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Endocrinology Vol. 143, No. 3 979-984
Copyright © 2002 by The Endocrine Society

RECEPTORS

TRß1 Protein Is Preferentially Expressed in the Pericentral Zone of Rat Liver and Exhibits Marked Diurnal Variation

Behrouz Zandieh Doulabi, Marianne Platvoet-ter Schiphorst, Hermina C. van Beeren, Wil T. Labruyere, Wouter H. Lamers, Eric Fliers, Onno Bakker and Wilmar M. Wiersinga

Departments of Endocrinology and Metabolism (B.Z.D., M.P.-T.S., H.C.v.B., E.F., O.B., W.M.W.) and Anatomy and Embryology (W.T.L., W.H.L.), Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands

Address all correspondence and requests for reprints to: Onno Bakker, Ph.D., Department of Endocrinology and Metabolism, F5-171, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail: . o.bakker{at}amc.uva.nl


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
We investigated the distribution and diurnal variation of TRß1 protein expression in liver with specific antibodies against TRß1. Immunohistochemistry showed a zonal distribution of TRß1 with maximum expression in the pericentral zone matching some known T3-responsive enzyme activities in the liver, such as glutamine synthetase, cholesterol 7{alpha}- hydroxylase, and spot 14. Combining immunohistochemistry and image analysis we found and quantified the same zonal distribution for 5'-deiodinase type 1 as for TRß1. Western blot analysis revealed a profound diurnal variation for TRß1 protein expression, with highest levels at the beginning of the dark period. TRß1 diurnal variation partly overlaps with the T3-responsive genes, cholesterol 7{alpha}-hydroxylase and spot 14. Furthermore, TRß1 distribution along the porto-central axis does not change during the day, indicating that the zonal expression of TRß1 is stable.

This is the first time that zonal distribution in liver has been demonstrated for a member of the nuclear receptor family. This finding together with the observed diurnal rhythm has major implications for interpreting and timing experiments concerning the TR and its downstream actions in liver.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
METABOLIC PROCESSES are regulated by a number of hormones, one of which is thyroid hormone. During hyperthyroidism the metabolic rate is increased as a result of an increase in activity of certain T3-dependent enzymes. Thyroid hormone signals its presence to the cell by binding to the thyroid hormone receptor, of which at least four isoforms exist. TRß1 is the predominant isoform in liver, where it binds to so-called thyroid hormone response elements (TRE) in the promoter of T3-responsive genes and thereby activates or represses the gene. The liver is the major source of circulating T3 (1), which is formed by converting the prohormone T4 into T3 through the action of the enzyme 5'-deiodinase type 1 (D1). The expression of this enzyme itself is partly dependent on thyroid hormone (2), and liver D1 remains weakly T3 inducible in TRß knockout mice, whereas its induction is abolished in TRß/TR{alpha}1 knockout mice, indicating importance of TRß1 for D1 expression in liver (3).

The liver is the organ where many metabolic processes occur simultaneously. A growing body of evidence indicates that not all processes take place in every liver parenchymale cell, but that the various metabolic reactions occur in different locations along the porto-central axis of the liver units (4, 5). For instance, lipogenesis and glycolysis are predominant in liver cells around the central vein, whereas lipolysis and gluconeogenesis are found in the area around the portal vein. This so-called metabolic zonation can be of a stable or dynamic kind, which means that the expression of certain enzymes is restricted to certain cells regardless of the metabolic or hormonal state, whereas the expression of other enzymes can expand or shrink along the porto-central axis depending on the metabolic state or the time of the day. Enzymes with a stable distribution can be located pericentrally [glutamine synthetase (GS)] or periportally (fructose 1,6-bisphosphatase) (6). Similarly, enzymes with a dynamic distribution can be located pericentrally (ornithine aminotransferase) (7) or periportally (phosphoenolpyruvate carboxy-kinase) (8).

