Desensitization and Incomplete Recovery of Hepatic Target Genes After Chronic Thyroid Hormone Treatment and Withdrawal in Male Adult Mice

Desensitization and Incomplete Recovery of Hepatic Target Genes After Chronic Thyroid Hormone Treatment and Withdrawal in Male Adult Mice
Title:
Desensitization and Incomplete Recovery of Hepatic Target Genes After Chronic Thyroid Hormone Treatment and Withdrawal in Male Adult Mice
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Endocrinology
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Publication Date:
01 April 2016
Citation:
Ohba K, Leow MK, Singh BK, et al. Desensitization and Incomplete Recovery of Hepatic Target Genes After Chronic Thyroid Hormone Treatment and Withdrawal in Male Adult Mice. Endocrinology. 2016;157(4):1660‐1672. doi:10.1210/en.2015-1848
Abstract:
Clinical symptoms may vary and not necessarily reflect serum thyroid hormone (TH) levels during acute and chronic hyperthyroidism as well as recovery from hyperthyroidism. We thus examined changes in hepatic gene expression and serum TH/TSH levels in adult male mice treated either with a single T3 (20 μg per 100 g body weight) injection (acute T3) or daily injections for 14 days (chronic T3) followed by 10 days of withdrawal. Gene expression arrays from livers harvested at these time points showed that among positively-regulated target genes, 320 were stimulated acutely and 429 chronically by T3. Surprisingly, only 69 of 680 genes (10.1%) were induced during both periods, suggesting desensitization of the majority of acutely stimulated target genes. About 90% of positively regulated target genes returned to baseline expression levels after 10 days of withdrawal; however, 67 of 680 (9.9%) did not return to baseline despite normalization of serum TH/TSH levels. Similar findings also were observed for negatively regulated target genes. Chromatin immunoprecipitation analysis of representative positively regulated target genes suggested that acetylation of H3K9/K14 was associated with acute stimulation, whereas trimethylation of H3K4 was associated with chronic stimulation. In an in vivo model of chronic intrahepatic hyperthyroidism since birth, adult male monocarboxylate transporter-8 knockout mice also demonstrated desensitization of most acutely stimulated target genes that were examined. In summary, we have identified transcriptional desensitization and incomplete recovery of gene expression during chronic hyperthyroidism and recovery. Our findings may be a potential reason for discordance between clinical symptoms and serum TH levels observed in these conditions.
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Funding Info:
This work was supported by Singapore National Medical Research Council Clinician Scientist Award and Clinician Scientist Individual Research Grant 12May0004 (to P.M.Y.), by an Endocrine and Metabolic Society of Singapore grant (to M.K.-S.L.), by the A*STAR intramural funding for the Neuroepigenetics Laboratory under the Integrative Neuroscience Programme, Singapore Institute for Clinical Sciences (to J.C.G.S.), and by Grant R37-DK15070 from the National Institutes of Health (to S.R.).
Description:
The full paper is available for download at the publisher's URL: https://doi.org/10.1210/en.2015-1848
ISSN:
0013-7227
1945-7170
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