Yingyun Gong1, Yizhe Ma1, Zhengqin Ye1, Zhenzhen Fu2, Panpan Yang2, Beibei Gao2, Wen Guo2, Dandan Hu2, Jingya Ye2, Shuai Ma2, Fan Zhang2, Li Zhou2, Xinyu Xu2, Zhong Li3, Tao Yang2, Hongwen Zhou4. 1. Department of Endocrinology and Metabolism, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; Key Laboratory of Rare Metabolic Diseases, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, 210023, China. 2. Department of Endocrinology and Metabolism, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China. 3. Key Laboratory of Rare Metabolic Diseases, Nanjing Medical University, Nanjing 211166, China; Jiangsu Province Key Laboratory of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing 211166, China. 4. Department of Endocrinology and Metabolism, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; Key Laboratory of Rare Metabolic Diseases, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, 210023, China. Electronic address: drhongwenzhou@njmu.edu.cn.
Abstract
CONTEXT: Thyroid stimulating hormone (TSH) has received increasing attention as being closely associated with increased low-density lipoprotein cholesterol (LDL-c) level and higher atherosclerotic risks. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is known for increasing circulating LDL-c level by inducing LDL receptor degradation. However, whether TSH influences hepatic PCSK9 expression and LDL-c metabolism remains unclear. METHODS: First, the correlation between TSH and lipid profiles were investigated in euthyroid population and in subclinical hypothyroidism patients. Then, an in vitro study was conducted to validate the effects of TSH on hepatic PCSK9 expression in HepG2 cells. RESULTS: Serum TSH concentrations positively correlated with LDL-c levels in euthyroid subjects. Subclinical hypothyroidism patients with higher serum TSH levels showed significantly increased serum PCSK9 levels than the matched euthyroid participants (151.29 (89.51-293.03) vs. 84.70 (34.98-141.72) ng/ml, P<0.001), along with increased LDL-c concentrations. In HepG2 cells, LDLR expression on the plasma membrane was decreased, and PCSK9 mRNA and protein levels were synchronously upregulated after recombinant human TSH (rhTSH) treatment, while the effects could be blocked by TSH receptor blocking antibody K1-70. Sterol regulatory element binding protein (SREBP) 1c and SREBP2 mRNA expressions were enhanced after rhTSH treatment, and specific siRNAs significantly inhibited the effects of rhTSH. Furthermore, there was a noticeable induction of PCSK9 expression by rhTSH even though HMGCR gene expression was silenced. CONCLUSION: We conclude a regulating role of TSH on hepatic PCSK9 expression, which further contributing to a higher LDL-c level.
CONTEXT: Thyroid stimulating hormone (TSH) has received increasing attention as being closely associated with increased low-density lipoprotein cholesterol (LDL-c) level and higher atherosclerotic risks. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is known for increasing circulating LDL-c level by inducing LDL receptor degradation. However, whether TSH influences hepatic PCSK9 expression and LDL-c metabolism remains unclear. METHODS: First, the correlation between TSH and lipid profiles were investigated in euthyroid population and in subclinical hypothyroidismpatients. Then, an in vitro study was conducted to validate the effects of TSH on hepatic PCSK9 expression in HepG2 cells. RESULTS: Serum TSH concentrations positively correlated with LDL-c levels in euthyroid subjects. Subclinical hypothyroidismpatients with higher serum TSH levels showed significantly increased serum PCSK9 levels than the matched euthyroid participants (151.29 (89.51-293.03) vs. 84.70 (34.98-141.72) ng/ml, P<0.001), along with increased LDL-c concentrations. In HepG2 cells, LDLR expression on the plasma membrane was decreased, and PCSK9 mRNA and protein levels were synchronously upregulated after recombinant humanTSH (rhTSH) treatment, while the effects could be blocked by TSH receptor blocking antibody K1-70. Sterol regulatory element binding protein (SREBP) 1c and SREBP2 mRNA expressions were enhanced after rhTSH treatment, and specific siRNAs significantly inhibited the effects of rhTSH. Furthermore, there was a noticeable induction of PCSK9 expression by rhTSH even though HMGCR gene expression was silenced. CONCLUSION: We conclude a regulating role of TSH on hepatic PCSK9 expression, which further contributing to a higher LDL-c level.
Authors: Trynke van der Boom; Congzhuo Jia; Joop D Lefrandt; Margery A Connelly; Thera P Links; Uwe J F Tietge; Robin P F Dullaart Journal: J Clin Endocrinol Metab Date: 2020-09-01 Impact factor: 5.958
Authors: Mateusz Maligłówka; Michał Kosowski; Marcin Hachuła; Marcin Cyrnek; Łukasz Bułdak; Marcin Basiak; Aleksandra Bołdys; Grzegorz Machnik; Rafał Jakub Bułdak; Bogusław Okopień Journal: Metabolites Date: 2022-03-17