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© 2005 The American Society for Nutritional Sciences J. Nutr. 135:1631-1635, July 2005

Biochemical and Molecular Actions of Nutrients

Soy Protein Isolate Increases Hepatic Thyroid Hormone Receptor Content and Inhibits Its Binding to Target Genes in Rats1,2,3

Wenxin Huang*, Carla Wood*, Mary R. L’Abbé*, G. Sarwar Gilani*, Kevin A. Cockell* and Chao Wu Xiao*,{dagger},4

* Nutrition Research Division, Food Directorate, Health Products and Food Branch, Health Canada, Banting Research Centre, Ottawa, ON, Canada K1A 0L2 and {dagger} Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada

4To whom correspondence should be addressed. E-mail: chaowu_xiao{at}hc-sc.gc.ca.


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 LITERATURE CITED
 
Our previous studies showed that intake of 20% alcohol-washed soy protein isolate (SPI) significantly increased hepatic thyroid hormone receptor (TR) ß1 protein content in rats. However, whether SPI influences the binding ability of TR to its target genes is unknown. The purpose of this study was to examine the effect of increasing amounts of dietary SPI on hepatic TRß1 content and the binding of TR to thyroid hormone response element (TRE) in rats. Sprague-Dawley rats (28 d old) were fed diets containing casein (20%) with or without isoflavone supplementation (50 mg/kg diet) or alcohol-washed SPI (5, 10, or 20%) for 90 d. The hepatic TRß1 protein content was measured by Western blot, and the binding ability of TR to DNA was examined by electrophoretic mobility shift assay. Consumption of the 20% SPI diet increased pancreatic relative weight and decreased spleen relative weight. Intake of SPI markedly elevated TRß1 content in both male and female rats compared with a casein-based control diet. The increase in TRß1 in females was much higher than that in males. Interestingly, the binding abilities of TR to DNA were significantly inhibited by increasing amounts of dietary SPI in female rats. In conclusion, this study shows for the first time that dietary SPI increases hepatic TRß1 protein content and inhibits the binding of TR to target genes. Modulation of hepatic TRß1, a key regulator of gene expression involved in lipid metabolism, by SPI may be a novel mechanism by which soy components lower blood lipid level and exert their hypocholesterolemic actions.

KEY WORDS: • rat • soy protein • isoflavones • thyroid hormone receptor • binding ability

Soy consumption has been linked to a lower incidence of chronic diseases such as cardiovascular diseases, atherosclerosis, type II diabetes, and certain types of cancers. These beneficial effects are attributed mainly to the abilities of soy components in improving blood lipid profiles, such as lowering total cholesterol, LDL cholesterol, and triglyceride levels, and decreasing the ratio of LDL to HDL cholesterol (1–3). However, the bioactive components in soybean responsible for the hypocholesterolemic and hypotriglyceridemic properties have not been consistently identified.

Isoflavones, the major phytoestrogens in soy, were shown to be hypolipidemic in both monkeys (4) and humans (5). Dietary supplementation with soy ethanol extract, rich in isoflavones, upregulated the expression of genes for hepatic cholesterol 7{alpha}-hydroxylase (CYP7A1)5 and LDL receptors in rats (6); these genes are important in mediating cholesterol catabolism. However, more convincing evidence tends to support the idea that soy proteins rather than isoflavones play major roles in lowering blood triglyceride and cholesterol concentrations (7–9). In addition, soy proteins were shown to regulate the expression of genes for fatty acid synthase (FAS), malic enzyme (ME), acetyl-CoA carboxylase (ACC), hydroxymethylglutaryl-CoA reductase, LDL receptor, and CYP7A1 in humans (10), animals (11–13), and cultured human hepatoma cells (14). Furthermore, soybean ß-conglycinin, 1 of the 2 main storage proteins, may be the bioactive component because it is capable of lowering lipid concentrations and modulating the expression of genes involved in lipogenesis and cholesterol catabolism (14). However, the underlying cellular and molecular mechanism(s) by which soy components regulate gene expression and change the blood lipid profiles have not been fully elucidated. Several putative mechanisms have been proposed to explain the hypolipidemic effects of soy in which soy proteins increase thyroxine (T4) levels (15), decrease insulin levels (16), and elevate the hepatic LDL receptor (14). In addition, we suggested previously that modulation of hepatic TRß1 content and function may be a novel mechanism by which soybean components regulate the expression of genes involved in cholesterol and lipid metabolism (17).