A number of T3-responsive genes involved in metabolism are zonally expressed in liver. In the case of GS, both mRNA and protein expression are restricted to the area around the central vein (9) in a stable fashion (10), whereas phosphoenolpyruvate carboxy-kinase expression is dynamic and focused around the portal vein (11). Other T3-responsive genes, such as malic enzyme (12), spot 14 (13, 14), acetyl-coenzyme A carboxylase (13), cholesterol 7{alpha}-hydroxylase (CYP7a) (15, 16, 17), and glucose-6-phosphate dehydrogenase (18, 19), are expressed in different zones within the liver (see Table 1Go). To further clarify some of the mechanisms governing this zonal expression we studied the expression of the TRß1 in rat liver using polyclonal antibodies we developed recently. We performed immunohistochemistry to localize and Western blotting to quantify the protein in the liver of rats. We also studied the distribution of two different T3-responsive genes (GS and D1).


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  		Table 1. Overview of the zonal distribution and diurnal variation in rat liver of several T3-responsive genes

 

   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Antibodies, immunohistochemistry, and image analysis
Anti-TRß1 antisera were raised in New Zealand White rabbits (Eurogentec, Seraing, Belgium) against a peptide (conjugated to keyhole limpet hemocyanin) encoding for amino acids 74–92 of the human TRß1 (GenBank accession no. gi:586092). The anti-D1 antiserum was raised against a C-terminal peptide of rat D1 (20) and was a gift from Dr. Jack Leonard (University of Massachusetts, Worcester, MA). Monoclonal anti-GS was obtained from Affinity Research Products (Nottingham, UK). As secondary antibodies, goat antirabbit IgG+M and goat antimouse conjugated with alkaline phosphatase (DAKO Corp., Golstrup, Denmark) were used for immunochemistry, and goat antirabbit IgG and goat antimouse conjugated with horseradish peroxidase (Roche Molecular Biochemicals, Mannheim, Germany) were used for Western blots.

For immunohistochemistry, the 6-µm thick, paraformaldehyde-fixed (4% in PBS for 16 h at 4 C), paraffin-embedded liver sections were subjected to microwave irradiation [Tris-buffered saline (TBS), pH 7.6, at 750 watts for 10 min] before immunodetection to unmask the antigenic epitope. The sections were incubated with antiserum (1:250 dilution) in TBS (pH 7.6), 5% (wt/vol) low fat milk, and 0.5% (wt/vol) Triton X-100 for 1 h at 22 C and then overnight at 4 C. Secondary antibody (1:250 dilution) incubation was performed for 60 min at 22 C in PBS (pH 7.6) with 0.5% (wt/vol) Triton X-100. The sections were then washed and incubated in buffer (0.1 M Tris, 0.1 M NaCl, and 50 mM MgCl2; pH 10.2) for 10 min. Twenty minutes after adding nitro blue tetrazolium 5-bromo-4-chloro-3-indolyl-phosphate (Roche Molecular Biochemicals) and levamisole (Sigma, St. Louis, MO), the staining reactions were stopped by washing with TBS.

Image analysis has been described previously (21). Briefly, the image acquisition was performed with a Photometrics CCD camera on a Carl Zeiss Axiophot microscope (New York, NY). The images were converted into OD by calculating the negative logarithm of the transmission image (I) divided by an image of the light source (I°; OD= -10log (I/I°). Image is processed by a automatic segmentation and skeletonization of central and portal zones images. The distance transformation with respect to these skeletons gives for each point in the image pair the distance to the nearest terminal branches of the portal vein and central vein. The relative position on the porto-central radius was calculated as: portal distance image/(central distance image + portal distance image).

Western blots
Liver or HeLa cells were homogenized in 0.25 M sucrose containing Complete protease inhibitor (Roche Molecular Biochemicals) using a Polytron homogenizer (Brinkmann Instruments, Inc., Westbury, NY) for 10 sec at maximum speed. The protein concentration of these whole cell extracts was determined using a reagent obtained from Bio-Rad Laboratories, Inc. (Munich, Germany). Subsequently, 25 µg protein were loaded on a 10% SDS-PAGE gel. After semidry blotting onto membrane (Protran BA45, Schleicher \|[amp ]\| Schuell, Inc., Dassel, Germany), the blots were blocked for 45 min in TBS containing 0.2% (wt/vol) casein hydrolysate (Roche Molecular Biochemicals) and 0.5% (wt/vol) Tween 20 (blocking buffer). Next, the blots were incubated for 2 h at 22 C with the primary antiserum anti-TRß1 (1:250 dilution) or monoclonal anti-GS (1:1,000 dilution) or overnight at 4 C with anti-D1 (1:250). After 30 min of incubation with secondary antibodies (1:20,000 dilution) in blocking buffer, the blots were washed and LumiLight Plus substrate (Roche Molecular Biochemicals) was added. The signals were visualized and quantified using a LumiImager (Roche Molecular Biochemicals).

