Vitamin A Metabolism and Kinetics During the Neonatal Period: Studies in the Rat Model
Open Access
- Author:
- Hodges, Joanna Kalina
- Graduate Program:
- Nutritional Sciences
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- September 13, 2016
- Committee Members:
- A. Catharine Ross, Dissertation Advisor/Co-Advisor
Michael H. Green, Committee Chair/Co-Chair
Gregory C. Shearer, Committee Member
Kevin J. Harvatine, Committee Member
Kevin J. Harvatine, Outside Member - Keywords:
- nutrition
micronutrients
vitamin A
retinol
neonate
newborn
infant
metabolism
supplementation
mathematical modeling
tissue distribution
liver
lung
kidney
brain
adipose tissue
skin
muscle
rat - Abstract:
- Background: Vitamin A (VA, retinol) supplementation is recommended for children older than 6 mo of age in countries with high rates of malnutrition. However, the distribution and retention of VA in body tissues has not been extensively explored. Objective: This study was conducted to determine the uptake, retention and distribution of retinol, without and after supplementation with VA, in plasma and tissues in neonatal rats raised under VA-marginal conditions. Methods: Sprague-Dawley neonatal rats (n = 104, 63 males) nursed by mothers fed a VA-marginal diet (0.35 mg retinol equivalents/kg diet) were randomized and treated on postnatal day (P) 4 with an oral dose of either VA (6 μg retinyl palmitate/g body weight) or canola oil as control, both containing 1.8 μCi of [3H]retinol. Pups (n = 4/group/time) were euthanized at 13 times from 30 min to 24 d after dosing. The total retinol (ROH) concentration and mass was determined by ultra-performance liquid chromatography in all collected organs. The fractional and absolute (expressed in nmol/d) transfer of ROH between plasma and organs was estimated in Windows version of Simulation, Analysis and Modeling (WinSAAM) software, with distinct kinetic profiles generated for the chylomicron retinyl esters (CM-REs) and retinol bound to retinol-binding protein (RBP-ROH). Retinol concentrations and kinetic parameters determined in the present study were compared with those obtained from the previous experiment, in which neonatal rats were supplemented with VA mixed with retinoic acid (VARA). Results: In the control group, plasma VA was marginal (0.8 µmol/L), whereas liver VA was deficient (<70 nmol/g). Nonetheless, the liver contained most (~76%) of the whole-body VA mass, while extrahepatic, non-digestive organs together contained ~13%. White adipose tissue (WAT), which was nearly absent prior to P12, contained only ~1% of the total VA mass in the body. In VA-supplemented neonates, the mean total retinol concentrations in all organs were significantly greater than in control pups. However, this increase lasted only ~1 d in most extrahepatic tissues, with the exception of WAT, where the increase lasted for 18 d. The subsequent kinetic analysis of tracer data revealed that VA supplementation redirected the flow of CM-REs away from the peripheral and toward the central organs, such as the liver, lungs and brain. Vitamin A supplementation also resulted in a greater fractional release of RBP-ROH from the liver, which was acquired mainly by the peripheral tissues, but not retained efficiently. This was evidenced by the higher turnover of RBP-derived ROH, especially in the carcass (composed largely of bones and muscles), and a substantially greater recycling number of ROH between plasma and organs in the supplemented group compared to control group (541 vs. 5 times before irreversible disposal). The turnover rate of RBP-derived ROH in WAT and brain was not higher after supplementation suggesting a greater retention capacity for ROH in these organs. Furthermore, based on the trend observed in tracer levels of various organs, ROH stores in the liver were gradually transferred to other organs starting at 2 weeks after supplementation. Finally, the comparison of results from the VA and the VARA study demonstrated that supplementation with VARA increased the fractional uptake of CM-REs into the intestines, lungs and carcass to a greater extent than did supplementation with VA and attenuated the fractional turnover as well as the recycling number of ROH from 288 to 100 times before irreversible disposal. Nevertheless, the supplementation with VA resulted in a greater accumulation of ROH in the liver, which may become available to other organs during the course of development. Conclusions: Vitamin A administered in a single, large dose during the first few days after birth to neonatal rats raised under VA-marginal conditions accumulates mainly in the liver. The extrahepatic organs in neonates store relatively little VA and the scarcity of adipose tissue may predispose them to a low VA status. Vitamin A present in the supplement is readily acquired by all organs, but recycles repeatedly back to plasma most likely due to high expression of the stimulated by retinoic acid 6 receptor in the extrahepatic organs in neonates, a bidirectional ROH transporter induced by VA during development. Presence of retinoic acid in the VA supplement improves ROH tissue retention and attenuates recycling, most likely due to the synergistic effect of VA and retinoic acid on the activity of lecithin-retinol acyltransferase, an enzyme responsible for ROH storage. Given the transient effect of large-dose VA supplementation on the extrahepatic tissue ROH contents in neonates, a more frequent, lower-dose supplementation, along with other nutrition interventions, may be necessary to maintain adequate VA levels in the rapidly developing neonatal organs.