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Technical University of Munich, Molecular Nutrition Unit, D-85350 Freising-Weihenstephan
3To whom correspondence should be addressed. E-mail: daniel{at}wzw.tum.de.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • zinc deficiency • hepatic gene expression • DNA array • rats
The essential trace element zinc is a constituent of hundreds of proteins involved in intermediary metabolism, hormone secretion pathways and immune defense. Zinc is also an essential component of many transcription factors, suggesting that alterations in zinc status are immediately translated into changes in gene expression. Indeed, mRNA levels of metallothionein, cholecystokinin, uroguanylin, endothelin, p53, retinol binding protein and apolipoproteins, for example, have been shown to be either increased or decreased as a consequence of changes in zinc status (1 –7 ). The effects of zinc deficiency have been established in both humans and experimental animals and include anorexia, impaired immunity, skin lesions, abnormal development and growth retardation (8 ). This highly complex phenotype may occur through major changes in gene expression, although a complete list of genes and/or proteins involved in the underlying biochemical pathways leading to these clinical symptoms is not yet available.
Given the pleiotropic metabolic changes caused by zinc deficiency and the evidence that zinc status alters gene expression, the present study was undertaken to identify and examine a comprehensive collection of genes regulated by dietary zinc with focus on the liver. Subtracted library hybridization (9 ) and mRNA differential display (7 ) techniques have been used to identify mammalian genes that are regulated by zinc status. These methods are usually time consuming and only a small number of zinc-regulated genes (at best 20) have been identified. In contrast, in the model organism Saccharomyces cerevisiae, almost 15% of all yeast genes have been shown to be regulated by zinc when employing DNA-arrays (10 ). This technology is a powerful screening tool for identification of genes regulated by nutrients and metal ions such as zinc or copper (11 ). To date, only two studies have been reported that applied DNA-arrays to identify zinc-regulated genes in mammalian tissues. Expression profile analysis of murine thymus identified only 4 genes that were regulated by zinc status (12 ). In the small intestine of zinc-deficient rats, 32 genes were identified as up- or down-regulated (13 ). We hypothesized that additional zinc-dependent genes must exist in the genome of mammals. We investigated specifically gene expression in liver, a metabolically active tissue that is also a target tissue of the growth hormone/insulin-like growth factor (IGF) -axis. Zinc-adequate or zinc-deficient diets were administered to growing rats while energy and other nutrient intakes were kept constant. By employing cDNA- and oligonucleotide-arrays we identified 66 genes that responded to zinc status in liver in vivo. The observed changes in gene expression provide a starting point for defining the molecular mechanisms that enable low zinc status to develop into severe metabolic disturbances.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Rats (n = 24), with a mean body weight of 122.6 ± 4.8 g, were randomly divided into two groups. All rats were fed a purified diet (AIN 93G) as described previously by Kraus et al. (14 ) with casein low in zinc as the protein source. As described, corn oil was chosen as the fat source and contained the following (g/L): palmitic acid, 10.5; oleic acid, 28.5; linolenic acid, 1.3; stearic acid, 1.7; and linoleic acid, 56.6. One group was fed a zinc-adequate diet (382 µmol Zn/kg diet), and the other group was fed a zinc-deficient diet (19.8 µmol Zn/kg diet). For synchronization of food intake, all rats were force-fed intragastrically four times per day (800, 1200, 1800 and 2200 h) for 11 d as described (14 ). Rats were weighed every day. After 11 d of feeding, the rats were anesthetized with diethyl ether and decapitated. Blood was collected in heparinized tubes. Resected tissues were immediately frozen at -196°C and stored at -80°C. Zinc status was assessed by determining serum zinc concentration and the activity of serum alkaline phosphatase (AP; EC 3.1.3.1) as described elsewhere (13 ). The concentration of zinc in liver was determined by atomic absorption spectroscopy (model 5100, Perkin Elmer; Norwalk, CT) as described (14 ).
Atlas cDNA array.
cDNA array analysis was performed by using the Atlas arrays rat 1.2 (Clontech, Palo Alto, CA) containing 1176 unique cDNAs spotted on a nylon membrane. Probing of cDNA arrays was performed according to the manufacturer’s directions. Briefly, total RNA was extracted from livers of control and zinc-deficient rats. Pooled RNAs (n = 3) and RNAs of three individual rats within each group were used to produce reverse-transcribed probes. A pooled set of primers complementary to the genes represented on the array was used for the reverse transcription probe synthesis, which was radiolabeled with [
33P]-dATP (ICN Biomedicals, Eschwege, Germany) and purified by passage over NucleoSpin extraction spin columns (Clontech). Hybridization was allowed to proceed for 20 h at 68°C. The array membrane was washed and intensity of signals recorded for 96 h (Packard Cyclone Imager, Packard Bioscience, Meriden, CT). Gene-specific binding of each spot was quantified, corrected for background and normalized using signals of housekeeping genes as well as the "sum of intensities method." Four independent hybridizations were carried out. A difference in mRNA level between the groups was considered to be meaningful at a threshold ratio of 1.6 or more in at least 3 independent hybridizations (out of 4). This arbitrary threshold was chosen because in most cases, Northern blot analysis revealed similar or even more changes in transcript levels than detected by array analysis.