Scatchard analysis
Binding of T3 to rat liver nuclei was studied using Scatchard analysis as described previously (22). Binding was measured in livers from rats killed at 1330 h (n = 6) and at 1930 h (n = 5). Binding data are expressed per mg DNA.

Transfection assay
HeLa cells were transfected with 1 µg plasmid pRShtrß1 (23), and COS cells were transfected with 5 µg rat TRß2 (a gift from Dr. W. W. Chin, Boston, MA) per 10 µl Lipofect (Life Technologies, Inc., Gaithersburg, MD) according to the manufacturer’s protocol. The cells were harvested 48 h after transfection and used for Western blots.

Statistical analysis
All data are presented as the mean ± SD. Variations between groups were evaluated with the unpaired, two-tailed t test. A difference was considered statistically significant at P < 0.05. All data were evaluated using SPSS version 9 (SPSS, Inc., Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Specificity of the TRß1 antiserum
We raised specific rabbit polyclonal antibodies to amino acids 74–92 of TRß1 (GenBank accession no. gi:586092). The specificity of the antiserum was supported by Western blot analysis after transfecting the full-length human cDNA of TRß1 in HeLa cells. Western blots revealed binding with a 55-kDa protein band corresponding to the TRß1 isoform (Fig. 1Go). No cross-reactivity was seen with either vaccinia- expressed TR{alpha}1 or TRß2 expressed in COS cells (Fig. 1Go). The specificity of the TRß1 antiserum was further supported by negative preimmune serum staining and by negative staining with antiserum preadsorbed with antigenic peptide. Isoform specificity was also supported by the absence of cross-reactivity, as examined by immunocytochemical staining of the fixed TR peptides TR{alpha}1 (amino acids 402–410), TR{alpha}2 (amino acids 425–442), and TRß2 (amino acids 131–145) on a nitrocellulose membrane.



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  		Figure 1. Specificity of the TRß1 antiserum. Rat liver, TRß1-transfected HeLa cells, and vaccinia-expressed TR{alpha}1- and TRß2-transfected COS cells were used to check the specificity of the antiserum. Western blots of whole cell extracts were incubated with the anti-TRß1 antiserum. Staining at 55 kDa was observed in rat liver and TRß1-expressing HeLa cells. No cross-reactivity was observed with TR{alpha}1 (47 kDa) or TRß2 (57 kDa). The signal around 40 kDa is nonspecific (compare HeLa with HeLa plus TRß1 and COS with COS plus TRß2).

 
Zonal expression of TRß1 protein
Immunohistochemistry of rat liver sections indicated that the TRß1 protein has its highest expression in a small zone of hepatocytes around the central vein, decreasing toward the portal vein. The TRß1 expression pattern overlapped with that of the centrally expressed, T3-responsive gene GS, which we stained as a control on consecutive slices (Fig. 2AGo). Immunostaining of TRß1 was predominantly (peri)nuclear, but staining was also seen in the cytoplasm (Fig. 2BGo). We also stained rat liver slices with 5'-D1-specific antiserum and found staining in roughly the same area as the TRß1 (Fig. 2BGo). Image analysis indicated that 5'-D1 expression has a slightly wider pericentral distribution than TRß1 expression (Fig. 2CGo).



