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Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Japan and * Department of Nutritional Science, Tokyo University of Agriculture, Japan
2To whom correspondence should be addressed. E-mail: akatoq{at}mail.ecc.u-tokyo.ac.jp.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • DNA microarray • gene expression • gluten • protein nutrition • rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The majority of the pleiotropic effects of protein nutrition are mediated by changes in the expression of the genes involved. A number of genes have been reported to respond to dietary protein (1
,2
). For example, genes encoding the insulin-like growth factor (IGF)3 system are highly sensitive to nutritional status (1
); changes in expression of these genes comprise one of the major causes of growth retardation in protein malnutrition. Investigations of such changes have provided many insights into the molecular mechanisms of metabolic and/or endocrine adaptations to protein malnutrition. In most cases, however, the results have been obtained in a "gene by gene" manner. In living organisms, of course, the mechanisms are more complex. For this reason, a global analysis of gene expression in response to changes in nutritional status is essential for understanding the biological mechanisms.
Recent developments in molecular techniques have made it possible to monitor changes in the gene expression of multiple transcripts, and thereby generate large gene expression profiles. One of these newly established methods is DNA microarray technology, which can be used to simultaneously monitor several thousand different transcripts (3
,4
). Microarrays are a powerful tool in a variety of research fields (5
–9
). To our knowledge, however, there has been no microarray-based investigation of protein malnutrition in an animal. The identification of gene expression patterns induced by protein nutritional status will undoubtedly provide useful insights into the molecular mechanisms underlying their diverse actions.
Another remarkable feature of dietary proteins is that, in addition to their conventional nutritional values, which are determined mainly by analyses such as growth assays and nitrogen balance tests, some play other specific, integral roles in the life of the organism. These functions include the cholesterol-lowering effect of soy protein (10
) and the facilitation of calcium absorption by milk protein (11
). Dietary protein may have many heretofore unrevealed functions that may be uncovered by the powerful tool of DNA microarray.
In the present study, we used a DNA microarray containing 
8000 different rat genes to investigate the effects of three different protein nutritional states on gene expression in rat liver. Comparisons of rats fed a protein-free diet, those fed a diet containing wheat gluten and those fed a diet containing casein revealed apparent changes of hundreds of genes. Some of these are genes known to be sensitive to nutritional status, but a majority were newly identified. Two of the most interesting findings, one related to transcriptional regulation and the other to cholesterol biosynthesis, are described in detail. Changes in the expression of some of the genes observed in the DNA microarray were confirmed by the RNase protection assay.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Male Wistar rats with a mean body weight of 120 g were purchased from Charles River Japan (Kanagawa, Japan). The rats were kept in a room maintained at 22 ± 1°C with a 12-h light:dark cycle (lights on at 0800 h). They consumed a 12 g/100g casein diet between 1000 and 1800h for 3 d before they were given experimental diets. Three experimental diets, a 12 g/100 g casein diet (12C), a 12 g/100 g gluten diet (12G) and a protein-free diet (PF), were prepared as shown in Table 1
. The experimental diets were given for 7 d on the same schedule, and water was freely available.
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DNA microarray assay.
Total RNA was prepared from livers using Trizol (Invitrogen, Carlsbad, CA). The quality and quantity of RNA samples were assessed by measuring the optical density of each sample at 260 and 280 nm. Equal amounts of the RNA from five rats of each group were mixed and used for purification of poly (A)+ mRNA by using a poly (A)+ purification kit (Promega, Madison, WI). RNA samples were reverse-transcribed with poly dT oligonucleotide attached to a sequence of the T7 promoter region, digested with RNase H, and copied into dsDNAs (SuperScript Choice System, Invitrogen). In vitro RNA transcription was performed to incorporate biotin-labeled ribonucleotides into the cRNA transcripts using an RNA transcript labeling kit (Enzo Biochem, Farmingdale, NY). Labeled cRNAs were purified and analyzed via agarose gel electrophoresis to confirm a size distribution ranging from 500 to 1200 bases. These cRNAs were fragmented to sizes ranging from 50 to 200 bases by heating at 94°C for 35 min, and 15 µg used for separate hybridization to a rat Genome U34A Array (Affymetrix, Santa Clara, CA) according to the manufacturer’s protocol, with a prior quality assay using Test2 Array probe chips. After hybridization and subsequent washing using the Affymetrix Fluidics station 400, the bound RNAs were stained with streptavidin phycoerythrin, and the signals were amplified with a fluorescent-tagged antibody to streptavidin. Fluorescence was measured using the Affymetrix scanner, and the results were analyzed using the GENECHIP analysis suite software. Variations in gene expression between the experimental diet groups and the 12C group are presented as fold differences.