Thyroid hormone receptors (TRs) function as nuclear transcription factors to mediate thyroid hormone actions. Mammalian TRs are encoded by 2 genes, TR{alpha} and TRß. The primary transcript from each gene can be alternatively spliced and form different isoforms. Four isoforms (TR{alpha}1, TR{alpha}2, TRß1, and TRß2) have been identified to date (18). TRs can bind to the thyroid hormone response element (TRE) of target genes (18) with or without ligand binding, and regulate the expression of many key genes involved in hepatic cholesterol metabolism, lipogenesis, and bone metabolism. They also play important mediating roles in the regulation of growth, differentiation, development, and carcinogenesis. We demonstrated previously that 20% alcohol-washed soy protein isolate (SPI) greatly increased hepatic thyroid hormone receptor-ß1 (TRß1) protein content compared with casein in a multigeneration rat study (17). However, the dose effect of SPI and whether dietary SPI affects the binding activity of TR to TRE of its target genes remain unclear. The objective of this study was to examine the effect of increasing amounts of dietary SPI on hepatic TRß1 content and the binding abilities of TR to TRE in rats.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 LITERATURE CITED
 
    Chemicals and reagents. Alcohol-washed SPI (Pro Fam 930) and Novasoy (soy isoflavone concentrate) were purchased from Archer Daniels Midland. Casein protein (90% total protein) was from ICN. Tris, phenylmethylsulfonyl fluoride (PMSF), maleic acid, boric acid, Nonidet P-40, and EDTA were from Sigma Chemical. Western blotting detection kits and Hybond-N+ Membrane were obtained from Amersham. Acrylamide, N,N'-methylene-bis-acrylamide, ammonium persulfate, dithiothreitol (DTT), glycine, goat anti-mouse IgG (H+L)-horseradish peroxidase (HRP) conjugated antibody, and Bio-Rad protein assay kits were purchased from Bio-Rad Laboratories. X-Ray film was from MJS Biolynx. Mouse monoclonal anti-human TRß1 antibody was from Santa Cruz Biotechnology. Dig Gel Shift Kit was from Roche Applied Science. Total triiodothyronine (T3) and total T4 ELISA kits were from Alpha Diagnostic International. Free T3 and free T4 ELISA kits were purchased from ALPCO Diagnostics.

    Animals and diets. The animal experimental protocol was approved by the Health Canada-Ottawa Animal Care Committee, and all animal handling and care followed the guidelines of the Canadian Council for Animal Care. Weanling Sprague-Dawley rats (Charles River) were randomly divided into 5 groups (8 males and 8 females/group), and housed individually in stainless steel cages in an environmentally controlled room with a 12-h light:dark cycle. After acclimation, starting at 28 d of age, rats were given free access to tap water and 1 of the 5 diets. All 5 diets (D1–5) were formulated according to the specifications for the AIN93G diet (19) except that in D3–5, casein was replaced by the equal amounts of alcohol-washed SPI (Pro Fam 930; 5, 10, or 20%). In addition, D2 was supplemented with 50 mg/kg diet of isoflavones from Novasoy as a control (Table 1). Body weights and food consumption were recorded weekly. The actual total isoflavone content of the diets including genistein, daidzein, and glycitein was determined by Waters HPLC linear gradient with UV detection monitored at 254 nm (20) and is shown in Table 1.


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  		TABLE 1 Composition of experimental diets1

 
After being fed for 90 d, all rats were killed by exsanguination through cardiac puncture under general anesthesia with isoflurane. Blood and major organs including liver, thyroid, thymus, heart, kidney, spleen, pancreas, prostate gland, testis, ovaries, and uterus were collected, immediately frozen in liquid nitrogen, and stored at –80°C until analysis.

    Plasma total and free T3, T4 concentrations. Plasma total T3 and T4 concentrations were measured as described previously (17). Plasma free T3 and T4 concentrations were determined by ELISA kits according to the manufacturer’s instructions. Briefly, plasma (50 µL) was added to microtiter plate wells precoated with anti-T3 or anti-T4 antibodies, and then incubated with T3- or T4-enzyme conjugates for 1 h before the wells were washed. The enzyme substrate was added to each well and incubated for 30 min, and the reaction was stopped by the addition of 3 mol/L HCl. The absorbance was read at 450 nm. The concentrations of free T3 and T4 were calculated using standard curves.

