Yongfeng Song1, Chao Xu1, Shanshan Shao1, Jun Liu2, Wanjia Xing1, Jin Xu1, Chengkun Qin3, Chunyou Li2, Baoxiang Hu1, Shounan Yi4, Xuefeng Xia5, Haiqing Zhang1, Xiujuan Zhang1, Tingting Wang1, Wenfei Pan1, Chunxiao Yu1, Qiangxiu Wang6, Xiaoyan Lin6, Laicheng Wang7, Ling Gao8, Jiajun Zhao9. 1. 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. 2. Department of Organ Transplantation Surgery, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong 250021, China. 3. Department of General Surgery, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong 250021, China. 4. Center for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Sydney, Australia. 5. Genomic Medicine and Center for Diabetes Research, The Methodist Hospital Research Institute, Weill Cornell Medical College, Houston, TX 77030, USA. 6. Department of Pathology, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong 250021, China. 7. Scientific Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong 250021, China. 8. 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. 9. 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.
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.
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.