title: Thyroid-stimulating hormone regulates hepatic bile acid homeostasis via SREBP-2/HNF-4α/CYP7A1 axis.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong 250021, China; Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong 250021, China.
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong 250021, China; Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong 250021, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong 250021, China; Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong 250021, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Shao
authors.affiliation: Department of Organ Transplantation Surgery, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong 250021, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong 250021, China; Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong 250021, China.
authors.forename: Wanjia
authors.initials: W
authors.lastname: Xing
authors.affiliation: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong 250021, China; Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong 250021, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of General Surgery, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong 250021, China.
authors.forename: Chengkun
authors.initials: C
authors.lastname: Qin
authors.affiliation: Department of Organ Transplantation Surgery, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong 250021, China.
authors.forename: Chunyou
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong 250021, China; Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong 250021, China.
authors.forename: Baoxiang
authors.initials: B
authors.lastname: Hu
authors.affiliation: Center for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Sydney, Australia.
authors.forename: Shounan
authors.initials: S
authors.lastname: Yi
authors.affiliation: Genomic Medicine and Center for Diabetes Research, The Methodist Hospital Research Institute, Weill Cornell Medical College, Houston, TX 77030, USA.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Xia
authors.affiliation: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong 250021, China; Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong 250021, China.
authors.forename: Haiqing
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong 250021, China; Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong 250021, China.
authors.forename: Xiujuan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong 250021, China; Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong 250021, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong 250021, China; Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong 250021, China.
authors.forename: Wenfei
authors.initials: W
authors.lastname: Pan
authors.affiliation: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong 250021, China; Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong 250021, China.
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of Pathology, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong 250021, China.
authors.forename: Qiangxiu
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Pathology, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong 250021, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Lin
authors.affiliation: Scientific Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong 250021, China.
authors.forename: Laicheng
authors.initials: L
authors.lastname: Wang
authors.affiliation: Scientific Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong 250021, China; Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong 250021, China. Electronic address: gaoling1@medmail.com.cn.
authors.forename: Ling
authors.initials: L
authors.lastname: Gao
authors.affiliation: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong 250021, China; Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong 250021, China. Electronic address: jjzhao@medmail.com.cn.
authors.forename: Jiajun
authors.initials: J
authors.lastname: Zhao
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism*; D064368:Healthy Volunteers; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008962:Models, Theoretical; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism*; D013972:Thyrotropin / Q000378:metabolism*
chemical_list: D001647:Bile Acids and Salts; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; D013972:Thyrotropin; C553219:CYP7A1 protein, human; D002790:Cholesterol 7-alpha-Hydroxylase
keywords: Bile acids; CYP7A1; HNF-4α; SREBP-2; Thyroid-stimulating hormone