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Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16802
4To whom correspondence should be addressed. E-mail: mhg{at}psu.edu.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTS AND DISCUSSIONLITERATURE CITED |
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7 nmol/d), the LA+RA rats were in a slight positive VA balance (0.325 nmol/d vs. –0.168 for LA) for 35 d after administration of [3H]retinol-labeled plasma. Using the Windows version of the Simulation, Analysis and Modeling software, we determined that the VA disposal rate was lower in LA+RA than in LA rats (3.98 vs. 5.00 nmol/d) as was the system fractional catabolic rate (0.0548 vs. 0.110 d–1). Model-predicted traced mass and residence times (the average time that a molecule of retinol spends in an organ before irreversible loss) were higher for liver (19.4 vs. 1.8 nmol; 5.0 vs. 0.36 d), kidneys (7.0 vs. 2.1 nmol; 1.4 vs. 0.42 d), small intestine (2.1 vs. 0.42 nmol; 0.43 vs. 0.084 d), and lungs (3.2 vs. 0.10 nmol; 1.6 vs. 0.021 d) in the LA+RA compared with the LA rats; there were no major differences for eyes, testes, adrenal glands, or remaining carcass. We conclude that RA supplementation of rats with low VA status affects VA metabolism at both the whole-body level and in specific organs. These organs (liver, kidneys, small intestine, and lungs) have the enzymatic capability and an appropriate cell type to store retinyl esters.
KEY WORDS: • compartmental model • vitamin A sparing • WinSAAM
Because of the serious consequences of vitamin A (VA)5 deficiency and in view of the role of retinoids in the prevention and treatment of numerous diseases, factors that influence VA utilization have been studied extensively. Previous work established that both VA stores and utilization are directly related to VA intake (1,2). For instance, Varma and Beaton (1) showed that as VA intake and liver stores increased, there was a parallel increase in VA utilization. More recently, work performed in this laboratory demonstrated that VA utilization is also influenced by the plasma pool size of retinol, especially in rats with low-to-moderate VA intake (3,4). Taken together, these studies have delineated some of the underlying mechanisms that control VA homeostasis, but many questions remain to be answered, including the effect of other retinoids on VA utilization and kinetics.
One retinoid that has been studied extensively in recent years is all-trans-retinoic acid (RA), an active metabolite of VA. RA regulates numerous physiologic processes in normal cells, including proliferation, differentiation, immune response, and embryonic development (5,6). Before the discovery of the molecular mechanisms of RA action, it was shown that dietary RA could substitute for VA in some but not all physiologic functions (7). Subsequent studies showed that feeding RA influenced liver VA levels and spared whole-body VA stores in rats with low VA status (8). In view of these observations, we were interested in determining how individual organs responded to chronic RA treatment and how their response affected VA turnover and mass. Thus, as part of a larger study on VA kinetics in rats with low VA status (9), data were also collected from rats with low VA status during chronic RA supplementation (9). Those latter results have not yet been analyzed extensively (10). We used model-based compartmental analysis to analyze the kinetic data from the RA-supplemented rats; results are compared with new and previously published information on rats with low VA status that were studied at the same time (11,12). The present analysis provides information on the effects of chronic administration of RA to rats with low VA status on the recycling, uptake, and mass of VA in specific organs and the whole body.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTS AND DISCUSSIONLITERATURE CITED |
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Animals and diets. Weanling male Sprague-Dawley rats (50–60 g; Hilltop Lab Animals) were housed individually in environmentally controlled quarters (11). Food and water were available continuously. Procedures for animal care and use complied with guidelines approved by The Pennsylvania State University.
Rats were provided a vitamin A-free purified diet (13) for 50 d to deplete liver vitamin A stores and then a diet that provided a low amount of vitamin A (LA) in the form of retinyl palmitate (350 nmol retinol/kg diet or 7 nmol/d). After consuming the LA diet for 19 d, rats were randomly assigned to either remain in this group or to consume the LA diet supplemented with retinoic acid (LA+RA; 40 µmol RA/kg or 800 nmol/d) for 25–26 d. Supplementation continued during the subsequent in vivo kinetic studies (up to 35 more days).
Retinol kinetic studies.