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  		Figure 2. Zonal expression of TRß1 in rat liver. A, Distribution of TRß1 and GS staining in rat liver. The rats were killed at 1930 h. Bar, 500 µm. B, Distribution of TRß1 and D1 expression in the pericentral regions of rat liver. The rats were killed at 0900 h. cv, Central vein; pv, portal vein. Bar, 200 µm. The higher magnification is shown in the insets (bar, 30 µm). C, Quantification by image analysis of ODs of both TRß1 and 5'-D1 protein expression. The rats were killed at 0900 h.

 
Diurnal variation of TRß1
When rats were killed at different time points during the day we found different staining intensities for TRß1 in the liver. Receptor expression was higher when the rats were killed in the morning than when they were killed in the afternoon. This observation suggested the possibility of diurnal variation of TRß1 protein in liver. Indeed, diurnal variation has been previously described for several T3- responsive genes (Table 1Go). For example the (pericentral) expression of the spot 14 gene in the liver varies diurnally at both mRNA (24) and protein (13) levels. To investigate the possible diurnal variation in and/or changes along the porto-central axis of TRß1 expression, Western blot of liver extracts of rats killed at different time points were analyzed. These blots showed a clear diurnal variation in TRß1 expression (Fig. 3Go, A and B), with the highest TRß1 protein level present at the beginning of the dark period (1930 h) and the lowest protein expression in the middle of the light period (1330 h). We also performed Scatchard analysis on livers of the animals killed at the highest and lowest points of TRß1 protein expression (Fig. 3DGo). These analyses show an increase in maximal binding capacity when the 1330-h point is compared with the 1930-h point [140 ± 9 (n = 6) vs. 176 ± 4 (n = 5) fmol/mg DNA, respectively; P = 0.0002], which supports the observations reported above using immunohistochemistry and Western blotting. No change was observed in the Ka of T3 binding when comparing the 1330- and 1930-h points [0.38 ± 0.09 (n = 6) vs. 0.34 ± 0.06 (n = 5) liter/nmol, respectively; P = 0.4].



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  		Figure 3. Diurnal variation in TRß1 protein expressed in rat liver. A, Western blot of liver whole cell extracts incubated with the TRß1 antiserum. The lowest expression is found at 1330 h, and the highest expression at 1930 h. B, LumiImager quantification of the bands from all six animals (data are presented as the mean ± SD; n = 6; P values were derived from t test). C, Immunohistochemistry demonstrated diminished staining during the light period compared with the dark period in the pericentral zone. No change in the extent of the porto-central gradient is seen. Bar, 100 µm. D, Scatchard analysis of nuclear T3 binding at 1330 h ({circ}) and 1930 h ({bullet}). T3 bound is expressed per mg DNA. The points represent the mean of six (1330 h) and five (1930 h) separate determinations. Both the x and y data are depicted as the mean ± SD.

 
To determine whether the zonation of TRß1 was of the stable or the dynamic type, we performed immunohistochemistry on liver sections of the rats from the diurnal rhythm experiment. TRß1 protein distribution did not change along the porto-central axis, but staining intensity was reduced within the pericentral zone during the light period (Fig. 3CGo), indicating that the TRß1 zonation is of the stable kind, similar to that of GS. The T3-responsive enzyme GS is also expressed in the pericentral zone of the liver (10). This prompted us to investigate and quantify GS and D1 expression at the different time points. The expression of both proteins also showed a tendency toward a diurnal variation (Fig. 4Go).



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  		Figure 4. Diurnal variation in the protein expression of T3-responsive genes. The expressions of D1 (A; n = 3) and GS (B; n = 6) were studied using Western blots. Band intensities were quantified using a LumiImager. Data are presented as the mean ± SD. P values were derived from t test.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Several immunohistochemical studies have reported the presence of TRß1 protein in the liver of rodents (25, 26, 27, 28) and humans (29). However, in none of these studies was the zonation of TRß isoform mentioned. Although not all hepatocytes were stained in these studies, in none of published images was it possible to distinguish between central and portal veins. In one case (26) the antiserum was directed against both TRß isoforms, whereas in other cases the antisera were directed against TRß1 protein. In all studies frozen sections with poor morphology were used for immunohistochemistry. This may be the reason why a topographical distribution concerning TR isoforms was not mentioned in any of the studies, whereas most known T3-dependent genes are expressed in the liver in different zones. For the above reasons we raised and validated new specific antisera against TRß1.

