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Department of Nutrition, The Pennsylvania State University, University Park, PA 16802
2To whom correspondence should be addressed. E-mail: acr6{at}psu.edu.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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50% of the levels expressed in the liver. In the lung of VA-deficient rats, LRAT mRNA and specific activity levels were <10% of those in the control group. Treatment of VA-deficient rats with 100 µg RA increased lung LRAT mRNA (P < 0.005) and specific activity (P < 0.0001), and treatment with 5 mg of RA increased LRAT mRNA level and specific activity more than 15- and 6-fold above those in control lung, respectively (both P 
0.001). The lung tissue of VA-adequate rats contained retinyl ester (3 nmol/g tissue), whereas none was detected in the lung tissue of VA-deficient rats. These results show that LRAT expression and vitamin A storage are regulated by vitamin A status and by treatment with all-trans-RA in the adult lung. These results suggest that the regulated storage of vitamin A may be important for maintaining the integrity and physiologic functions of the lung.
KEY WORDS: • retinyl ester • retinyl palmitate • vitamin A deficiency • rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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–3
). Vitamin A deficiency results in the loss of mucus-secreting goblet cells and ciliated epithelial cells, and the subsequent development of squamous metaplasia in the trachea, bronchiolar airways and lung alveolar tissue (1
,2
,4
–7
). Such abnormal changes have been observed in premature infants with bronchopulmonary dysplasia, a neonatal lung disease that results in delayed septation as well as chronic impairment of lung function (8
,9
). Supplementation of vitamin A has been suggested to lower the severity of such incidence and its associated morbidity in those premature infants (10
,11
). Vitamin A has been reported to play an important role in the regulation of lung growth and development (6
,12
,13
), maintenance of normal cell morphology and function (14
), and regulation of the expression of surfactant proteins (15
–17
) in lung type II cells, a cell type important for vitamin A storage (18
). Treatment with RA has been shown to result in the repair of lung tissue damage associated with elastase-induced pulmonary emphysema (19
), to enhance lung growth after pneumonectomy in rats (20
) and to partially rescue failed lung septation in both rat and mouse models of lung development (21
).
The lungs store a substantial amount of vitamin A during both fetal development and adulthood. In the developmental period, vitamin A storage increases between gestation days 16 and 19–20 in rats, and then declines gradually during the postnatal period (22
–24
). The increase in vitamin A concentration in fetal lung and its depletion before birth suggest that the lung’s vitamin A stores may be important for active growth and differentiation during lung development. Although the majority of the body’s vitamin A is stored in the liver of most adult animals, many other organs including the adult lung have a large concentration of vitamin A, mainly in the form of esterified retinol, and often predominantly as retinyl palmitate (22
, 25
).
Lecithin:retinol acyltransferase (LRAT) is present in microsomal fractions of several tissues that contain high levels of retinyl esters, including the liver, retinal pigment epithelium, small intestine, testes and others. LRAT esterifies retinol, present in tissue cytosol bound to a cellular retinol-binding protein [CRBP or CRBP-II (26
)], by transferring the sn-1 fatty acid from phosphatidylcholine to retinol. Previously, we reported (27
) that LRAT present in the liver is highly regulated by dietary vitamin A and exogenous RA, at both the mRNA and activity levels. In the same experiments, LRAT expression was not different in the small intestine (27
,28
) or testes (27
) of vitamin A (VA)-deficient and control rats, implying that there are marked tissue-specific differences in the regulation of LRAT. In VA-deficient rats, the provision of RA resulted in the rapid induction of liver LRAT mRNA expression in vivo and the ability of liver microsomes to esterify CRBP-bound retinol in vitro. These data indicated that RA, vitamin A’s principal metabolite, is the likely regulator of LRAT expression, at least in the liver (27
). However, no studies on the expression and regulation of LRAT in the lung have been reported. The present study was designed to quantify LRAT expression, both as mRNA and activity, in lung tissue and to determine its response to dietary vitamin A and exogenous RA.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Approval for animal experiments was obtained from the Institutional Animal Use and Care Committee of the Pennsylvania State University. Lactating Lewis rats with their pups were purchased from Charles River Breeding Laboratories (Wilmington, DE); after arrival, dams were fed AIN-93 diet (29
) modified to be vitamin A free. VA-deficient and VA-adequate, individually pair-fed, rats were prepared as described previously (27
,30
). When the rats were 54 d old, vitamin A-deficient rats and vitamin A-adequate rats (n = 3/group) were treated with a single dose of either 0 (vehicle, canola oil), or 5000 µg of RA by mouth. An extra group of VA-deficient rats was treated with 100 µg of RA (30
) to test whether a single, physiologic dose would restore activity in retinoid-depleted rats. After 16 h, the rats were killed individually by asphyxiation with carbon dioxide and weighed; blood was withdrawn from the abdominal vena cava into a heparinized syringe for preparation of plasma. Both lung and liver tissues were dissected, immediately frozen in portions in liquid nitrogen, and then stored at -80°C for later use for RNA analysis and LRAT activity assays.