Plasma labeled with [3H]retinol in its physiologic transport complex was prepared as previously described (14) by administering a dispersion of [3H]retinyl acetate (11.1 MBq and 61 nmol/donor rat) in Tween 40 to vitamin A-deficient donor rats (11) and harvesting blood plasma containing [3H]retinol in its normal physiologic transport complex. Plasma was stored at 4°C under nitrogen and injected into recipients over the next 3 d.
Retinol kinetic studies were conducted as previously described (11). The [3H]retinol-labeled plasma (0.9 g containing 0.11 MBq and 1.4 nmol retinol) administered to LA+RA and LA recipient rats caused an 20% perturbation of the plasma retinol pool. Serial blood samples were collected from a caudal vein from 9 min after dose administration until rats were killed at 12 min (n = 3/dietary group), 2 h (n = 3/group), 10 h (n = 3/group), 4 d (n = 3/group), 28 d (n = 3/group), and 35 d (n = 5 for LA and n = 3 for LA+RA); aliquots of plasma were frozen under nitrogen. At the time of killing, the whole body was perfused; organs (liver, kidneys, small intestine rinsed of contents, lungs, testes, adrenal glands, eyes, and remaining carcass) were removed, weighed, and frozen at –16°C for subsequent analysis (see below).
Analytical procedures. Aliquots of plasma and the [3H]retinol-labeled dose were extracted using a modification (11) of the method of Thompson et al. (15). When retinol mass was to be determined, an internal standard (retinyl acetate in absolute ethanol) was added before extraction. Appropriate aliquots of the lipid extracts were taken for analysis by HPLC and/or liquid scintillation spectrometry (see below). Adrenals, eyes, aliquots of homogenized carcass, and aliquots of freeze-dried liver, kidneys, small intestine, lungs, and testes were extracted using a modification (11) of the method of Hara and Radin (16). For quantification of retinol mass, the internal standard was added to aliquots of liver before extraction. Aliquots of the extracts were removed for HPLC analysis (liver samples) and/or liquid scintillation spectrometry.
Retinoid masses were quantified by reverse-phase HPLC as previously described (17), except that retinol and retinyl acetate in extracts of liver were eluted with methanol:water, 90:10, v:v (1 mL/min), and retinyl esters were eluted with 100% methanol (2 mL/min). Solvent-free extracts of plasma and tissues were solubilized in scintillation solution and analyzed for radioactivity as previously described (11).
Kinetic analysis and parameters. Data on the geometric mean fraction of the administered dose in plasma, organs, and irreversibly lost [1 –(fraction of dose in plasma + organs + carcass)] at each time, as well as SEM, were obtained from Lewis (9). Because results for the RA-supplemented rats were our main focus, data for the LA+RA group were analyzed first and then the LA group data were modeled similarly for comparison. To begin, group mean plasma data vs. time for rats in the 28- and 35-d groups were fit to a multiexponential equation using the Windows version of the Simulation, Analysis and Modeling computer program (WinSAAM) (18) on a Dell OptiPlex GX1P computer. Then the "forcing function" option in WinSAAM (12,19) was used to develop a compartmental model for each organ subsystem based on the mathematical description of the tracer response profiles in plasma and tracer data from that organ; LA+RA data were analyzed first and then parallel models were developed for LA data. The forcing function approach makes use of the fact that plasma is the sole source of input of VA to individual organs or tissues. Thus, because each organ exchanges VA directly with plasma but not with other organs, we can uncouple individual organs from the whole system and model each one individually. This approach allows the modeler to develop initial models for each organ before working with all organs simultaneously. For each organ, we first tried to fit the data to a single compartment; when that was not sufficient, a second, or sometimes third, more slowly turning-over compartment was introduced, which exchanged VA with the first, or second, compartment. Once a satisfactory fit was obtained, weighted nonlinear regression analysis using WinSAAM was applied to obtain the best fit value for the fractional transfer coefficients [L(I,J)s; see below]. Once all organs were satisfactorily fit for each group, the forcing functions were removed and the entire data set for each group, including irreversible loss, was modeled together. The LA+RA model was developed first and then a parallel model was developed for the LA group, thereby taking the organ analysis a step farther than previously published (12).