From our data it appears that the expression of TRß1 protein, a member of the nuclear receptor family, is zonally distributed in the liver, and its highest expression is restricted to a smaller pericentral zone than the T3-producing enzyme 5'-D1. However, due to a possible limited sensitivity of our antiserum, we cannot rule out that the actual expression extends further along the porto-central axis, resulting in a broader porto-central gradient than is seen on the images. In addition to the zonal expression, the cellular receptor concentration varies with a diurnal rhythm (Fig. 3Go). At the beginning of the dark period, when the rats are nutritionally active (30), maximum TRß1 protein expression is observed, which is also reflected in an increase in maximal binding capacity. These results suggest that the timing of experiments concerned with the TR and its actions in liver is important.

The overlap found in the liver between TRß1 and D1 expression suggests a relationship similar to that in inner ear development, where deiodinase type 2 expression appears to be the trigger for TRß1 action (31). A possible spatio- temporal control of T3 availability would therefore mean that in this case TRß1 action in the liver could be partly dependent on locally produced T3. On the other hand, D1 expression itself is regulated by thyroid hormone (2), and in our study appears to increase together with TRß1 expression at the beginning of the dark period. Furthermore, it has been shown in transfection studies that TRß1 can regulate its own expression through TREs in its promoter, and that this may happen under certain circumstances in vivo as well (Ref. 32 and references therein).

The biological relevance of our study results is underlined by the finding that certain T3-responsive genes, such as CYP7a, GS, and spot 14, are expressed mainly in the pericentral zones in conjunction with TRß1. CYP7a, a key enzyme for the production of bile acids from cholesterol, can be regulated in rat liver by several effectors, including thyroid hormones (15, 33, 34). When comparing the diurnal rhythm of CYP7a with that of TRß1, it can be seen that TRß1 protein expression peaks earlier than that of CYP7a mRNA, protein, and enzyme activities (35), which would be expected if T3 is one of the effectors of CYP7a. The difference between the two is that the CYP7a expression is of a dynamic kind. In the morning only a few pericentral hepatocytes contained CYP7a mRNA, whereas approximately half of the hepatocytes along the porto-central axis contained CYP7a mRNA in the evening (16), indicating the involvement of additional mechanisms.

A similar zonation expression pattern and diurnal variation also strengthen the link between TRß1 and the S14 gene. The S14 gene encodes a protein in liver that is induced by T3 and dietary carbohydrate and possesses several TREs located between -2.8 and -2.5 kb upstream of the transcription start site (36, 37). Furthermore, the S14 mRNA exhibits a 3-fold diurnal variation, with a peak in the evening and a nadir in the morning (24), similar to the TRß1 protein expression in our experiments. Thus, all T3-dependent genes discussed in this paper show an overlap between the topographical position and the diurnal rhythm of TRß1 and the gene products.

In conclusion, we have shown that the expression of the TRß1 protein is of a stable pericentral type and argued that its expression overlaps with some (but not all) well known T3-dependent genes. In cases where there is no or only a partial overlap, TR{alpha}1 may play a role. This isoform is also present in rat liver, where it makes up about 20% of the total T3-binding capacity in rat liver (38). It remains unknown at present whether the diurnal changes in TRß1 expression are regulated by the biological clock or by food intake.


   Acknowledgments
 
We thank Dr. J. M. Ruiter for his outstanding contribution and image analysis for this study, and Anethe Mansen (Karolinska Institute, Stockholm, Sweden) for providing us with a blot containing vaccinia- expressed TR{alpha}1.


   Footnotes
 
This work was supported by Grant 903-40-194 of The Netherlands Organization for Scientific Research.

Abbreviations: CYP7a, Cholesterol 7{alpha}-hydroxylase; D1, 5'-deiodinase type 1; GS, glutamine synthetase; TBS, Tris-buffered saline; TRE, thyroid hormone response element.

Received August 20, 2001.

Accepted for publication November 29, 2001.


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 Introduction
 Materials and Methods
 Results
 Discussion
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