Tissue-specific regulation of medium-chain acyl-CoA dehydrogenase gene by thyroid hormones in the developing rat
Tissue-specific regulation of medium-chain acyl-CoA dehydrogenase gene by thyroid hormones in the developing rat
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DOI：
10.1042/bj3240289
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发表时间：
1997-05-15
影响因子：
4.1
通讯作者：
Bastin, J
中科院分区：
文献类型：
--
作者：
Djouadi, F;Riveau, B;Bastin, J
在发育过程中，中链酰基辅酶A脱氢酶（MCAD）的基因表达是一种核编码的线粒体酶，催化中链脂肪酸β-氧化的第一步，在组织中根据脂肪酸的利用受到高度调节，但参与这种调节的因素在很大程度上是未知的。为了研究甲状腺激素的可能作用，从妊娠第12天开始，通过向母亲给予丙基硫脲基使大鼠幼仔甲状腺功能减退，并在出生后第16天取出其肾脏、心脏和肝脏，以测定MCAD mRNA丰度、蛋白质水平和酶活性。在3，3 '，5-三碘甲状腺原氨酸（T-3）替代的甲状腺功能减退（出生后第5 - 15天1 μ g T-3/100 g体重）和甲状腺功能正常的幼仔中进行了类似的实验。甲状腺功能减退导致肾脏中MCAD mRNA丰度增加，心脏中MCAD mRNA丰度减少，但对肝脏无影响。甲状腺功能减退心脏和肾脏的蛋白质水平和酶活性降低，表明甲状腺功能减退影响肾脏基因表达的转录后步骤。甲状腺功能减退的所有影响在心脏和肾脏中被T-3替代完全逆转。将单剂量T-3注射到16日龄甲状腺功能正常的大鼠中也导致mRNA丰度的组织特异性变化。从甲状腺功能减退和甲状腺功能减退加T-3大鼠进行的核运行试验表明，T-3刺激心脏中的MCAD基因转录，并抑制肾脏中的MCAD基因转录。这些结果表明，出生后上升循环T-3是必不可少的MCAD基因在体内的发育调控。
During development, gene expression of medium-chain acyl-CoA dehydrogenase (MCAD), a nuclear-encoded mitochondrial enzyme that catalyses the first step of medium-chain fatty acid beta-oxidation, is highly regulated in tissues in accordance with fatty acid utilization, but the factors involved in this regulation are largely unknown. To investigate a possible role of thyroid hormones, rat pups were made hypothyroid by the administration of propylthiouracyl to the mother from day 12 of gestation, and their kidneys, heart and liver were removed on postnatal day 16 to determine MCAD mRNA abundance, protein level and enzyme activity. Similar experiments were run in 3,3',5-triiodothyronine (T-3)-replaced hypothyroid (1 mu g of T-3/100 g body weight from postnatal day 5 to 15) and euthyroid pups. Hypothyroidism led to an increase in MCAD mRNA abundance in kidney and a decrease in abundance in heart, but had no effect in liver. The protein levels and enzyme activity were lowered in hypothyroid heart and kidney, suggesting that hypothyroidism affects post-transcriptional steps of gene expression in the kidney. All the effects of hypothyroidism were completely reversed in both heart and kidney by T-3 replacement. Injection of a single T-3 dose into 16-day-old euthyroid rats also led to tissue-specific changes in mRNA abundance. Nuclear run-on assays performed from hypothyroid and hypothyroid plus T-3 rats showed that T-3 stimulates MCAD gene transcription in heart and represses it in the kidney. These results indicate that the postnatal rise in circulating T-3 is essential to the developmental regulation of the MCAD gene in vivo.