The following kinetic parameters were determined; see Green and Green (14,20) for more details. The fractional transfer coefficients [L(I,J); d–1] are defined as the portion of retinol in compartment J that is transferred to compartment I each day. The mean residence time [T(I,J); d] is the average of the distribution of times that a molecule of retinol spends in compartment I before irreversibly leaving that compartment after entering the system via compartment J. The system mean residence time [Tsys] is the average time that a molecule of retinol spends in the system before irreversible loss and is calculated as the sum of the T(I,J)s. Plasma retinol pool sizes (nmol) for the LA+RA and LA groups were estimated from the average plasma retinol concentration during the kinetic study and the estimated plasma volume (21). Then, plasma retinol pool sizes were used in a steady-state solution in WinSAAM to estimate retinol pool sizes or traced mass [M(I); nmol] in other compartments so that transfer rates [R(I,J); nmol/d] could be calculated. Transfer rates, including the system disposal rate, are defined as the amount of retinol (nmol) transferred from compartment J to compartment I each day.
Statistics.
Descriptive data are presented as group means ± SD. Data were compared statistically using a Student’s unpaired t test in Microsoft Excel (2001 version) with P 
0.05 considered significant. Because compartmental modeling was done using group mean data at each time, it is not possible to compare kinetic parameters statistically between groups.
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RESULTS AND DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTS AND DISCUSSIONLITERATURE CITED |
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7 nmol/d), rats grew normally and appeared to be in good health.
In spite of normal growth, measurements of plasma and liver VA levels confirmed the low vitamin A status of LA+RA and LA rats. Compared with vitamin A-adequate rats studied at the same time (plasma retinol, 1.57 µmol/L) (13), plasma retinol concentrations at the beginning and end of the kinetic studies were 0.308 ± 0.037 (n = 3) and 0.347 ± 0.065 µmol/L (n = 3) in the LA+RA group and 0.381 ± 0.036 (n = 5) and 0.344 ± 0.026 µmol/L (n = 5) in the LA group; the concentrations differed between the groups at the beginning of the study (P < 0.05). Although Underwood et al. (22) reported that feeding RA to rats consuming a low amount of VA was associated with a rapid and sustained decrease in plasma retinol levels, the VA status of those rats was much higher (i.e., initial plasma retinol concentrations were higher than in the current study). Unfortunately, plasma RA concentrations were not measured in this experiment. On the basis of other rat studies in which plasma RA levels were 7–9 nmol/L [reviewed by Blaner and Olson (23)], we assume that plasma RA levels were low in LA rats and substantially higher in those supplemented with RA. Retinoic acid in plasma is transported by albumin and is derived from the diet or metabolism in tissues.
Hepatic VA content at the time of initiation of the kinetic studies was 6.03 ± 1.74 nmol (n = 3) in the LA+RA group and 7.64 ± 0.81 nmol in the LA group (n = 3; NS). In rats killed 35 d later, liver VA content was 17.4 ± 11.4 nmol (n = 3) and 1.75 ± 0.35 nmol (n = 5) in the LA+RA and LA groups, respectively (P < 0.05). Thus, LA+RA rats appeared to be in a slight positive VA balance during the kinetic study (0.325 nmol/d), whereas LA group rats were in a slight negative VA balance (–0.168 nmol/d). Note that VA intake was estimated to be 7 nmol/d.
Kinetic data.
Plasma [3H]retinol kinetics differed between LA+RA and LA group rats (Fig. 1). Similar curves for a larger group of rats fed the LA diet were presented previously (11). Initially, there was a rapid disappearance of tracer from plasma in both groups, as shown in the supplemental plot of data from the first 12 h after dose administration. By 6 h, however, the curve for the LA group began to level off and it continued to decline gradually throughout the remainder of the study. In contrast, a more rapid disappearance of tracer from plasma persisted in the LA+RA group until 2.5 d after dose administration; then the decline became more gradual until 4.5 d after the dose when the curve began to flatten. Extensive recycling of retinol to plasma, as was described previously for rats with moderate VA status (24), occurred in both groups as indicated by the decrease in the slope of both curves before 8 d. By 8 d postinjection, the curve for LA+RA rats crossed over that for the LA rats, and it remained above the LA curve for the remainder of the study. The plasma response profiles indicated that the total traced mass was larger in the LA+RA rats and that the system fractional catabolic rate was higher in LA rats. The pattern of irreversible loss of [3H]retinol (Fig. 1) also differed between LA+RA and LA rats.