    Protein extraction and Western blot analysis. Total protein extraction from rat livers and Western blot analysis of TRß1 were carried out as described previously (17) with minor modifications. Total proteins (80 µg) were resolved by 12% SDS-PAGE, and electrotransferred (30 V, 4°C, overnight) onto nitrocellulose membranes. After blocking, membranes were incubated overnight at 4°C with primary antibody, and subsequently with HRP-conjugated secondary antibody (1:5000) at room temperature for 45 min. Immunoreactivity was detected by chemiluminescence autoradiography according to the manufacturer’s instructions, and the images were scanned. The intensities of the protein bands of interest and the Ponceau-stained proteins were determined densitometrically using Scion Image software. The intensities of the target proteins were normalized by the respective Ponceau-stained total protein (21).

    Preparation of nuclear protein extracts. Hepatic nuclear protein extracts were prepared from rat liver tissue as described previously (21) with minor modifications. Briefly, fresh liver sample was homogenized in 100 µL cold buffer A (10 mmol/L HEPES, pH 7.9, 10 mmol/L KCl, 1.5 mmol/L MgCl2, 0.5 mmol/L DTT, 0.5 mmol/L PMSF, 0.67% Nonidet P-40). The cells were allowed to swell for 15 min on ice, and centrifuged (10,000 x g at 4°C). The supernatant was collected and stored at –80°C. The pellet was resuspended in 20 µL cold buffer B (20 mmol/L HEPES, pH 7.9, 0.4 mmol/L NaCl, 1.5 mmol/L MgCl2, 0.2 mmol/L EDTA, 25% glycerol, 0.5 mmol/L DTT, 0.5 mmol/L PMSF, 0.5 mmol/L spermidine, 0.15 mmol/L spermine), and rocked gently (4°C, 15 min). The nuclear extract was centrifuged (10,000 x g, 30 min) and divided into aliquots for storage at –80°C.

    Electrophoretic mobility shift assay (EMSA). Double-stranded DNA oligonucleotides containing consensus sequences (5'-AGCTTCAGGTCACAGGAGGTCAGAGAGCT-3') for TR specific binding were labeled at 3'-end with digoxigenin (DIG)-11-ddUTP and terminal transferase. Nuclear protein extracts (20 µg) were incubated with DIG-labeled DNA probes in the binding buffer [20 mmol/L Hepes, pH 7.6, 1 mmol/L EDTA, 10 mmol/L (NH4)2SO4, 1 mmol/L DTT, 0.2% (wt/v) Tween-20, 30 mmol/L KCl] for 15 min at room temperature. DNA-protein complexes were resolved on a native 6% polyacrylamide gel in Tris-buffered EDTA (pH 8.0), and electrotransferred (80 V for 1.5 h) onto positively charged Nylon membranes. The DIG-labeled DNA probes bound to the nuclear proteins were immunostained with alkaline phosphatase-conjugated anti-DIG antibody, and detected by chemiluminescence autoradiography. The intensity of the specific nuclear protein band was determined densitometrically.

    Statistical analyses. Results are expressed as means ± SEM. Effects of diets on food consumption, body weight, relative organ weights, plasma thyroid hormone concentrations, hepatic TRß1 protein content, and TR binding abilities were analyzed separately by gender using 1-way ANOVA. Effects of treatment on hepatic TRß1 protein content were analyzed by 2-way ANOVA, which included the main effects of diet and gender and the diet x gender interaction. Differences between means were determined by Fisher’s least significant difference test. A probability of P < 0.05 was considered to be significant. Data were analyzed using STATISTICA Version 6.1 (StatSoft).


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 LITERATURE CITED
 
    Food consumption, body weight, and organ relative weights. Food consumption did not differ among the dietary groups in either male or female rats. In male rats, the body weight and thymus, kidney, and testis relative weights were not affected by the diets. However, rats fed the 20% SPI diet had significantly lower liver, heart, and spleen relative weights and higher pancreatic relative weight than those fed casein-based diets (P < 0.05). The thyroid and prostate relative weights of the rats fed the 10% SPI diet were greater than those of rats fed the casein diet (D1, P < 0.05, Supplemental Table 1).

In female rats, the relative weights of liver, thyroid, thymus, heart, ovaries, and uterus were unaffected by the diets. However, rats fed the 10% SPI diet had a higher body weight than those fed other diets, whereas they had a lower kidney relative weight than those fed casein diets (D1 and D2, P < 0.05). In addition, consumption of the SPI diets (D3, D4, and D5) remarkably reduced the spleen relative weights compared with consumption of the casein diet (D1, P < 0.05). Ingestion of the 20% SPI diet (D5) significantly increased the pancreatic relative weight compared with rats fed the casein control diet (D1, P < 0.05, Supplemental Table 1).

