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
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DOI：
10.1210/en.2015-1848
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发表时间：
2016-04-01
期刊：
影响因子：
4.8
通讯作者：
Yen, Paul Michael
中科院分区：
文献类型：
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作者：
Ohba, Kenji;Leow, Melvin Khee-Shing;Yen, Paul Michael
临床症状可能有所不同，并不一定反映血清甲状腺激素（TH）水平在急性和慢性甲状腺功能亢进症，以及从甲状腺功能亢进症的恢复。因此，我们研究了肝脏基因表达和血清TH/TSH水平的变化，在成年雄性小鼠治疗与一个单一的T3（20微克每100克体重）注射（急性T3）或每日注射14天（慢性T3），随后10天的撤退。在这些时间点收获的肝脏的基因表达阵列显示，在阳性调节的靶基因中，320个被T3急性刺激，429个被T3慢性刺激。令人惊讶的是，680个基因中只有69个（10.1%）在这两个时期被诱导，这表明大多数急性刺激的靶基因的脱敏。大约90%的正调控靶基因在停药10天后恢复到基线表达水平;然而，680例患者中有67例（9.9%）尽管血清TH/TSH水平正常化，但未恢复到基线水平。对于负调控的靶基因也观察到类似的发现。染色质免疫沉淀分析的代表性的正调控的靶基因表明，乙酰化的H3 K9/K14与急性刺激，而三甲基化的H3 K4与慢性刺激。在出生后慢性肝内甲状腺功能亢进症的体内模型中，成年雄性单羧酸转运蛋白8敲除小鼠也表现出所检查的大多数急性刺激靶基因的脱敏。总之，我们已经确定了慢性甲状腺功能亢进症和恢复过程中基因表达的转录脱敏和不完全恢复。我们的研究结果可能是在这些条件下观察到的临床症状和血清TH水平之间不一致的潜在原因。
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 mu g 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.