title: Desensitization and Incomplete Recovery of Hepatic Target Genes After Chronic Thyroid Hormone Treatment and Withdrawal in Male Adult Mice.
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.
authors: Cardiovascular and Metabolic Disorders Program (K.O., B.K.S., R.A.S., R.L., S.G., P.M.Y.), Duke-NUS Medical School, Singapore, Singapore 169857; Department of Endocrinology (M.K.-S.L.), Tan Tock Seng Hospital, Singapore, Singapore 229899; Singapore Institute for Clinical Sciences (M.K.-S.L.), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore 117609; Department of Physiology (R.L.), Universitas Padjadjaran, Bandung, West Java 45363, Indonesia; Departments of Medicine (X.-H.L., S.R.) and Pediatrics and Committee on Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637; and Department of Pharmacology (J.C.G.S.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore 119228.
authors: Kenji
authors: K
authors: Ohba
authors: Cardiovascular and Metabolic Disorders Program (K.O., B.K.S., R.A.S., R.L., S.G., P.M.Y.), Duke-NUS Medical School, Singapore, Singapore 169857; Department of Endocrinology (M.K.-S.L.), Tan Tock Seng Hospital, Singapore, Singapore 229899; Singapore Institute for Clinical Sciences (M.K.-S.L.), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore 117609; Department of Physiology (R.L.), Universitas Padjadjaran, Bandung, West Java 45363, Indonesia; Departments of Medicine (X.-H.L., S.R.) and Pediatrics and Committee on Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637; and Department of Pharmacology (J.C.G.S.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore 119228.
authors: Melvin Khee-Shing
authors: MK
authors: Leow
authors: Cardiovascular and Metabolic Disorders Program (K.O., B.K.S., R.A.S., R.L., S.G., P.M.Y.), Duke-NUS Medical School, Singapore, Singapore 169857; Department of Endocrinology (M.K.-S.L.), Tan Tock Seng Hospital, Singapore, Singapore 229899; Singapore Institute for Clinical Sciences (M.K.-S.L.), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore 117609; Department of Physiology (R.L.), Universitas Padjadjaran, Bandung, West Java 45363, Indonesia; Departments of Medicine (X.-H.L., S.R.) and Pediatrics and Committee on Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637; and Department of Pharmacology (J.C.G.S.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore 119228.
authors: Brijesh Kumar
authors: BK
authors: Singh
authors: Cardiovascular and Metabolic Disorders Program (K.O., B.K.S., R.A.S., R.L., S.G., P.M.Y.), Duke-NUS Medical School, Singapore, Singapore 169857; Department of Endocrinology (M.K.-S.L.), Tan Tock Seng Hospital, Singapore, Singapore 229899; Singapore Institute for Clinical Sciences (M.K.-S.L.), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore 117609; Department of Physiology (R.L.), Universitas Padjadjaran, Bandung, West Java 45363, Indonesia; Departments of Medicine (X.-H.L., S.R.) and Pediatrics and Committee on Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637; and Department of Pharmacology (J.C.G.S.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore 119228.
authors: Rohit Anthony
authors: RA
authors: Sinha
authors: Cardiovascular and Metabolic Disorders Program (K.O., B.K.S., R.A.S., R.L., S.G., P.M.Y.), Duke-NUS Medical School, Singapore, Singapore 169857; Department of Endocrinology (M.K.-S.L.), Tan Tock Seng Hospital, Singapore, Singapore 229899; Singapore Institute for Clinical Sciences (M.K.-S.L.), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore 117609; Department of Physiology (R.L.), Universitas Padjadjaran, Bandung, West Java 45363, Indonesia; Departments of Medicine (X.-H.L., S.R.) and Pediatrics and Committee on Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637; and Department of Pharmacology (J.C.G.S.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore 119228.