Pan rat liver array.
Oligonucleotide arrays on glass slides containing 1353 gene-specific oligonucleotides probes (50mer) were obtained from MWG Biotech AG (Ebersberg, Germany). RNA preparation, reverse transcription, labeling and hybridization were performed according to the recommendations of the manufacturer. In short, 100 µg total RNA was reverse transcribed in the presence of either Cy3- or Cy5-labeled dCTP (Amersham Bioscience Europe, Freiburg, Germany) to produce fluorescence-labeled first-strand cDNAs. Samples from liver of control rats (n = 3) were labeled with Cy5. Samples from liver of zinc-deficient rats (n = 3) were labeled with Cy3. Arrays were scanned (Affymetrix 428 Array Scanner, Santa Clara, CA) under dry conditions. The amount of a given mRNA in each sample was determined by measuring the Cy3 and Cy5 signal of each spot after scanning the array at 532 and 633 nm, respectively. The data obtained were normalized and analyzed using ImaGene 4.2-Software (BioDiscovery, Los Angeles, CA). Three independent hybridizations were carried out. Genes were considered up- or down-regulated if the change was 
1.6-fold in at least two hybridizations. Under these conditions, in most cases, Northern blot analysis showed similar or greater changes in expression than detected by microarray analysis.
Northern blots.
Northern blot analysis was carried out using an established capillary blotting method (15
). Total RNA was extracted using RNAWiz-reagent (Ambion, Austin, Texas). Total RNA/lane (10 µg) was separated on denaturing formaldehyde gels and transferred to nylon membranes. cDNA fragments representing unique open reading frames of the following genes were used for hybridization: 
2, 3 enoyl CoA-isomerase (Accession # D00729; nucleotides 341–931), NADPH-cytochrome P450 (CYP) reductase (M12516; 1151–1881), alcohol dehydrogenase A subunit (M15327; 491-1157), epidermal growth factor receptor (M37394; 2861–3679), insulin-like growth factor binding protein (IGFBP)2 (J04486; 635–997), neuropeptide Y (M20373;62–342), carboxylesterase (AF171640, 691-1401), UDP glucuronosyltransferase (J02589; 551-1401), acyl peptide hydrolase (J04733; 1331–2061), hepatic product spot 14 (also called lipogenic factor; K01934, 351–701), 5-aminolevulinate synthase (J03190; 1021–1850), CYP4a locus, CYP (M33936; 901-1510), ubiquitin-like protein (AF095740; 71–298), serine dehydratase (Y00752, 187–950), liver aldehyde oxidase (AF110477; 3300–4040), cytosolic aspartate aminotransferase (D00252; 571-1200), IGFBP complex acid labile subunit (S46785; 1141–1887), ceruloplasmin (L33869; 1840–2550), glycerolkinase (D16102; 901-1531), IGFBP1 (M89791; 160–830), subunit of F0F1-ATP synthase (D13127; 41–630), arrestin D (U03629; 22–207) and metallothionein (MT) (M11794/J00750; 124–366). cDNA fragments were randomly labeled with [32P]-dATP (ICN Biomedicals). Hybridization was carried out at 68°C overnight in commercial hybridization solution (Expresshyb, Clontech). Membranes were first washed with 2X sodium chloride/sodium citrate (SSC), 0.1% SDS. For the second wash, 0.1X SSC, 0.1% SDS was used. Hybridization signals were visualized by exposure to a phosphorimager screen. Imager screens were scanned, depending on signal intensity, after 24–96 h exposure. Blots were stripped by immersing the membranes in a boiling solution of 0.5% SDS. Blots were reprobed for glyceraldehyde-3-phosphate dehydrogenase (accession # M17701, nucleotides 549-1001) and the resulting signal was quantified and used for normalization.
Western blots.
Immunoblotting was carried out using an established standard blotting method (14 ). Protein preparations (100 µg protein/lane) were separated by 10% SDS-PAGE and transferred to nitrocellulose. The blot was blocked in PBS/0.1% Tween-20 containing 30 g/L nonfat dry milk. The blot was immunostained with anti-IGFBP1 M-19 antibody (1:1000 dilution; Santa Cruz Biotechnology, Santa Cruz, CA), a horseradish peroxidase conjugated anti-goat immunoglobulin G antibody (1:1000 dilution; Sigma, Taufkirchen, Germany) and 3-amino-9-ethylcarbazol. Protein concentrations were determined by optical density (OD) at 600 nm using the Bio-Rad protein assay (Bio-Rad, Munich, Germany). Staining of proteins with Ponceau S before further blot processing was used to determine that equal amounts of protein were loaded and transferred to the membrane.