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Two compartments were sufficient to fit the data for kidneys, lungs, small intestine, adrenal glands, eyes, and testes in both groups, and for LA group liver and LA+RA group carcass. That is, retinol kinetics in these organs could be described using one compartment that rapidly exchanged retinol with plasma as well as with a second, more slowly turning-over compartment. One compartment was adequate to fit the liver tracer data for the LA+RA group, and 3 compartments were required to fit the carcass data for the LA group. We speculate that these differences between groups occurred because there was more vitamin A in liver and (presumably) carcass of LA+RA rats, and this VA dominated the kinetics, resulting in "lumping" of the more rapidly turning-over vitamin A with the more slowly turning-over pool. For the LA group, these compartmental structures are comparable to those previously presented (11,12) except for the eyes. Here, 2 compartments were required to fit the LA+RA group data; in our previous work, 1 compartment was used to fit LA group data (12). In the current analysis, there was no difference in the sum-of-squares using 1 vs. 2 compartments for LA group eyes; thus, 2 compartments were used for both groups.
Once organs were modeled individually, the plasma forcing function was released, and all data including irreversible loss were modeled simultaneously for each group. Our working hypothesis model includes the 7 sampled organs and remaining carcass around the central plasma compartment (Fig. 3). The model includes recycling of tracer from the more quickly turning-over compartment to plasma in each tissue, and it shows output (irreversible loss) from carcass compartment 12. A good fit to tracer data for plasma, organs/tissues, and irreversible loss was obtained only when the output was from compartment 12. Although not normally considered a major site of VA loss, previous compartmental models, including one developed for a larger group of rats fed the LA diet (11) and another developed for rats with moderate levels of liver vitamin A (24), predicted that the carcass was the site of vitamin A output. The fit of the proposed model to the data can be seen by comparing the observed data with the model-predicted values (Figs. 1and 2); in addition, the weighted residual sums-of-squares (not shown) indicated that the models were highly compatible with the data.
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In this study, the lungs were the tissue most responsive to chronic RA treatment. In LA+RA rats, the more slowly turning-over compartment in the lungs (compartment 9, Fig. 3) acted as a sink for [3H]retinol. That is, during chronic RA treatment, our model predicted that retinol could be transferred from the first compartment (compartment 8, Fig. 3) to the more slowly turning-over compartment of the lungs (compartment 9); however, its return to the first compartment was at an undetectable rate. Thus, [3H]retinol was efficiently retained by the lungs in the LA+RA group as evidenced by the prediction that the residence time for [3H]retinol was 75 times higher than that of the LA group (Table 3). This dramatic increase in tissue residence time is also reflected in the predicted amount of VA traced mass in the lungs, which was 31 times greater in the LA+RA than in the LA group (Table 2). The model-predicted values for these parameters in the LA+RA group are minimum estimates because compartment 9 acts as a sink.
In contrast to the liver, kidneys, small intestine, and lungs, observed and model-predicted fractions of the injected dose (Fig. 2), tissue residence times (Table 3), and traced masses (Table 2) did not differ in the LA+RA and LA groups for the eyes, testes, adrenals, and carcass, despite small differences in fractional transfer coefficients and transfer rates (Table 1). That is, in spite of some differences between the groups in the movement of retinol into and out of specific compartments in these organs, overall organ kinetics were not affected by RA supplementation. These results are not surprising for eyes and testes because dietary RA cannot fulfill the vitamin A needs of those tissues (7). In addition, Kurlandsky et al. (25) found that very little of the infused [3H]retinoic acid was recovered in the testes of rats, indicating that little RA was taken up from plasma by this tissue. In contrast, infused RA contributed almost 80% of the RA pool in liver.
