Thyroid hormone receptors in liver metabolism
Author: Gullberg, Hjalmar
Date: 2002-06-07
Location: CMB auditorium, Berzelius väg 21, Karolinska Institutet
Time: 10.00
Department: Institutionen för cell- och molekylärbiologi (CMB) / Department of Cell and Molecular Biology
Abstract
Thyroid hormone has a profound impact on mammalian metabolism;
hypothyroidism causes decreased metabolic rate and increased serum
cholesterol levels. One major target organ for the hormone is the liver,
the most important metabolic organ in mammals, that balances anabolism of
carbohydrates and lipids against catabolism. This organ is also the main
regulator of cholesterol homeostasis. The active form of the hormone is
T3, the ligand for thyroid hormone receptors (TRs) which are ligand
dependent transcription factors belonging to the nuclear hormone receptor
superfamily. TRs affect transcription by binding to the regulatory
regions of target genes and subsequently either stimulate or repress
transcription. The major ligand-binding isoforms of the receptor are TR
alpha1 TR beta1 and TR beta2. In addition, alternative splicing of the
TRalpha gene transcript generates TRalpha2, a variant isoform that cannot
bind hormone. Gene targeting experiments with mice indicate that the
different isoforms have both distinct and overlapping functions in vivo.
The aim of our studies was to investigate T3 action and TR isoform
specificity on gene regulation and metabolism in liver. For this, we used
different TR deficient mouse strains and determined responses to T3 in
hepatic gene regulation as well as in cholesterol homeostasis.
To study overall hepatic gene regulation by T3, and TRbeta dependence in
this, we used microarrays for investigating regulation by T3 of 4000
genes in hypothyroid TRbeta-/- and control mice. The study was designed
to detect direct regulation of target genes by T3 as well as changes
induced by sustained hyperthyroidism. We identified 250 genes that were
regulated by T3, of which 100 had not previously been recognized as
target genes. Sixty percent of the target genes were dependent on TRbeta.
Approximately half of the affected genes were downregulated by the
hormone. Interestingly, many of the rapidly and transiently regulated
genes were involved in lipogenesis whereas e.g. genes in the
mitochondrial respiratory chain responded only after prolonged
hyperthyroidism. In addition, we identified genes that presumably are
directly regulated by the P isoform.
T3 effectively decreases serum cholesterol levels. To determine the TR
isoform responsible for this, the responses to T3 and dietary cholesterol
were studied in different TR deficient mouse strains under hypo-and
hyperthyroid conditions. We found that TRbeta is essential for normal T3
regulation of serum cholesterol levels and transcriptional regulation of
cholesterol-7-alpha hydroxylase (CYP7A1), the ratelimiting enzyme in
cholesterol degradation to bile acids. This dependence was specific for
the TRbeta gene: overexpression of TRalpha 1, at levels that normalize
the total hepatic T3 receptor content, failed to rescue the
dysregulation. Furthermore, hypothyroid TRbeta-/- mice were resistant to
development of hypercholesterolemia.
In the studies above, we found that many of the hepatic genes were
dependent on TRbeta for transcriptional regulation by T3. Since TRbeta1
has a heterogeneous, zonal, distribution over the liver lobule, we
hypothesized that the mechanism for the TRbeta dependence was governed by
a co- localization of target gene and TR isoform. This was confirmed by
our demonstration that TRalpha1 has a wider distribution over the lobule
than TRbeta1. Secondly, we determined the dependence on TRbeta of three
prototype hepatic target genes (malic enzyme, deiodinase 1 and spot 14)
known to have differential lobular distributions. We found a good
correlation between TRbeta dependence and lobular distribution of all
three genes, suggesting that the zonal distribution of the respective
receptors govern isoform specificity in gene regulation for at least
these genes. Isoform dependence is thus dependent not only on the
regulatory elements in the target genes, but also on the elements
governing local expression of the receptors themselves.
In conclusion, we have identified TRbeta as the isoform responsible for
T3 regulation of serum cholesterol levels as well as several important
hepatic genes. We have also identified 100 novel hepatic T3 target genes
and elucidated their dependence on TRbeta. Furthermore, our data indicate
that receptor isoform dependence in hepatic gene regulation is governed
by different zonal distribution of the respective TR isoform.
List of papers:
I. Flores-Morales A, Gullberg H, Fernandez L, Stahlberg N, Lee NH, Vennstrom B, Norstedt G (2002). "Patterns of Liver Gene Expression Governed by TRbeta. " Mol Endocrinol 16(6): 1257-68 (Accepted)
Pubmed
II. Gullberg H, Rudling M, Forrest D, Angelin B, Vennstrom B (2000). "Thyroid hormone receptor beta-deficient mice show complete loss of the normal cholesterol 7alpha-hydroxylase (CYP7A) response to thyroid hormone but display enhanced resistance to dietary cholesterol. " Mol Endocrinol 14(11): 1739-49
Pubmed
III. Gullberg H, Rudling M, Salto C, Forrest D, Angelin B, Vennstrom B (2002). "Requirement for thyroid hormone receptor beta in T3 regulation of cholesterol metabolism in mice." Molecular Endocrinology (Accepted)
IV. Gullberg H, Doulabi Zandieh B, Forrest D, Bakker O, Vennstrom B (2002). "Zonal distribution of thyroid hormone receptors alpha1 and beta governs receptor isoform specificity in hepatic gene regulation." (Submitted)
I. Flores-Morales A, Gullberg H, Fernandez L, Stahlberg N, Lee NH, Vennstrom B, Norstedt G (2002). "Patterns of Liver Gene Expression Governed by TRbeta. " Mol Endocrinol 16(6): 1257-68 (Accepted)
Pubmed
II. Gullberg H, Rudling M, Forrest D, Angelin B, Vennstrom B (2000). "Thyroid hormone receptor beta-deficient mice show complete loss of the normal cholesterol 7alpha-hydroxylase (CYP7A) response to thyroid hormone but display enhanced resistance to dietary cholesterol. " Mol Endocrinol 14(11): 1739-49
Pubmed
III. Gullberg H, Rudling M, Salto C, Forrest D, Angelin B, Vennstrom B (2002). "Requirement for thyroid hormone receptor beta in T3 regulation of cholesterol metabolism in mice." Molecular Endocrinology (Accepted)
IV. Gullberg H, Doulabi Zandieh B, Forrest D, Bakker O, Vennstrom B (2002). "Zonal distribution of thyroid hormone receptors alpha1 and beta governs receptor isoform specificity in hepatic gene regulation." (Submitted)
Issue date: 2002-05-17
Publication year: 2002
ISBN: 91-7349-190-X
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