RNA extraction and analysis.
Total RNA was extracted from lung tissue samples of individual rats following the procedures described previously (27
). For poly A+ RNA isolation, the total RNA samples from each treatment group were pooled and then passed through an oligo dT-cellulose (Roche Biochemical, Indianapolis IN) column according to the method previously described (27
). The poly A+ RNA samples were subjected to electrophoresis in agarose gel and the separated RNA samples were transferred to Nytran membranes (Schleicher & Schuell, Keene NH) for Northern blot analysis using [
-32P]-dCTP (Amersham Pharmacia Biochemicals, Piscataway, NJ) labeled rat liver LRAT cDNA as the LRAT probe and [-32P]-labeled rat cytoplasmic ß-actin cDNA as the control probe (27
). The membranes were then exposed to X-ray film as previously described (27
). LRAT mRNA was measured by a quantitative real-time polymerase chain reaction (PCR) procedure using a Perkin-Elmer ABI 7700 cycler system (Perkin Elmer, Norwalk CT). The endogenous 18S RNA transcript was used as the internal control. For the reverse transcription (RT) reaction, 2.5 µL of total RNA (up to 250 ng) was first denatured at 65°C for 5 min and then the following were added to a final volume of 20 µL: 20 U RNasin (Promega, Madison WI), 1X TaqMan Universal Master Mix buffer (Perkin Elmer), 4.5 mmol/L MgCl2, 0.5 µmol/L LRAT reverse primer (5'-TTCTGAGTGCGTTCCTTGTCA-3'), 12.5 nmol/L 18S reverse primer (5'-GCTGGAATTACCGCGGCT-3'), 0.5 mmol/L each of dNTP and 22 U of MMLV RT (Perkin Elmer). The RT reaction mixture was incubated at 42°C for 1 h, 72°C for 5 min, and then 25°C for 2 min. The PCR reaction mixture was assembled with 5 µL of 10X TaqMan Universal Master Mix buffer, 10 µL of 25 mmol/L MgCl2, 1 µL of 10 µmol/L LRAT forward primer (5'-AACCGTGTCGCCCATCTAAT-3'), 1 µL of 10 µmol/L LRAT reverse primer (the LRAT amplicon was 68 bp encompassing the LRAT coding region from nucleotide # 472 to 539), 5 µL of 1 µmol/L LRAT fluorogenic oligonucleotide probe (FAM-5'-CCTGACATCCTGTTGGCCCTGA-3'-BHQ, Biosearch Tech, Novato, CA), 1 µL of 0.25 µmol/L 18S forward primer (5'-CGGCTACCACATCCAAGGAA-3'), 1 µL of 0.25 µmol/L 18S reverse primer, 1 µL of 0.25 µmol/L 18S fluorogenic oligonucleotide probe (VIC-5'-tgctggcaccagacttgccctc-3'-Tamra, Biosearch Tech), 1 µL of 10 mmol/L each of dNTP, 1.25 U Taq Gold DNA polymerase (Perkin Elmer), 8 µL of the first strand RT reaction product and dH2O to 50 µL final volume. The PCR cycling program was run for 1 cycle of 50°C for 2 min, 95°C for 10 min followed by 40 cycles of 95°C for 15 s, 60°C for 1 min and then 1 cycle of 25°C for 2 min in a Perkin-Elmer ABI 7700 cycler system. Samples were assayed in duplicate or triplicate. The relative LRAT mRNA levels reported here are expressed as the ratio of lung LRAT mRNA compared with the expression of 18S mRNA in each sample. For comparisons, the average value for the group of VA-adequate, vehicle-treated control rats was defined as 1.00, and all other values were then expressed relative to this value.
