Thyroid-stimulating hormone regulates hepatic bile acid homeostasis via SREBP-2/HNF-4α/CYP7A1 axis

Yongfeng Song, Chao Xu, Shanshan Shao, Jun Liu, Wanjia Xing, Jin Xu, Chengkun Qin, Chunyou Li, Baoxiang Hu, Shounan Yi, Xuefeng Xia, Haiqing Zhang, Xiujuan Zhang, Tingting Wang, Wenfei Pan, Chunxiao Yu, Qiangxiu Wang, Xiaoyan Lin, Laicheng Wang, Ling GaoJiajun Zhao

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

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-4α, 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-4α 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-4α 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-4α/CYP7A1 signaling pathway. This finding strongly supports the notion that TSH is an important pathophysiological regulator of liver BA homeostasis independently of thyroid hormones.

Original languageEnglish (US)
Pages (from-to)1171-1179
Number of pages9
JournalJournal of Hepatology
Volume62
Issue number5
DOIs
StatePublished - May 1 2015

Keywords

  • Bile acids
  • CYP7A1
  • HNF-4a
  • SREBP-2
  • Thyroid-stimulating hormone

ASJC Scopus subject areas

  • Hepatology

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