Using the model in Fig. 3 and the R(I,J)s in Table 1, we predicted the contribution of different organs to plasma retinol output. LA+RA rats had a higher plasma retinol turnover rate (88.6 nmol/d) than the LA group (54.6 nmol/d). In both groups, <5% of plasma retinol turnover went to the liver, 54–56% to the kidneys, 30–33% to carcass, 5–6% to the small intestine, and <5% went to the other 4 organs sampled. For example, only 0.1% of the plasma retinol turnover went to the eyes. In addition, <10% of plasma retinol output was irreversibly lost. Because VA disposal rate [R (20,12)] is determined by the difference between plasma retinol output [R(I,1)] and plasma retinol input [R(1,J), where I is the output to all organs and J is the input to plasma from all organs] plus liver vitamin A balance (i.e., the change in liver VA during the kinetic study), we can calculate that diet provided 4.3 (LA+RA) or 4.8 nmol/d (LA) to plasma retinol input. If rats were consuming 7 nmol VA/d, then absorption efficiency was 62% (LA+RA) or 69% (LA), similar to what was measured in lymph duct-cannulated rats (27).
In addition to kinetic differences between groups at the organ level, our models also predicted differences in whole-body vitamin A kinetics between the LA+RA and LA rats. The model-predicted VA disposal rate was 20% lower in the LA+RA rats [R (20,12); Table 1] and the system fractional catabolic rate was half that of the LA group (0.0548 vs. 0.110 d–1). In a preliminary comparison of these groups using input-output analysis (10), the same trends were observed. Together, the lower disposal rate and system fractional catabolic rate in the LA+RA rats contributed to a system VA residence time that was 2 times higher than that in the LA rats (Table 3).
Integrating our results on the effects of dietary RA on VA kinetics in specific organs (liver, kidneys, small intestine, and lungs) as well as the whole body, we hypothesize that model-predicted differences in residence time (Table 3) are related to the larger body pools of VA with which [3H]retinol could equilibrate in LA+RA rats and a lower disposal rate. In examining body VA pools, liver VA levels were higher in LA+RA than in LA rats; in addition, the model predicts larger VA levels in LA+RA liver, kidneys, small intestine, and lungs (Table 2). They are also predicted by the relative geometries of the tracer response curves between groups (Fig. 2). Interestingly, Nagy et al. (28) identified vitamin A-storing stellate cells in all 4 of these organs in both control and VA-supplemented rats. Also, Zolfaghari et al. showed that although the mRNA and activity of lecithin:retinol acyltransferase (LRAT), an enzyme that catalyzes VA esterification, was not detectable in liver (29) and lungs (30) of rats with low VA status, administration of RA increased both variables. These authors reported (29) that RA must be present continuously to keep LRAT activated.
At the whole-body level, RA-supplemented rats more efficiently utilized dietary retinol, thus resulting in a slight positive VA balance (0.325 nmol/d vs. a negative balance of –0.168 nmol/d in the LA group). That is, the vitamin A activity supplied by the LA+RA diet (retinyl palmitate plus RA) was sufficient to meet VA needs; however, without the supplemental RA (LA group), VA intake was insufficient to meet needs for the vitamin. We hypothesize that the difference in VA balance was the result of 2 independent mechanisms working in parallel. First, it is likely that dietary RA may have been available for some of the numerous physiologic and molecular functions that require RA in such tissues as liver and kidneys that can derive RA from plasma (25). This would spare the irreversible conversion of retinol to RA and allow VA to accumulate. Our model predicts that both VA residence time and traced mass for the system were significantly higher in the RA-supplemented rats (Table 3).
The second factor contributing to the positive VA balance observed in the RA-supplemented rats was the change in the amount of [3H]retinol that was irreversibly lost. Our model predicted that the VA disposal rate was reduced by 20% in RA-supplemented rats. Kelley and Green (4) showed that VA utilization in rats with low VA intake depended more on plasma retinol levels than on VA stores or VA intake. Indeed, the results presented here further support this relation. The plasma retinol pool was slightly lower in the LA+RA group rats than in the LA rats (4.55 vs. 4.90 nmol), as was the model-predicted system fractional catabolic rate (0.0548 vs. 0.110 d–1). That is, after the initial uptake of retinol by tissues, the amount of retinol present to provide the mass action for irreversible utilization and disposal was lower in the LA+RA rats than in the LA rats. Together, the proposed increase in tissue RA in the LA+RA rats and their lower plasma retinol levels contributed directly to a decrease in VA utilization, resulting in a slight positive VA balance.
