis and inflammation in rats with dextran sodium sulfate-induced colitis

The risks of nonalcoholic steatohepatitis (NASH) and deficiency in vitamin B12 and folate (methyl donor deficiency, MDD) are increased in inflammatory bowel disease (IBD). We investigated the influence of MDD on NASH in rats with DSS-induced colitis. Two-month-old male Wistar rats were subjected to MDD diet and/or ingestion of DSS and compared to control animals. We studied steatosis, inflammation, fibrosis, plasma levels of metabolic markers, cytokines and lipopolysaccharide, and inflammatory pathways in liver. MDD triggered a severe macrovesicular steatosis with inflammation in DSS animals that was not observed in animals subjected to DSS or MDD only. The macrovesicular steatosis was closely correlated to folate, vitamin B12, homocysteine plasma level and liver S-adenosyl methionine/S-adenosyl homocysteine (SAM/SAH) ratio. Liver inflammation was evidenced by activation of nuclear factor kappa B (NFκB) pathway and nuclear translocation of NFκB phospho-p65. MDD worsened the increase of interleukin 1-beta (IL-1β) and abolished the increase of IL10 produced by DSS colitis. It increased monocyte chemoattractant protein 1 (MCP-1). MDD triggers liver macrovesicular steatosis and inflammation through imbalanced expression of IL-1β vs. IL10 and increase of MCP-1 in DSS colitis. Our results suggest evaluating whether IBD patients with MDD and increase of MCP-1 are at higher risk of NASH.     

Impaired biliary secretion of immunoglobulin A in vitamin A-deficient rats

The effect of vitamin A deficiency on biliary secretion of IgA was investigated. Rats used in this study were rendered vitamin A deficient following withdrawal of retinoic acid from the diet of retinoate-cycled animals. This procedure allows a precise control of both the onset of deficiency and dietary protein-energy input. Defective synthesis and transport of IgA antibodies into the bile was evident when vitamin A-deficient rats (A-) were immunized by injections of either Brucella abortus or sheep red blood cells directly into the Peyer's patches. Antibody titers in the bile of A- animals were significantly lower than those of A+ controls (P less than 0.01). These A- rats also had significantly lower levels of total IgA in the bile compared with A+ controls (P less than 0.05). Moreover, the transport of labeled rat IgA injected intravenously was adversely affected in these animals. These results, together with our previous report on the impaired intestinal antibody in A- rats, clearly indicate that vitamin A deficiency interferes with the transport of IgA antibodies into the bile of these animals.     

A method for quantifying synchrony in testes of rats treated with vitamin A deprivation and readministration

Using a variation of a previously published method for manipulating vitamin A levels, we obtained synchronized rat testes and determined the frequency of stages of the seminiferous epithelium in each rat. In this study, we have demonstrated a method for quantitative analysis of the synchrony. The degree of synchronization was expressed as a fraction of the cycle of the seminiferous epithelium, and thus in terms not influenced by the different durations of the stages of this cycle. The median stage about which the tubules were synchronized was calculated. This method may be used to compare the effects of different synchronizing treatments, which may be subtle, and to study various aspects of spermatogenesis in the synchronized testes. For example, the duration of the cycle of the seminiferous epithelium in synchronized testes is estimated to be 12.5 days.     

Compartmental modeling of whole-body vitamin A kinetics in unsupplemented and vitamin A-retinoic acid-supplemented neonatal rats

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.