Thyroid-Stimulating Hormone Increases HNF-4α Phosphorylation via cAMP/PKA Pathway in the Liver.
Thyroid-Stimulating Hormone Increases HNF-4α Phosphorylation via cAMP/PKA Pathway in the Liver.
复制标题
促甲状腺激素通过肝脏中的 cAMP/PKA 途径增加 HNF-4 α 磷酸化
DOI：
10.1038/srep13409
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发表时间：
2015-08-25
影响因子：
4.6
通讯作者：
Zhao J
中科院分区：
文献类型：
--
作者：
Song Y;Zheng D;Zhao M;Qin Y;Wang T;Xing W;Gao L;Zhao J
肝细胞核因子 4 α (HNF-4α) 是一种孤儿核受体，在肝脏代谢中发挥重要作用。蛋白质磷酸化在其核定位、DNA 结合和反式激活中发挥着功能性作用。促甲状腺激素（TSH）是垂体前叶产生的一种激素，已观察到其对代谢途径的直接影响。我们之前的研究表明，TSH 显着降低肝核 HNF-4α 的表达。然而，TSH 是否可以影响 HNF-4α 磷酸化尚不清楚。在这里，我们发现 TSH 可以增加 HNF-4α 磷酸化并调节其亚细胞定位。当 HepG2 细胞用 TSH 处理时，HNF-4α 的磷酸化增加，其核定位被中断。细胞质HNF-4α增加，而核HNF-4α减少。当 cAMP/PKA 通路被 PKA 抑制剂 H89 和腺苷酸环化酶 (AC) 抑制剂 SQ22536 抑制时，TSH 介导的 HNF-4α 磷酸化被破坏。当小鼠 Tshr 被沉默时，HNF-4α 的磷酸化降低，细胞质 HNF-4α 减少，核 HNF-4α 增加。总之，我们的研究揭示了 TSH 调节肝脏 HNF-4α 亚细胞定位的新机制，表明 TSH 的作用之一可能是减少 HNF-4α 靶基因的表达。
Hepatocyte nuclear factor-4 alpha (HNF-4α) is an orphan nuclear receptor with important roles in hepatic metabolism. Protein phosphorylation plays a functional role in its nuclear localization, DNA binding, and transactivation. Thyroid-stimulating hormone (TSH) is a hormone produced by the anterior pituitary gland, whose direct effect on the metabolic pathway has been observed. Our previous study demonstrated that TSH significantly decreases hepatic nuclear HNF-4α expression. However, whether TSH can influence HNF-4α phosphorylation is unclear. Here, we discovered that TSH can increase HNF-4α phosphorylation and modulate its subcellularlocalization. When HepG2 cells were treated with TSH, the phosphorylation of HNF-4α increased and its nuclear localization was interrupted. Cytoplasmic HNF-4α increased, while nuclear HNF-4α decreased. When the cAMP/PKA pathway was inhibited by the PKA inhibitor H89 and the adenylate cyclase (AC) inhibitor SQ22536, the TSH-mediated phosphorylation of HNF-4α was disrupted. When Tshr was silenced in mice, the phosphorylation of HNF-4α decreased, and cytoplasmic HNF-4α decreased while nuclear HNF-4α increased. In conclusion, our study revealed a novel mechanism by which TSH regulated the hepatic HNF-4α subcellular localization, suggesting the possibility that one of the effects of TSH is to reduce the expression of HNF-4α target genes.