Cluster analysis was carried out on the gene expression data from microarray experiments. An average linkage hierarchical clustering algorithm (12
) was used to group the genes according to the similarity of their relative expression patterns in the12G or PF group compared with the 12C group.
RNase protection assay.
Template DNAs for the synthesis of antisense RNA probes were obtained by reverse transcription-polymerase chain reaction. The 5' ends of the gene-specific sense and antisense primers corresponded, respectively, to the following nucleotide positions on the rat gene sequences in GenBank with the indicated accession numbers: 3-hydroxy-3-methylglutaryl (HMG)-CoA synthase, 525–888 (X52625); HMG-CoA reductase, 95–532 (X55286); squalene synthetase, 521–930 (M95591); squalene epoxidase, 326–778 (D37920); lanosterol 14-demethylase, 165–604 (M29249); 7-dehydrocholesterol reductase, 272–695 (AB016800) and cholesterol 7 
-hydroxylase (Cyp7A1), 1006–1409 (J05460). The amplified cDNAs were subcloned into pGEM-T easy vector (Promega), and the sequences were confirmed using an automated DNA sequencer (ABI 310).
An equal amount of total RNA (20 µg) from each sample was then used for determining mRNA levels of each target gene using an RNase protection assay as described previously (13
,14
). Rat glyceraldehyde-3-phosphate dehydrogenase (150 bp) mRNA levels were used as internal controls for normalizing loading of the same total RNA amounts among treatments. Protected bands were imaged and analyzed using FLA3000 (Fuji Photo Film, Tokyo, Japan). All mRNA levels are given as relative values.
Serum cholesterol and HDL cholesterol measurements.
Serum total and HDL cholesterol concentrations were measured by cholesterol oxidase methods (Cholesterol C II Test Wako and HDL-Cholesterol Test Wako; Wako Pure Chemical Industries, Osaka, Japan) according to the manufacturer’s instructions.
Statistical analysis.
Values are expressed as the mean ± SEM. Data were evaluated by one-way ANOVA, and post-hoc analysis was performed using Fisher’s Protected Least Significant Difference test (StatView J-4.51.1 for Macintosh; Abacus Concepts, Berkeley, CA). Differences with P-values <0.05 were considered significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The DNA microarray revealed that the expression of many genes was affected by protein malnutrition. Comparison of the hybridization patterns from the 12C and PF diet groups revealed that the PF diet resulted in a twofold or greater upregulation of 97 genes and a twofold or greater downregulation of 184 genes (Table 2
) (for a full list, see supplemental tables S1and S2),4 together accounting for 3.5% of the 8000 genes tested. The genes shown in Table 2
are tentatively classified into groups by their known biochemical functions. Many of the genes that are likely to be involved in growth, signal transduction and energy metabolism were highly responsive to the PF diet. Some of them have previously been reported to have their expression affected by alternations in protein nutrition. For example, IGF-I is reduced, whereas IGF binding proteins-1 and -2 are greatly induced by a PF diet (15
,16
) (Table 3
). The genes whose functions are presently unclear are grouped under the heading "unassigned."
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1.4% of the genes tested, which corresponded to less than half the number changed by the PF diet. Among them, 61 genes were increased and 50 were decreased (Table 2)
(for a full list, see supplemental tables S3 and S4).4 Many of the affected genes have been implicated in growth, metabolism and signal transduction. It has previously been shown that a wheat gluten-containing diet lowers serum cholesterol in rats (17
,18
). It is therefore of interest that many of the genes involved in the cholesterol biosynthetic pathway and cholesterol catabolism were upregulated by the 12G diet in the present study (Table 3
, Table S3). These genes included HMG-CoA reductase, the rate-limiting enzyme for the cholesterol biosynthesis (19
), and Cyp7A1, the rate-limiting enzyme in the classic pathway of bile acid biosynthesis from cholesterol (20
,21
). The genes that changed more than twofold due to the PF diet, the 12G diet or both were analyzed using a statistical cluster program. The cluster analysis classified these genes into four subgroups. Group 1 includes the genes upregulated by both 12G and PF diets and Group 2 comprises those downregulated by both. Group 3 consists of the genes upregulated by the 12G diet but downregulated by the PF diet, whereas group 4 is the reverse of Group 3. Many growth-inhibiting genes (Tables S1, S3) belong to Group 1, whereas a number of growth-stimulating genes (Tables S2, S4) are included in Group 2; these are genes whose changes in expression may eventually result in the growth retardation caused by the protein malnutrition. These cluster-analysis results are available as a supplemental figure S14.
Verification of the changes in gene expression by the RNase protection assay.