LRAT activity assay.
LRAT activity was measured in lung tissue homogenates of individual rats using [3H]-retinol bound to CRBP (30
,31
) as the substrate following the protocol routinely used in our laboratory (32
), under assay conditions that were first optimized with respect to the amount of lung homogenate used, the time of incubation and a nonlimiting concentration of retinol. Briefly, 0.5 g of frozen tissue was homogenized in 2.5 mL of 0.02 mol/L potassium phosphate buffer, pH 7.4, containing 0.25 mol/L sucrose and 1 mmol/L dithiothreitol. Samples of the diluted homogenate containing 0.2 mg of protein as determined by the dye-binding assay of Bradford (33
) were then used in a reaction mixture, final volume of 0.1 mL, containing 0.15 potassium phosphate buffer, pH 7.4, 2 mmol/L dithiothreitol and 2 nmol of [3H]-retinol-CRBP (specific activity, 1.1 kBq/nmol). The reaction mixture was incubated at 37°C for 4 min and the [3H]retinyl ester product was isolated and quantified as described previously (32
).
Vitamin A analysis.
Total lipids were extracted from lung tissue homogenates and from minced liver tissue of the control group, by the method of Folch et al. (34
), and retinol and retinyl esters were analyzed by reverse-phase HPLC essentially as described by (22
), with the exception that trimethylmethoxyphenyl retinol was added as an internal standard. The limit of detection was 0.3 nmol vitamin A/g tissue. Total retinol was determined after saponification of plasma, as previously described (35
).
Statistical analysis.
Data are expressed as means ± SEM. Data from the real-time mRNA assay and LRAT specific activity assay were first log10-transformed, due to unequal variances among the treatment groups; they were then analyzed by two-way ANOVA with vitamin A status (adequate or deficient) and treatment (vehicle or RA) as the main factors; differences among treatment groups were determined by least square means test. SuperANOVA software (Abacus Concepts, Sunnyvale, CA) was used for these analyses. Simple regression analysis was performed between log10-transformed mRNA data and log10-transformed LRAT specific activity data. Differences with P < 0.01 were considered significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Initially, Northern blot analysis of lung and liver tissue polyA+ RNA was conducted to survey the expression of LRAT mRNA in these tissues. As shown in Figure 1A
, LRAT mRNA was expressed in the lung of VA-adequate rats. Its abundance in the lung was considerably less than in liver of the same rats, whereas the size of the main LRAT transcript was the same in lung and liver. Almost no LRAT mRNA was detected in the lung of VA-deficient rats. Treatment of VA-deficient rats with 100 µg of RA increased LRAT mRNA expression to a level similar to that in VA-adequate rats. Expression was even greater in VA-deficient rats treated with 5 mg of RA. Moreover, administration of the same amount of RA to VA-adequate rats also increased the LRAT mRNA level above that in lung tissue of control rats. ß-Actin expression, determined on the same blot, indicated comparable loading of RNA from the various samples.
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B), both vitamin A status (P = 0.01, two-way ANOVA) and treatment (RA or vehicle) (P < 0.0001, two-way ANOVA) affected the expression of lung LRAT mRNA. The relative abundance of LRAT mRNA in lung of VA-deficient rats was <10% of that in lung of control rats (P < 0.005). Treatment of VA-deficient rats with 100 µg RA increased lung LRAT mRNA (P < 0.005) to levels not different from those in control rats (P = 0.55). Administration of 5 mg RA to either VA-deficient or VA-adequate rats increased lung LRAT mRNA levels to >15 times that in the VA-adequate control group (both P 0.001). Thus, by both Northern blot analysis and quantitative PCR analysis, lung LRAT mRNA was strongly regulated by long-term vitamin A nutritional status and by acute exposure to RA. LRAT enzyme activity.