In conclusion, the present analysis demonstrated that chronic administration of RA to rats with low VA status affects the recycling, uptake, and mass of VA in a tissue-specific manner and results in a positive VA balance. We propose that this positive balance is related to the ability of some organs such as liver and kidneys to take up RA from plasma, thus sparing retinol, and that VA accumulated as a result of the sparing may be stored in tissues in which the continuous availability of RA maintains LRAT in an active state. Our results tie in well with recent work by Ross’ laboratory, which shows that one way in which RA influences VA homeostasis is by altering retinol storage (31,32); they hypothesized that RA may act as a signal of vitamin A status (31). It is also interesting to note that 3 of the organs in which retinol metabolism was most affected by RA supplementation in this study (kidneys, small intestine, and lungs) are rich in epithelial cells, a cell type whose integrity depends on RA.
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FOOTNOTES |
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2 Supported in part by U.S. Department of Agriculture grant 81-CRCR-0702 and by funds from the College of Health and Human Development at Penn State.
3 Supplemental supporting material is available with the online posting of this paper at www.nutrition.org.
5 Abbreviations used: FCRsys, system fractional catabolic rate; LA, low vitamin A; L(I,J), fractional transfer coefficient; LRAT, lecithin:retinol acyltransferase; M(I), traced mass; RA, all-trans-retinoic acid; R(I,J), transfer rate; SAAM, Simulation, Analysis and Modeling; T(I,J), mean residence time; Tsys, system mean residence time; VA, vitamin A.
Manuscript received 1 October 2004. Initial review completed 17 November 2004. Revision accepted 3 January 2005.
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LITERATURE CITED |
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TOPABSTRACTMATERIALS AND METHODSRESULTS AND DISCUSSIONLITERATURE CITED |
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  A. L. Escaron, M. H. Green, and S. A. Tanumihardjo Plasma turnover of 3,4-didehydroretinol (vitamin A2) increases in vitamin A-deficient rats fed low versus high dietary fat J. Lipid Res., April 1, 2009; 50(4): 694 - 703. [Abstract] [Full Text] [PDF]
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 T. Sun, R. L. Surles, and S. A. Tanumihardjo Vitamin A Concentrations in Piglet Extrahepatic Tissues Respond Differently Ten Days after Vitamin A Treatment J. Nutr., June 1, 2008; 138(6): 1101 - 1106. [Abstract] [Full Text] [PDF]
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C. J. Cifelli, J. B. Green, Z. Wang, S. Yin, R. M. Russell, G. Tang, and M. H. Green Kinetic Analysis Shows that Vitamin A Disposal Rate in Humans Is Positively Correlated with Vitamin A Stores J. Nutr., May 1, 2008; 138(5): 971 - 977. [Abstract] [Full Text] [PDF]
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C. J. Cifelli and A. C. Ross Chronic Vitamin A Status and Acute Repletion with Retinyl Palmitate Are Determinants of the Distribution and Catabolism of all-trans-Retinoic Acid in Rats J. Nutr., January 1, 2007; 137(1): 63 - 70. [Abstract] [Full Text] [PDF]
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A. C. Ross, N.-q. Li, and L. Wu The Components of VARA, a Nutrient-Metabolite Combination of Vitamin A and Retinoic Acid, Act Efficiently Together and Separately to Increase Retinyl Esters in the Lungs of Neonatal Rats J. Nutr., November 1, 2006; 136(11): 2803 - 2807. [Abstract] [Full Text] [PDF]
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 C. J. Cifelli and A. C. Ross All-trans-retinoic acid distribution and metabolism in vitamin A-marginal rats. Am J Physiol Gastrointest Liver Physiol, August 1, 2006; 291(2): G195 - G202. [Abstract] [Full Text] [PDF]
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A. C. Ross, N. Ambalavanan, R. Zolfaghari, and N.-q. Li Vitamin A combined with retinoic acid increases retinol uptake and lung retinyl ester formation in a synergistic manner in neonatal rats J. Lipid Res., August 1, 2006; 47(8): 1844 - 1851. [Abstract] [Full Text] [PDF]
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