Because of the high cost of microarray analysis, we pooled the samples from the same treatment as described above. Thus, to verify the accuracy of the results obtained from the microarray, the mRNA levels of selected genes of individual rats were analyzed by the RNase protection assay, a specific and sensitive method for detection and quantification of mRNA species. We chose to verify the genes for enzymes related to the biosynthesis of cholesterol because many of these were drastically upregulated by the 12G diet. The increases in the mRNA levels obtained by the RNase protection assay were very close to the values deduced by the microarray analysis for all of the genes tested (Fig. 1
). In addition, the results of the RNase protection assay confirmed the microarray results with respect to the decrease in mRNAs of the above selected genes in the PF diet-fed compared with the 12C diet-fed rats (data not shown). Furthermore, the 12G diet-induced increase in mRNAs of Hsp27, a protein related to stress responses, and the PF diet-induced decreases in mRNAs of collagen I (1) and III (1) proteins (Table 3)
, were also confirmed by the RNase protection assay (unpublished data).
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As described above, the expression of genes involved in the cholesterol biosynthetic pathway exhibited striking and different responses to the 12G or PF diet. From these data, along with the reported effect of wheat gluten to reduce serum cholesterol, it seemed essential to determine the serum cholesterol levels of rats in the three diet groups. Both the 12G and PF diet-fed rats had lower serum total and HDL cholesterol concentrations than rats fed the 12C diet (P < 0.05) (Table 4
). Serum total and HDL cholesterol concentrations did not differ between the 12G and PF diet-fed rats.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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–9
,22
), are very promising and powerful tools for large-scale and genome-wide analyses of genetic variation and gene expression patterns. The current study has demonstrated the utility of this method for the identification of a differential gene expression profile in response to changes in protein nutritional status. It has presented some interesting findings that may be associated with the growth retardation caused by protein malnutrition-treatment, suggesting that a DNA microarray approach could also be used to help clarify the mechanisms of the physiologic consequences of protein malnutrition.
In the present study, we compared the effects of two diets that result in protein malnutrition on the hepatic gene expression profile. The first was a wheat gluten-containing diet (12G) that was deficient in the amino acids lysine and threonine; the other was a diet completely devoid of protein (PF). Microarrays revealed that 111 genes were up- or downregulated more than twofold by the 12G diet compared with the control, 12C diet, whereas 281 genes were altered by the PF diet. These results seem to reflect, to some extent, the dietary protein status. In rats fed the PF diet, the number of highly affected genes accounted for 3% of the genes investigated, representing about one fourth of the rat genome (Affymetrix). A number of the affected genes have previously been identified as dietary protein-responsive genes using conventional approaches (23
–27
), but the majority have not previously been identified as being affected by protein nutritional state. The responsive genes were involved in a wide range of physiologic functions, such as growth, metabolism, signal transduction and cell structure, although the direct relationship to protein malnutrition is unknown for many of them (Tables S1–S4).4 This wide range of effects is not surprising because multiple cellular processes are regulated by nutritional factors as well as hormones. Two of the most striking findings will be discussed below in detail.
When comparing the expression patterns between the12G and PF diet-fed rats, we found that some genes exhibited similar responses to both. For example, inhibitors of DNA-binding (Id)-1 and Id-3 categorized in the class of "transport and binding proteins" (Table 3)
were elevated by both the 12G (5.1-fold for Id-1 and 2.4-fold for Id-3) and PF diets (8.3-fold for Id-1) compared with their levels in rats fed the 12C diet. Id proteins are basic helix-loop-helix (HLH) proteins, but are distinct from the major basic helix-loop-helix (bHLH) proteins of transcription factors in that they lack the basic DNA binding domain (28
). Id proteins form heterodimers with ubiquitous and/or tissue-specific bHLH transcription factors. The Id-bound bHLH factors lose their activities of DNA binding and, as a consequence, those of transcriptional regulation (29
). bHLH proteins have been shown to be essential for the differentiation program of multiple cell types (30
–32
). Thus, the interaction between Id and bHLH proteins has been proposed as a key regulatory event leading to a negative regulation of cell differentiation. We recently reported that two isoforms of upstream stimulatory factor (USF), a bHLH factor, are important regulators of the IGFBP-1 gene, and that their expressions in the liver are under the control of protein nutrition (26
). Together with a multitude of other known functions of USF, the present results reveal a new link between protein nutrition and cellular function. Given the large numbers of bHLH factor members and their essential roles for every aspect of cellular function, the Id family could be a key player in terms of the regulation of animal systems by dietary proteins and amino acids. For this reason, we are currently conducting an extensive series of studies into the function and gene regulation of this family. Thus far, the responses of the mRNA levels of both Id have been verified by RNase protection assay (data not shown).