LRAT specific activity, measured under conditions of nonlimiting substrate concentration, was 13.1 ± 1.4 pmol/(min · mg) in lung of VA-adequate rats, which was about half of that in the liver homogenate samples of the same rats [25.5 ± 3.0 pmol/(min · mg)]. Similar to the level of lung LRAT mRNA, the average lung LRAT specific activity in VA-deficient rats was about one tenth that in the lung of VA-adequate control rats (P < 0.0001) (Fig. 2
). Treatment of VA-deficient rats with 100 µg RA increased lung LRAT specific activity compared with the untreated VA-deficient group (P < 0.0001), to a level which was 3 times of that in VA-adequate rats (P < 0.0005). Treatment of VA-deficient and VA-adequate rats with 5 mg RA increased LRAT specific activity 6.2- and 8.9-fold (P < 0.0001), respectively, compared with VA-adequate rats.
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Tissue vitamin A concentration.
Plasma retinol concentration was undetectable in the VA-deficient group (Table 1
). Plasma retinol was lower in VA-adequate RA-treated rats than in the controls, an expected effect of treatment with RA (36
). Nearly all of the vitamin A in the adult lung was present as retinyl ester, and nearly all of this was retinyl palmitate. The vitamin A concentration in the lung of control rats was low (2.95 ± 0.64 nmol/g) (Table 1)
compared with that in the liver (90 ± 11 nmol/g, not shown) of the same rats. Vitamin A was either absent or below the limit of detection in the lung of VA-deficient rats, regardless of RA treatment. Treatment with RA did not affect the concentration of lung retinyl esters of VA-adequate rats, measured 16 h after treatment.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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,24
). However, little information is available on the mechanism of retinyl ester synthesis in the lung, and the regulation of this process is unknown. The present study showed that LRAT, an enzyme capable of esterifying retinol presented in CRBP-bound form, is expressed at a measurable level in the adult lung. In the VA-adequate state, both LRAT mRNA and LRAT enzyme activity, assayed under conditions in which the substrate was not limiting (30
), were readily detected in lung at levels 50% of those in the liver of the same rats. LRAT expression in the lung was regulated by long-term dietary vitamin A and by administration of a single dose of RA, similar to the regulation previously shown for LRAT in rat and mouse liver (27
,30
). Treatment with exogenous RA, which is thought to mimic and amplify the effect of RA produced endogenously from retinol, strongly regulated both LRAT mRNA expression and enzyme activity in adult rat lung. In VA-deficient rats treated with 100 µg of RA, lung LRAT expression reached the level observed in the control group. In both VA-deficient and VA-adequate rats treated with 5 mg of RA, lung LRAT expression exceeded that in the control group. There was a strong positive correlation (r = 0.92) between lung LRAT mRNA and LRAT enzyme specific activity for all conditions studied.
Several observations deserve comment. First, in the lung of control rats treated with RA (5 mg), both LRAT mRNA and activity were increased well above the control level. The amount of RA administered in this study was pharmacologic; it was selected to elicit regulation, if it exists. However, regulation was not limited to pharmacologic doses of RA because it was also apparent in an extra group of VA-deficient rats that was treated with a single 100-µg dose of RA; in that group, LRAT mRNA and activity equaled those of the VA-adequate control group. It may be noted that in other experiments that were designed to determine the regulation of gene expression of LRAT (37
) and the retinoid-metabolizing cytochrome P450RAI (CYP26) (38
) in liver, we found dose-response relationships over a wide range of RA doses, up to and including 5 mg. Most important, the increase in lung LRAT mRNA and activity above the level of the group suggests that the mechanism(s) by which RA regulates LRAT expression is(are) not saturated by normal dietary levels of vitamin A. On the basis of the results in control rats, we hypothesize that pharmacologic treatments using RA will induce lung LRAT gene expression above the level that is maintained during the consumption of a normal diet. Because retinoids including all-trans-RA are used clinically (39
), the effect of these treatments on lung vitamin A storage and lung health should be examined further.