Statistical methods.
Calculations were performed using Prism 2.01 (GraphPad Software, Los Angeles, CA). For each variable, 6–12 independent experiments were conducted. Differences between diet groups at d 11 were tested for significance using unpaired Student’s t test. Differences were considered significant if P < 0.001. Data are given as mean ± SD.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Zinc-deficient rats had a significantly reduced weight gain compared with controls (Table 1 ). Zinc concentration and the activity of AP in serum are considered to reflect zinc status and both were significantly reduced (Table 1) . The concentration of zinc in liver of rats fed the low zinc diet was also significantly decreased. Because the MT-1 mRNA level is also frequently considered to be a valid indicator of zinc supply, we determined its hepatic expression and observed that it was almost undetectable in zinc-deficient rats (Fig. 1 ). Rats fed the zinc-deficient diet also showed typical symptoms such as spars and rough hair as well as mild skin lesions. Thus, all of the expected impairments of zinc deficiency were present in the rats fed the zinc-deficient diet.
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To monitor changes in gene expression due to zinc deficiency in liver, we carried out expression profiling using commercial oligonucleotide- and cDNA-based arrays. Considering the ongoing controversy concerning array-derived data (16
), we choose two different systems to compare their reliability. Both systems may have advantages and disadvantages for selected genes, sensitivity, specificity, signal-to-background ratio and hybridization conditions, for example. In spite of these complex factors, it seems appropriate to employ different array technologies to obtain a more comprehensive collection of affected genes. Cross-analysis of our acquired data set showed that 1550 (
62%) of the 2500 genes on the arrays yielded signal intensities above background levels. A gene was considered to be differentially expressed at a threshold ratio of 1.6 in at least two or three independent hybridizations. Applying this arbitrary threshold, we found 66 genes that are candidates for zinc-regulated genes (Table 2
). The list contains 31 up-regulated and 35 down-regulated genes.
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-lactone oxidase). Northern blot analysis of genes selected on the basis of array data.
A set of zinc-regulated genes (n = 24) within each gene cluster identified by array analysis was selected for confirmation by Northern blot analysis. Differential expression rates of selected gene products, obtained by normalized quantification of the Northern blots, demonstrated that changes in expression level of 80% of the selected genes (n = 19) were independently confirmed by Northern analysis (Fig. 2 , Table 2 ). In most cases (74%), changes in transcript levels were more pronounced than those determined using cDNA- and oligonucleotide-arrays.
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For IGFBP1, expression was also determined at the protein level. As verified by ponceau-S staining, equal amounts of protein were applied to each lane. Consistent with the Northern blot analysis, the protein product of IGFBP1 also was lower than controls in zinc-deficient rats (Fig. 3 ).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The effects of zinc on the growth of mammals are well documented and are mediated at least in part through the somatotropic axis, with alterations in the level of available IGF-I (19 ,20 ). Corresponding to the clinically obvious growth retardation in zinc deficiency, seven of the identified transcripts with altered expression relate to liver targets of growth regulation, including IGF-I, IGFBP1, IGFBP2 and a subunit of IGFPB. Zinc deficiency has been shown to be associated with an increased expression of IGFI-mRNA, whereas the IGFBP-mRNAs are down-regulated. This decline in mRNA expression of IGFBP1 was also confirmed at the protein level by Western blot analysis (Fig. 3) . IGFBP2 concentration is also reduced in zinc-deficient rats, as demonstrated recently (21 ). Therefore, the growth retardation due to zinc deficiency in our experimental model is caused at least in part by zinc-dependent reduction in the expression of IGFBP. Thyroid hormones also affect growth, and it appears likely that zinc influenced the biological function of these hormones and their receptors; however, the mechanism by which zinc affects thyroid hormone function is still controversial (21 ). Our data showed an up-regulation of the thyroxine deiodinase type I mRNA, which may lead to an increase in the protein product that deiodinates thyroxine to triiodothyronine (T3) in liver and kidney. Enhanced enzymatic activity of hepatic deiodinase has also been reported in zinc-deficient rats (22 ). These findings suggest an improvement in thyroid hormone function in zinc deficiency. On the other hand, zinc deficiency reduced thyroid hormone signaling by reducing the ability of the hormone receptor to bind to DNA and thereby impairing target gene transcription (22 ). To evaluate the outcome of these contrary effects on thyroid hormone function in zinc-deficient rats, it seems to be appropriate to determine the expression levels of thyroid hormone target genes in zinc deficiency. Fortunately, the hepatic expression of the T3 responsive S14 gene, coding for a lipogenic factor, was increased in zinc-deficient rats (Table 2) . Although the S14 gene promoter contains other responsive elements, increased expression of the S14 gene is a strong indicator of T3 action as described by Freake et al. (21 ). Assuming that other T3 targeted genes are also influenced by zinc deficiency, the growth retardation that results is mediated by impairment of thyroid hormone function in addition to the influence of zinc on the somatotropic axis.