authors: Ronny
authors: R
authors: Lesmana
authors: Cardiovascular and Metabolic Disorders Program (K.O., B.K.S., R.A.S., R.L., S.G., P.M.Y.), Duke-NUS Medical School, Singapore, Singapore 169857; Department of Endocrinology (M.K.-S.L.), Tan Tock Seng Hospital, Singapore, Singapore 229899; Singapore Institute for Clinical Sciences (M.K.-S.L.), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore 117609; Department of Physiology (R.L.), Universitas Padjadjaran, Bandung, West Java 45363, Indonesia; Departments of Medicine (X.-H.L., S.R.) and Pediatrics and Committee on Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637; and Department of Pharmacology (J.C.G.S.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore 119228.
authors: Xiao-Hui
authors: XH
authors: Liao
authors: Cardiovascular and Metabolic Disorders Program (K.O., B.K.S., R.A.S., R.L., S.G., P.M.Y.), Duke-NUS Medical School, Singapore, Singapore 169857; Department of Endocrinology (M.K.-S.L.), Tan Tock Seng Hospital, Singapore, Singapore 229899; Singapore Institute for Clinical Sciences (M.K.-S.L.), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore 117609; Department of Physiology (R.L.), Universitas Padjadjaran, Bandung, West Java 45363, Indonesia; Departments of Medicine (X.-H.L., S.R.) and Pediatrics and Committee on Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637; and Department of Pharmacology (J.C.G.S.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore 119228.
authors: Sujoy
authors: S
authors: Ghosh
authors: Cardiovascular and Metabolic Disorders Program (K.O., B.K.S., R.A.S., R.L., S.G., P.M.Y.), Duke-NUS Medical School, Singapore, Singapore 169857; Department of Endocrinology (M.K.-S.L.), Tan Tock Seng Hospital, Singapore, Singapore 229899; Singapore Institute for Clinical Sciences (M.K.-S.L.), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore 117609; Department of Physiology (R.L.), Universitas Padjadjaran, Bandung, West Java 45363, Indonesia; Departments of Medicine (X.-H.L., S.R.) and Pediatrics and Committee on Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637; and Department of Pharmacology (J.C.G.S.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore 119228.
authors: Samuel
authors: S
authors: Refetoff
authors: Cardiovascular and Metabolic Disorders Program (K.O., B.K.S., R.A.S., R.L., S.G., P.M.Y.), Duke-NUS Medical School, Singapore, Singapore 169857; Department of Endocrinology (M.K.-S.L.), Tan Tock Seng Hospital, Singapore, Singapore 229899; Singapore Institute for Clinical Sciences (M.K.-S.L.), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore 117609; Department of Physiology (R.L.), Universitas Padjadjaran, Bandung, West Java 45363, Indonesia; Departments of Medicine (X.-H.L., S.R.) and Pediatrics and Committee on Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637; and Department of Pharmacology (J.C.G.S.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore 119228.
authors: Judy Chia Ghee
authors: JC
authors: Sng
authors: Cardiovascular and Metabolic Disorders Program (K.O., B.K.S., R.A.S., R.L., S.G., P.M.Y.), Duke-NUS Medical School, Singapore, Singapore 169857; Department of Endocrinology (M.K.-S.L.), Tan Tock Seng Hospital, Singapore, Singapore 229899; Singapore Institute for Clinical Sciences (M.K.-S.L.), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore 117609; Department of Physiology (R.L.), Universitas Padjadjaran, Bandung, West Java 45363, Indonesia; Departments of Medicine (X.-H.L., S.R.) and Pediatrics and Committee on Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637; and Department of Pharmacology (J.C.G.S.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore 119228.
authors: Paul Michael
authors: PM
authors: Yen
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D020869:Gene Expression Profiling / Q000379:methods*; D006657:Histones / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D008297:Male; D008745:Methylation / Q000187:drug effects; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood; D013997:Time Factors; D059467:Transcriptome / Q000187:drug effects*; D014284:Triiodothyronine / Q000097:blood / Q000494:pharmacology*
chemical_list: D006657:Histones; D014284:Triiodothyronine; D013972:Thyrotropin; D008239:Lysine; D013974:Thyroxine