Second, although LRAT mRNA and enzyme activity were increased in the lung tissue of VA-adequate RA-treated rats, we did not observe any effect on lung retinyl ester concentration. These data indicate a need for further studies, but we do not believe they are necessarily contradictory because the period of treatment with RA was short (16 h), close to the time required for the maximum induction of LRAT activity in the liver (37
). Therefore it seems likely that a longer time would be required for new retinyl esters to be synthesized and to accumulate in lung tissue. Another possibility is that retinol itself was rate limiting in vivo under the conditions tested. Our in vitro LRAT activity assay was optimized to measure maximal enzymatic velocity under conditions in which substrate is not the limiting factor. However, in the intact animal, the availability of retinol as LRAT substrate may be the rate-limiting factor, or it may become rate limiting when LRAT activity is rapidly induced above its normal level of expression. Thus, another hypothesis generated from the results of this study is that lung vitamin A content is regulated by the interplay of both substrate availability (retinol bound to CRBP) and LRAT activity, which is modulated by RA. Essentially, RA may control the level of enzyme expression, whereas diet and metabolic factors may control availability of substrate. Both factors would be expected to interact in determining retinol esterification in vivo. Because many humans consume diets containing vitamin A at levels well above the recommended dietary allowance (40
), it is conceivable that tissue levels of both retinol and its metabolite, RA, are higher under these conditions and that both may affect the ability to store vitamin A. Further studies of lung LRAT regulation under conditions of vitamin A supplementation may help clarify this interaction.
Third, LRAT mRNA may be translated with different efficiency in the lung than in the liver. Treatment of VA-deficient rats with RA increased the relative LRAT mRNA levels several fold in the lung (Fig. 1
B), as well as in the liver (27
). However, in the lung, the LRAT specific activity increased by almost the same magnitude (6.2- to 8.9-fold) as the LRAT mRNA, whereas in the liver, the LRAT specific activity increased not >40% above that in the liver of VA-adequate rats (R. Zolfaghari, unpublished results). This may indicate that post-transcriptional processes for LRAT mRNA in the lung are different from those in the liver.
Fourth, the expression of LRAT and the presence of retinyl esters in the lung may differ from one species to another. Takase and Goda (41
) reported that they found no detectable retinyl esters in the lung of chicks compared with the lung of rats, which contained a small amount of vitamin A (5% of the level in the liver), mostly as retinyl palmitate. In a later study (42
), the same investigators did not detect LRAT activity in the microsomes from the lung of young chicks or hens, in contrast with rat lung in which LRAT had a specific activity of 11 and 16 pmol/(min · mg protein) with retinol bound to either CRBP or CRBP-II, respectively, as the substrates.
In conclusion, it is likely that the local production of retinyl esters is an important mechanism for maintaining tissue retinoid in a form that is easily stored and readily mobilized for further metabolism. Vitamin A is important for the development and maintenance of normal lung tissue morphology and function. Recently, attention has turned to the potential therapeutic effects of retinoids in the repair of damaged lung tissue (7
, 19
–21
, 43
). The results of this study suggest that both chronic diet and acute exposure to retinoids are important factors in regulating the expression of LRAT in the adult lung. Because RA functions as a transcriptional regulator for many genes, including several known to be important in lung architecture and health (13
,15
,16
,44
), the regulation of vitamin A storage, mobilization and metabolism in the lung could have important consequences for gene expression within this tissue.
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FOOTNOTES |
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3 Abbreviations used: CRBP, cellular retinol-binding protein, LRAT, lecithin:retinol acyltransferase; PCR, polymerase chain reaction; RA, all-trans-retinoic acid; RT, reverse transcription; VA, vitamin A.
Manuscript received 9 January 2002. Initial review completed 30 January 2002. Revision accepted 26 February 2002.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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