Thyroid Stimulating Hormone Exhibits the Impact on LDLR/LDL-c Via up-Regulating PCSK9 Expression in HepG2 Cells

Presentation Number: MON 516
Date of Presentation: April 3rd, 2017

Yingyun Gong*, Yizhe Ma, Zhenzhen Fu, Panpan Yang, Dandan Hu, Zhengqin Ye, Tao Yang and Hongwen Zhou
the First Affiliated Hospital of Nanjing Medical University, Nanjing, China

Abstract

Thyroid stimulating hormone (TSH) receives accumulating attention for closely associated with increased low density lipoprotein (LDL-c) level and higher atherosclerotic risks not only in patients with hypothyroidism, but also in euthyroid subjects having higher serum TSH levels. It was reported that TSH may induce cholesterol de novo synthesis in hepatocytes through directly activating HMG-CoA reductase (HMGCR) (1). However, whether TSH could influence LDL-c metabolism still remains unclear. Meanwhile, proprotein convertase subtilisin kexin (PCSK9) is well-known to mediate LDLR degradation on the surface of hepatocytes, being one of the important attributors to increased circulating LDL-c concentration. We previously found that plasma PCSK9 level is significantly increased in subclinical hypothyroidism patients who only presented with higher TSH level (6.65(4.37-22.44) vs. 2.38(1.01-4.18) mIU/L), when compared with matched euthyroid participants (151.29(89.51-293.03) vs. 84.70(34.98-141.72) ng/ml, P<0.001). Our In vitro study in HepG2 cells further showed that LDLR expression on the plasma membrane was decreased in flow cytometry but the mRNA and protein expression of PCSK9 were synchronously up-regulated after recombinant human TSH (rhTSH) treatment, sharing with a dose-dependent effect, while the observed effects could be blocked when introducing the TSH receptor blocker K1-70 in the cell culture media. Furthermore, sterol regulatory element binding protein (SREBP)1c, SREBP2 and liver X receptor mRNA expression were enhanced after TSH treatment, and SREBP1c and SREBP2 siRNAs significantly inhibited the effects of rhTSH mentioned above. More interestingly, 125ng/ml rhTSH induced PCSK9 expression did not affected by knocking down the HMGCR expression in hepatocytes. Herein, we interpret a direct regulating role of TSH on hepatic PCSK9 expression, further attributing to a higher LDL-c level. This study aimed to bring more evidences to the effects of TSH on lipid metabolism. Based on our present results, we suggest that further clinical observations are largely warranted to focusing on the outcomes of PCSK9 inhibitors on thyroid hormone levels especially in those manifested with dyslipidemia combined with higher serum TSH levels. This may do help to screening for more potential subjects who may benefit from PCSK9 inhibitor application in the future.

 

Nothing to Disclose: YG, YM, ZF, PY, DH, ZY, TY, HZ