Lipidomic Perturbations in Cynomolgus Monkeys are Regulated by Thyroid Stimulating Hormone

Abstract

Thyroid disease affects an estimated 200 million people worldwide, and is commonly associated with increased blood lipid levels. However, the mechanism by which thyroid-stimulating hormone (TSH) affects lipid profiles is not clear. Twenty-four cynomolgus monkeys were treated with a novel exogenous recombinant human TSH (rhTSH) (SNA001) at 9 μg kg−1, 22 μg kg−1, or 54 μg kg−1, and reference rhTSH (Thyrogen®) at 22 μg kg−1. The primary TSH (SNA001) pharmacokinetic (PK) parameters increased in a dose-dependent manner across the dose range of 9 μg kg−1, 22 μg kg−1, or 54 μg kg−1. Peak triiodothyronine (T3) and thyroxine (T4) levels were reached within 24 h after rhTSH administration, which was delayed by approximately 20 h. In total, 420 lipid species were detected and quantified by ultra-performance liquid chromatography high resolution spectrometry (UPLC-HR-MS)-based lipidomics. Notably, peak levels of lipid accumulation, particularly sphingomyelin (SM) and triglycerides (TG), appeared at 4 and 24 h, which was consistent with the pattern of TSH and T3/T4 levels, respectively. According to weighted correlation network analysis (WGCNA), perturbations of many lipid species were strongly correlated with TSH and T3/T4 levels. TSH and the stimulated T3/T4 levels and lipid profiles following SNA001 administration were comparable to those after administration of the reference rhTSH (Thyrogen®). The plasma lipidome and changes in lipid levels after rhTSH stimulation were associated with TSH and T3/T4 concentrations. T3/T4 and lipid profiles were delayed after TSH stimulation. Such phenomena require further exploration.