The other major outcome of our study is that the genes involved in cholesterol synthesis and catabolism exhibited very sensitive responses to changes in protein nutritional status. In rats fed the 12G diet, many of the genes involved in cholesterol biosynthesis and degradation were upregulated relative to their expression in the control group. These changes observed by DNA microarray assay were confirmed by the RNase protection assay (Fig. 1)
. Despite this enhanced hepatic cholesterol synthesis, the serum total and HDL cholesterol concentrations were reduced by the 12G diet. It has been established that the source of dietary protein influences the serum cholesterol level (10
,33
). For gluten, several reports have indicated that a gluten-containing diet exerts a hypocholesterolemic effect in growing rats compared with rats fed a control casein diet (18
), a finding that is consistent with the present study. These effects of gluten on cholesterol metabolism may be due to the poor amino acid balance of gluten, in which lysine and threonine are limited. However, this possibility was ruled out by the fact that the hypocholesterolemic actions of gluten on serum cholesterol concentration and gene expression were not abolished by supplementation of lysine and threonine to the gluten diet (18
, our unpublished data). These results suggest that components of gluten or some physiologic peptides derived from gluten are probably responsible for its hypocholesterolemic effect.
Previous studies have shown that the low levels of serum cholesterol caused by dietary gluten were accompanied by enhanced hepatic lipogenesis and cholesterol synthesis (18
). One possible explanation for this paradox is that the lower serum cholesterol concentrations may be tightly linked to increased removal from the circulation. It has been reported that the low serum cholesterol concentrations in gluten-fed rats were due to increased fecal excretion of cholesterol and bile acids (18
). This is also the case for the soybean protein isolate, which is hypocholesterolemic (34
). However, the molecular mechanisms leading to decreases in serum cholesterol concentrations by gluten or other proteins remain unclear. In our study, we found that almost all genes involved in the cholesterol biosynthetic pathway from acetyl coenzyme A to cholesterol were elevated by gluten. The increase in gene expressions for the biosynthetic enzymes could be associated with increased cholesterol synthesis, as reported previously (35
), although we did not measure the synthesis rate in the present study. The cholesterol catabolic pathway from cholesterol to bile acid was also activated as indicated by the increased expression of Cyp7A1, the rate-limiting enzyme for bile acid biosynthesis from cholesterol (36
,37
). Moreover, the expression of the LDL receptor that controls the clearance of cholesterol from the circulation was also upregulated by about fivefold in the DNA microarray assay (Table S3).4 Another notable factor relating to cholesterol homeostasis would be small heterodimer partner (SHP), an orphan nuclear receptor, whose expression in rats fed 12G was increased by about fivefold (Table S3).4 SHP has been shown to play an important role in the molecular mechanism of the feedback regulation of bile acid synthesis (36
). These results suggest that gluten contributes to a wide range of diverse processes in the cholesterol metabolic pathways. The results obtained from the present study might thus provide new insight into the molecular mechanisms by which gluten affects cholesterol metabolism, although further studies will be required with respect to the protein levels and other related factors.
In contrast, the PF diet reduced both the serum cholesterol concentrations and the expression of cholesterol biosynthetic genes. Bassat and Mokady (18
) speculated that the reduction of LDL biosynthesis and the resulting hepatic accumulation of cholesterol were probably the main reasons for the depressed cholesterol synthesis and hypocholesterolemia induced by the protein deficiency. Although the present study did not reveal any changes in LDL biosynthesis or the level of the LDL receptor, the decreases in the expression of a set of cholesterol biosynthesis-related genes may provide some clues to the molecular mechanisms underlying the regulation of cholesterol metabolism by protein deficiency.
In conclusion, this study, the first attempt to apply the DNA microarray technique to evaluation of the effects of dietary protein quantity and quality on the gene expression profile of mammalian tissue, has revealed that a variety of genes are affected by protein nutritional status. This approach was shown to be highly reliable based on the reproducibility of the responses of known responder genes. In addition, we found a number of hitherto unrecognized genes to be regulated by ingested protein, indicating that the array technique is extremely effective in uncovering new functions of dietary protein. The results of this study should make an important contribution to our understanding of the mechanisms by which dietary protein affects the activities of animal life.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: bHLH, basic helix-loop-helix; 12C, diet containing 12 g/100 g casein; Cyp7A1, cholesterol 7- hydroxylase; 12G, diet containing 12 g/100 g wheat gluten; HMG, 3-hydroxy-3-methylglutaryl; Id, inhibitor of DNA-binding; IGF-I, insulin-like growth factor I; PF, protein-free diet; SHP, small heterodimer partner; USF, upstream stimulatory factor.
4 Supplemental material is available as part of the online version of this paper at www.nutrition.org.
Manuscript received 1 August 2002. Initial review completed 27 August 2002. Revision accepted 11 September 2002.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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H. Kato and T. Kimura Evaluation of the Effects of the Dietary Intake of Proteins and Amino Acids by DNA Microarray Technology J. Nutr., June 1, 2003; 133(6): 2073S - 2077. [Abstract] [Full Text] [PDF]
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