Gong Yingyun, Ma Yizhe, Ye Zhengqin, Fu Zhenzhen, Yang Panpan, Gao Beibei, Guo Wen, Hu Dandan, Ye Jingya, Ma Shuai, Zhang Fan, Zhou Li, Xu Xinyu, Li Zhong, Yang Tao, Zhou Hongwen
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.
Department of Endocrinology and Metabolism, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Metabolism. 2017 Nov;76:32-41. doi: 10.1016/j.metabol.2017.07.006. Epub 2017 Aug 2.
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.
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.
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.
We conclude a regulating role of TSH on hepatic PCSK9 expression, which further contributing to a higher LDL-c level.
促甲状腺激素（TSH）因与低密度脂蛋白胆固醇（LDL-c）水平升高及动脉粥样硬化风险增加密切相关而受到越来越多的关注。前蛋白转化酶枯草溶菌素/kexin 9型（PCSK9）因诱导LDL受体降解而使循环LDL-c水平升高。然而，TSH是否影响肝脏PCSK9表达及LDL-c代谢仍不清楚。
首先，在甲状腺功能正常人群和亚临床甲状腺功能减退患者中研究TSH与血脂谱之间的相关性。然后，进行体外研究以验证TSH对HepG2细胞中肝脏PCSK9表达的影响。
甲状腺功能正常受试者的血清TSH浓度与LDL-c水平呈正相关。血清TSH水平较高的亚临床甲状腺功能减退患者的血清PCSK9水平明显高于匹配的甲状腺功能正常参与者（151.29（89.51 - 293.03）对84.70（34.98 - 141.72）ng/ml，P<0.001），同时LDL-c浓度升高。在HepG2细胞中，重组人TSH（rhTSH）处理后，质膜上的LDLR表达降低，PCSK9 mRNA和蛋白水平同步上调，而TSH受体阻断抗体K1-70可阻断这些作用。rhTSH处理后，固醇调节元件结合蛋白（SREBP）1c和SREBP2 mRNA表达增强，特异性siRNA显著抑制rhTSH的作用。此外，即使HMGCR基因表达沉默，rhTSH仍能显著诱导PCSK9表达。
我们得出TSH对肝脏PCSK9表达具有调节作用，这进一步导致更高的LDL-c水平。
