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.
Abbreviations:
SCH (subclinical hypothyroidism), TC (total cholesterol), LDL-c (low-density lipoprotein cholesterol), TSH (thyroid stimulating hormone), TSHR (thyroid stimulating hormone receptor), HMGCR (3-hydroxy-3-methylglutaryl-CoA reductase), PCSK9 (proprotein convertase subtilisin/kexin type 9), LDLR (low-density lipoprotein receptor), HDL-c (high-density lipoprotein cholesterol), TG (triglyceride), fT3 (free triiodothyronine), fT4 (free thyroxine), MFI (median fluoresce intensity), SREBP (sterol regulatory element-binding protein), CYP7A1 (human cholesterol 7α-hydroxylase), HNF-4α (hepatocyte nuclear factor 4α), CYP8B1 (human sterol 12α-hydroxylase gene), LRH-1 (liver receptor homologue-1), FXR (farnesoid X receptor)Keywords
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Article info
Publication history
Published online: August 01, 2017
Accepted:
July 19,
2017
Received:
April 25,
2017
Identification
Copyright
© 2017 Published by Elsevier Inc.
