TY - JOUR
T1 - Thyroid-stimulating hormone regulates hepatic bile acid homeostasis via SREBP-2/HNF-4α/CYP7A1 axis
AU - Song, Yongfeng
AU - Xu, Chao
AU - Shao, Shanshan
AU - Liu, Jun
AU - Xing, Wanjia
AU - Xu, Jin
AU - Qin, Chengkun
AU - Li, Chunyou
AU - Hu, Baoxiang
AU - Yi, Shounan
AU - Xia, Xuefeng
AU - Zhang, Haiqing
AU - Zhang, Xiujuan
AU - Wang, Tingting
AU - Pan, Wenfei
AU - Yu, Chunxiao
AU - Wang, Qiangxiu
AU - Lin, Xiaoyan
AU - Wang, Laicheng
AU - Gao, Ling
AU - Zhao, Jiajun
N1 - Publisher Copyright:
© 2015 European Association for the Study of the Liver.
Copyright:
Copyright 2016 Elsevier B.V., All rights reserved.
PY - 2015/5/1
Y1 - 2015/5/1
N2 - 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.
AB - 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.
KW - Bile acids
KW - CYP7A1
KW - HNF-4a
KW - SREBP-2
KW - Thyroid-stimulating hormone
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U2 - 10.1016/j.jhep.2014.12.006
DO - 10.1016/j.jhep.2014.12.006
M3 - Article
C2 - 25533663
AN - SCOPUS:84927800700
VL - 62
SP - 1171
EP - 1179
JO - Journal of Hepatology
JF - Journal of Hepatology
SN - 0168-8278
IS - 5
ER -