    Plasma thyroid hormone concentrations. For both sexes, plasma total T3 concentrations were not affected in any dietary group. However, a high level of SPI (20%) increased free T3 concentrations compared with the other dietary groups in males, and compared with D3 and D4 in female rats (Supplemental Table 2).

Male rats fed the diet containing supplemental isoflavones (D2) had a higher concentration of plasma total T4 than rats fed the other diets (P < 0.05), and female rats fed the diet containing 20% SPI had a higher plasma total T4 concentration than rats fed the casein-based diets (D1 and D2, P < 0.05). In addition, both male and female rats fed the diet containing 10% SPI (D4) had significantly lower free T4 concentrations than those fed diets containing either casein + isoflavones (D2) or 20% SPI (D5) (Supplemental Table 2).

    Hepatic TRß1 protein content. Dietary SPI markedly increased hepatic TRß1 protein content in both female (Fig. 1a) and male (Fig. 1b) rats compared with the casein-based diets (D1 and D2) (P < 0.01). Supplemental isoflavones (50 mg/kg diet, D2) had no effect on this receptor compared with casein alone (D1) (Fig. 1a and b). Moreover, the stimulatory effect of SPI on hepatic TRß1 protein in female rats was greater than that in male rats (P < 0.01, Fig. 2).



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  		FIGURE 1 Hepatic TRß1 protein content in female (a) and male (b) rats fed diets containing casein with or without supplemental isoflavones (ISF; 50 mg/kg diet) or increasing amounts of alcohol-washed SPI (5, 10, or 20%) for 90 d. The images shown are representative of 3 replicates. Values are means ± SEM, n = 3. Means with different letters differ, P < 0.01.

 


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  		FIGURE 2 Comparison of hepatic TRß1 contents in female and male rats fed diets containing 20% casein or 20% alcohol-washed SPI. Values are means ± SEM, n = 3. Means with different letters differ, P < 0.01.

 
    Binding ability of hepatic TR to DNA. Nuclear TR binding ability in female rats fed diets containing either 5 or 20% SPI, as measured by EMSA, was lower than in those fed the casein diet (D1, P < 0.05, Fig. 3). However, SPI did not have this effect in male rats (data not shown). The addition of a 100-fold excess of unlabeled TR probes (cold probe) eliminated all binding activity, indicating the specificity of the binding of DNA probes to nuclear TR proteins.



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  		FIGURE 3 Binding activity of hepatic TR to the thyroid hormone response element of target genes in female rats fed diets containing either casein or alcohol-washed SPI (5 or 20%). The nuclear protein extracts were prepared from liver. The image shown is a representative of 3 replicates. Values are means ± SEM, n = 3. Means with different letters differ, P < 0.05.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
LITERATURE CITED
 
Soy proteins have been used extensively as a replacement for bovine milk protein in soy-based infant formulas, which are consumed by 20–25% of Canadian (22) and American formula-fed infants (23) each year. We showed previously that 20% dietary SPI remarkably elevated hepatic TRß1 protein content in a multigeneration rat study. In the present study, we extended our previous observations by measuring the effects of increasing amounts of SPI on hepatic TRß1 content and the binding ability of TR to the target genes, which is a crucial functional indicator of nuclear transcription factors.

The results of this study demonstrated that dietary SPI increased hepatic TRß1 protein content, and this effect was much higher in females than in males, whereas the binding abilities of the nuclear TR to TRE of the target genes were suppressed by SPI in female rats. This gender difference for the effect of SPI on TRß1 protein content and binding ability of TR to DNA suggests that sex hormones may play a role in the modulation of SPI actions. Estrogen was shown to be actively involved in the regulation of TR. The densities of pituitary TR were significantly greater in female than in male rats. Male rats treated with estrogen had more TR than control male rats (24).

Although the cellular and molecular mechanism(s) by which SPI affects hepatic TRß1 content and binding ability are still unknown, we showed previously that TRß1 mRNA abundance was unchanged by SPI, suggesting that the effect of SPI may be post-transcriptional. We hypothesize that SPI may directly or indirectly (via other induced factors) change the TRß1 protein structure or configuration, which would influence the receptor-DNA interaction and prevent receptor protein from degradation, thereby increasing TRß1 protein content. Alternatively, SPI or SPI-induced factors may block TRß1 binding to DNA through interaction with its DNA binding domain, and stimulate cells to synthesize more receptor protein to compensate for the functional inhibition of the receptor via a feedback mechanism. However, these remain to be elucidated.

