Thyroid hormones act indirectly to increase sex hormone-binding globulin production by liver via hepatocyte nuclear factor-4α
Thyroid hormones act indirectly to increase sex hormone-binding globulin production by liver via hepatocyte nuclear factor-4α
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DOI：
10.1677/jme-09-0025
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发表时间：
2009-07-01
影响因子：
3.5
通讯作者：
Hammond, Geoffrey L.
中科院分区：
文献类型：
--
作者：
Selva, David M.;Hammond, Geoffrey L.
甲状腺激素增加肝性激素结合球蛋白（SHBG）的产生，这也是由肝细胞核因子-4 α（HNF-4 α）调节，以响应肝脏代谢状态的变化。由于人SHBG启动子缺乏典型的甲状腺激素反应元件，并且由于甲状腺激素影响代谢状态，因此我们开始确定甲状腺激素是否通过HepG 2人肝母细胞瘤细胞中HNF-4 α水平的变化间接介导SHBG表达，以及在转基因小鼠的肝脏中表达4.3 kb人SHBG转基因，该转基因小鼠在其自身的0.8 kb启动子序列控制下。甲状腺激素（三碘甲状腺原氨酸（T-3）和甲状腺素（T-4））增加HepG 2细胞培养基中SHBG的积累超过5天，并增加细胞SHBG mRNA水平。此外，T-4处理HepG 2细胞5天增加了HNF-4 α mRNA和HNF-4 α水平，同时降低了细胞棕榈酸酯水平。用T-3沿着5天治疗后，表达人SHBG转基因的小鼠血浆SHBG水平也升高，同时肝脏HNF-4 α水平升高。在HepG 2细胞中，人SHBG启动子未能对T-4治疗产生急性反应（24小时内），但用T-4预处理4天导致了强烈的反应，该反应可通过与HNF-4 α siRNA共同治疗或通过与肉毒碱棕榈酰转移酶I抑制剂etomoxir共同治疗来阻断棕榈酸酯的β-氧化来预防。这些数据使我们得出结论，甲状腺激素通过增加HNF-4 α基因表达间接增加SHBG的产生，并通过降低细胞棕榈酸水平进一步促进肝细胞中HNF-4 α水平的增加。
Thyroid hormones increase hepatic sex hormone-binding globulin (SHBG) production, which is also regulated by hepatocyte nuclear factor-4 alpha (HNF-4 alpha) in response to changes in the metabolic state of the liver. Since the human SHBG promoter lacks a typical thyroid hormone response element, and because thyroid hormones influence metabolic state, we set out to determine whether thyroid hormones mediate SHBG expression indirectly via changes in HNF-4 alpha levels in HepG2 human hepatoblastoma cells, and in the livers of transgenic mice that express a 4.3 kb human SHBG transgene under the control of its own 0.8 kb promoter sequence. Thyroid hormones (triiodothyronine (T-3) and thyroxine (T-4)) increase SHBG accumulation in HepG2 cell culture medium over 5 days, and increase cellular SHBG mRNA levels. In addition, T-4 treatment of HepG2 cells for 5 days increased HNF-4 alpha mRNA and HNF-4 alpha levels in concert with decreased cellular palmitate levels. Plasma SHBG levels were also increased in mice expressing a human SHBG transgene after 5 days treatment with T-3 along with increased hepatic HNF-4 alpha levels. In HepG2 cells, the human SHBG promoter failed to respond acutely (within 24 h) to T-4 treatment, but a 4-day pre-treatment with T-4 resulted in a robust response that was prevented by co-treatment with HNF-4 alpha siRNA, or by blocking the beta-oxidation of palmitate through co-treatment with the carnitine palmitoyltransferase I inhibitor, etomoxir. These data lead us to conclude that thyroid hormones increase SHBG production indirectly by increasing HNF-4 alpha gene expression, and by reducing cellular palmitate levels that further contribute to increased HNF-4 alpha levels in hepatocytes.