Adiposity Blunts the Positive Relationship of Thyrotropin with Proprotein Convertase Subtilisin-Kexin Type 9 Levels in Euthyroid Subjects

Background: Effects of thyroid function status on lipoprotein metabolism may extend into the euthyroid range. Low-density lipoprotein (LDL) metabolism is governed by proprotein convertase subtilisin-kexin type 9 (PCSK9), which down-regulates LDL receptor expression, resulting in higher LDL cholesterol (LDL-C). Here, we tested whether plasma PCSK9 correlates with thyroid function in nonobese and obese euthyroid subjects. Methods: We assessed the extent to which plasma PCSK9 is determined by thyrotropin (TSH) in 74 euthyroid subjects (31 women; TSH between 0.5 and 4.0mU/L and free thyroxine [FT4] between 11.0 and 19.5 pM) with varying degrees of obesity (body mass index [BMI] ranging from 20.2 to 40.4 kg/m(2)). Results: TSH, FT4, PCSK9, non-high-density lipoprotein cholesterol (non-HDL-C), LDL-C, and apolipoprotein B (apoB) levels were not different between 64 nonobese subjects (BMI < 30 kg/m(2)) and 10 obese subjects (BMI >= 30 kg/m2; p > 0.20 for each). PCSK9 correlated positively with TSH in nonobese subjects (r = 0.285, p = 0.023). In contrast, PCSK9 was not associated positively with TSH in obese subjects (r = -0.249, p = 0.49). The relationship of PCSK9 with TSH was different between nonobese and obese subjects when taking age, sex, FT4, and the presence of anti-thyroid antibodies into account (multiple linear regression analysis: beta = -0.320, p = 0.012 for the interaction term between the presence of obesity and TSH on PCSK9), and was also modified by BMI as a continuous trait (beta = -0.241, p = 0.062 for the interaction term between BMI and TSH on PCSK9). Non-HDL-C, LDL-C, and apoB levels were dependent on PCSK9 in nonobese subjects (p <= 0.01 for each), but not in obese subjects (p > 0.50), Accordingly, BMI interacted negatively with PCSK9 on non-HDL-C (p = 0.028) and apoB (p = 0.071). Conclusions: This study suggests that circulating PCSK9 levels correlate with thyroid function even in the normal range. This relationship appears to be blunted by obesity. Thyroid functional status may influence cholesterol metabolism through the PCSK9 pathway.