Liver is an important organ for cholesterol metabolism and lipogenesis, and plays critical roles in the regulation of blood cholesterol and triglyceride levels. TRß1 is the predominant isoform in the liver, and a key regulator of many genes involved in cholesterol and lipid metabolisms such as those for ME (25), FAS (26), and ACC (27) because the promoters of these genes contain TRE. In addition, TRß1 is a ligand-dependent and -independent nuclear receptor. Binding of liganded TR to TRE stimulates gene transcription, whereas the unliganded TR suppresses transcription of the target genes. This indicates that regardless of thyroid hormone status, changes in TRß1 content and function may always be physiologically significant.

Thyroid hormones stimulated expression of the genes for ME, ACC, and FAS, and increased hepatic lipogenesis in rats (28–30). Dietary soy protein reduced lipid levels and suppressed the gene expression (13) and activities of hepatic lipogenic enzymes in both normal (31) and obese rats (13). Accumulated evidence has shown that soy-based diets either had no effect on or slightly increased the thyroid hormone levels (15), which is further supported by the present results that plasma free T3 in male rats and total T4 in female rats were increased by intake of 20% SPI (Supplemental Table 2). TRs are mediators of thyroid hormone actions. Therefore, inhibition of TRß1 binding to the target genes by SPI could block the stimulatory effects of thyroid hormones on the expression of lipogenic genes, and may contribute to the lipid-lowering function of soy proteins. This notion appears to be consistent with other reports that soy proteins reduced serum triglyceride concentrations in female, but not in male hamsters (32,33).

In the present study, SPI (20%) markedly increased pancreatic weights in both male and female rats. This effect of SPI may be attributed to the presence of active residual trypsin inhibitors, which were shown to stimulate the development of hypertrophy and hyperplasia of the acinar cells in the pancreas and cause pancreatic enlargement in rats (34). The activity of the trypsin inhibitors contained in the SPI used in this study was not determined. In addition, the spleen weights of both male and female rats were markedly reduced by dietary SPI relative to the casein diet, which appears to be consistent with the observations in rats fed soluble soybean fiber (35).

In conclusion, this study demonstrated for the first time that intake of alcohol-washed SPI increased hepatic TRß1 protein content and inhibited the binding ability of nuclear TR protein to the consensus DNA sequence of target genes. These effects of SPI were much higher in female than in male rats, and may be potentiated by female sex steroids. In addition, SPI (20%) increased pancreatic relative weight and reduced the spleen relative weight. Inhibition of hepatic TRß1 binding to target genes may be a novel mechanism by which soy proteins lower blood lipid and cholesterol concentrations and improve cardiovascular disease risk factors.


   FOOTNOTES
 
1 This is publication no. 603 of the Bureau of Nutritional Sciences. Presented in part at Health Canada Science Forum: Current Health Challenges Facing Canadians, October 18–19, 2004, Ottawa, Canada [Huang, W., Wood, C., L’Abbé, M. R., Gilani, G. S., Cockell, K. A. & Xiao, C. W. (2004) Soy protein isolate increases hepatic thyroid hormone receptor content and inhibits its binding to the target genes. 1.24 (abs.)]. Back

2 Supported by Food Directorate A-Base Fund and Postdoctoral Fellowship (to W.H.) of Health Canada. Back

3 Supplemental Tables 1 and 2 are available as Online Supporting Material with the online posting of this paper at www.nutrition.org. Back

5 Abbreviations used: ACC, acetyl-CoA carboxylase; CYP7A1, cholesterol 7{alpha}-hydroxylase; D1–5, diets 1–5; DIG, digoxigenin; DTT, dithiothreitol; EMSA, electrophoretic mobility shift assay; FAS, fatty acid synthase; HRP, horseradish peroxidase; ME, malic enzyme; PMSF, phenylmethylsulfonyl fluoride; SPI, soy protein isolate; T3, triiodothyronine; T4, thyroxine; TBS-T, tris-buffered saline and Tween-20; TR, thyroid hormone receptor; TRE, thyroid hormone response element. Back

Manuscript received 28 February 2005. Initial review completed 11 March 2005. Revision accepted 11 April 2005.


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 DISCUSSION
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C. W. Xiao
Health Effects of Soy Protein and Isoflavones in Humans
J. Nutr., June 1, 2008; 138(6): 1244S - 1249S.
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C. W. Xiao, J. Mei, W. Huang, C. Wood, M. R. L'Abbe, G. S. Gilani, G. M. Cooke, and I. H. Curran
Dietary Soy Protein Isolate Modifies Hepatic Retinoic Acid Receptor-{beta} Proteins and Inhibits Their DNA Binding Activity in Rats
J. Nutr., January 1, 2007; 137(1): 1 - 6.
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