Thyroid-stimulating hormone regulates hepatic bile acid homeostasis via SREBP-2/HNF-4α/CYP7A1 axis
Thyroid-stimulating hormone regulates hepatic bile acid homeostasis via SREBP-2/HNF-4α/CYP7A1 axis
复制标题
促甲状腺激素 (TSH) 通过 SREBP-2/HNF-4α/CYP7A1 轴调节肝胆汁酸稳态
DOI：
10.1016/j.jhep.2014.12.006
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发表时间：
2015-05-01
影响因子：
25.7
通讯作者：
Zhao, Jiajun
中科院分区：
文献类型：
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作者：
Song, Yongfeng;Xu, Chao;Zhao, Jiajun
背景与目的：胆汁酸（Bile Acids，BAs）在膳食脂肪消化和调节脂质、葡萄糖和能量代谢中起着至关重要的作用。促甲状腺激素（TSH）是一种由脑垂体前叶产生的激素，直接调节几种代谢途径。然而，TSH对BA稳态的影响在很大程度上仍然未知。方法：我们分析了严格控制热量摄入的健康志愿者的血清BA和TSH水平。甲状腺切除大鼠给予甲状腺素和注射不同剂量的TSH。Tshr（-/-）小鼠补充甲状腺素，C57 BL/6小鼠通过尾静脉注射Tshr-siRNA。测定血清BA水平、BA池大小和粪便BA排泄率。采用荧光素酶报告基因技术、RNA干扰技术、EMSA技术和CHIP技术分析TSH对SREBP-2、HNF-4 α和CYP 7A 1的调节作用。TSH给药导致甲状腺切除大鼠补充甲状腺素后BA含量和CYP 7A 1活性降低。当Tshr在小鼠中沉默时，BA池大小、粪便BA排泄率和血清BA水平均增加。此外，我们发现，HNF-4 α作为一个关键的分子，通过TSH抑制CYP 7A 1活性。我们进一步证实，成熟SREBP-2蛋白的积累可能会损害核HNF-4 α的能力，结合到CYP 7A 1启动子，一种机制，似乎介导的影响TSH.Conclusions：TSH抑制肝BA合成通过SREBP-2/HNF-4 α/CYP 7A 1信号通路。这一发现有力地支持了TSH是独立于甲状腺激素的肝脏BA稳态的重要病理生理调节剂的观点。(C)2015年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: Bile acids (BAs) play a crucial role in dietary fat digestion and in the regulation of lipid, glucose, and energy metabolism. Thyroid-stimulating hormone (TSH) is a hormone produced by the anterior pituitary gland that directly regulates several metabolic pathways. However, the impact of TSH on BA homeostasis remains largely unknown.Methods: We analyzed serum BA and TSH levels in healthy volunteers under strict control of caloric intake. Thyroidectomized rats were administered thyroxine and injected with different doses of TSH. Tshr(-/-) mice were supplemented with thyroxine, and C57BL/6 mice were injected with Tshr-siRNA via the tail vein. The serum BA levels, BA pool size, and fecal BA excretion rate were measured. The regulation of SREBP-2, HNF-4 alpha, and CYP7A1 by TSH were analyzed using luciferase reporter, RNAi, EMSA, and CHIP assays.Results: A negative correlation was observed between the serum levels of TSH and the serum BA levels in healthy volunteers. TSH administration led to a decrease in BA content and CYP7A1 activity in thyroidectomized rats supplemented with thyroxine. When Tshr was silenced in mice, the BA pool size, fecal BA excretion rate, and serum BA levels all increased. Additionally, we found that HNF-4 alpha acts as a critical molecule through which TSH represses CYP7A1 activity. We further confirmed that the accumulation of mature SREBP-2 protein could impair the capacity of nuclear HNF-4 alpha to bind to the CYP7A1 promoter, a mechanism that appears to mediate the effects of TSH.Conclusions: TSH represses hepatic BA synthesis via a SREBP-2/HNF-4 alpha/CYP7A1 signaling pathway. This finding strongly supports the notion that TSH is an important pathophysiological regulator of liver BA homeostasis independently of thyroid hormones. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.