The effect of zinc deficiency on the fat concentration of liver has been studied in rats force-fed a diet containing coconut oil (23
). Zinc-deficient rats fed this diet had fatty livers characterized by an increase in total fat (68%) and dry matter (23%) associated with elevated activities of lipogenic enzymes such as acetyl-CoA carboxylase and fatty acid synthase (24
). In agreement with these findings, in our studies, low zinc status affected the mRNA level of a variety of genes involved in lipid metabolism. The single largest cluster encompassed 13 genes whose transcription was altered by zinc deficiency (Table 2)
. Consistent with the increased fat storage reported by Eder and Kirchgessner (23
,24
) we observed increased mRNA levels of genes encoding enzymes of lipid synthesis (ATP-citrate lyase, glycerol kinase, lipogenic factor) and down-regulation of genes encoding enzymes required for lipid degradation and mobilization (3-keto thiolase acyl CoA, 2, 3 enoyl-CoA isomerase, lysophospholipase). Thus, the high fat concentration in liver of zinc-deficient rats fed coconut oil could be caused by enhanced de novo synthesis of fatty acids and triglycerides and less degradation of stored fat; of course, this does not take into account allosteric regulation mechanisms.
Interestingly, dietary copper deficiency also induced hepatic lipogenic enzyme gene transcription by increasing the nuclear translocation of the transcription factor sterol regulatory element binding protein-1 in rats fed the AIN diet with corn oil (25 ,26 ). A similar or related mechanism may be responsible for disseminating the effects of zinc deficiency into hepatocytes and should be tested in future experiments. In addition to the increased fat concentration in liver of zinc-deficient rats, these authors also found a drastically altered fatty acid composition (23 ). Here, decreased expressions of CYP4- and CYP2C-isoenzymes (CYP4A3, CYP2C23) in zinc-deficient rats were detected. These enzymes are hydroxylases and are involved mainly in the metabolism of saturated and unsaturated fatty acids (27 ). Therefore, the altered fatty acid composition in zinc-deficient rats (23 ) might be the result of a reduced expression of CYP2C- and 4A-gene subfamilies.
Animal studies have shown that zinc supplementation confers MT-dependent and -independent protection against hepatotoxic xenobiotics or alcohol (28
–32
). Here, we provide evidence that a low zinc status alters the expression of genes of the CYP isoenzyme family and changes their role in hepatotoxicity. The mRNA-levels of 4 of the CYP genes as well as NADPH-CYP reductase were decreased in zinc-deficient rats. Effects of dietary zinc on hepatic CYP expression were shown previously in postpubertal male rats and a growth hormone–regulated signal transduction pathway involved in controlling CYP gene expression has been proposed (33
). The possible hepato-protective role of zinc is also supported by the finding that collagen biosynthesis is an important factor in the etiology of hepatic fibrogenesis, which is altered by zinc (34
). In agreement with this finding, we observed a zinc-dependent modulation of expression of the gene encoding the prolyl 4-hydroxylase, which is an L-ascorbic acid–dependent enzyme involved in collagen metabolism. Interestingly, the expression of L-gulono--lactone oxidase, the enzyme that catalyzes the last step of L-ascorbic acid biosynthesis in those mammals that do not rely on dietary ascorbate, is also altered in zinc deficiency. Taken together, the postulated hepato-protective role of zinc could be partially mediated by changes in the expression of genes important for xenobiotic and collagen metabolism.
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FOOTNOTES |
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2 Presented in poster form at the First International Nutrigenomics Conference in Noordwijk aan Zee, Netherlands, 28 February–1 March 2002[tom Dieck, H., Döring, F., Roth, H.-P., Pfaffl, M. & Daniel, H. (2002) Identification of genes with altered expression in zinc-deficient rats by use of DNA microarrays].
4 Abbreviations used: AP, alkaline phosphatase; CYP, cytochrome P450; IGF, insulin-like growth factor; IGFBP, insulin-like growth factor binding-protein; MT-1, metallothionein-1; SSC, sodium chloride/sodium citrate; T3, triiodothyronine.
Manuscript received 9 December 2002. Initial review completed 30 December 2002. Revision accepted 20 January 2003.
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LITERATURE CITED |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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E. Ho, C. Courtemanche, and B. N. Ames Zinc Deficiency Induces Oxidative DNA Damage and Increases P53 Expression in Human Lung Fibroblasts J. Nutr., August 1, 2003; 133(8): 2543 - 2548. [Abstract] [Full Text] [PDF]
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