Omics Study Of Lipid Metabolism After Thyrotropin Stimulation

Thyroid disease,which affects about 20% of people worldwide,is often associated with elevated lipid levels,and lipid abnormalities,which usually increase the risk of endothelial dysfunction,hypertension and cardiovascular disease.Thyroid hormones,especially thyoid stimulating hormone(TSH),often affect lipid metabolism.However,the mechanism of how TSH affecting the whole lipid spectrum has not been clearly studied.First,endogenous TSH suppressed mouse model after L-triiodothyronine(T3)treated was established.After high dose T3 treatment,the serum lipid spectrum changed significantly,including the decrease of triglyceride(TG),sphingomyelin(SM)and ceramide(Cer).It is also observed that lipids especially TG,Phosphatidyl cholines(PC),Lysophosphatidyl cholines(LPC)were dramatically up-regulated after recombinant human thyroid stimulating hormone(rh TSH)stimulation.Further analysis showed that some groups of PC,LPC,SM and TG had positive correlation with TSH but no correlation with T3,suggesting a direct role of TSH in stimulating lipids.Subsequently,we treated the cynomolgus monkeys with rh TSH in the low,medium and high dose.Pharmacokinetic and pharmacodynamic analysis showed that peak concentrations of TSH reached within 2-4 hours,and peak concentrations of T3/T4 occurred within 8-24 hours after rh TSH administration.Lipidomic study showed significant changes in lipids after rh TSH stimulation.WGCNA co-correlation lipid network analysis and cluster pattern analysis revealed that the peak time of PC,SM and TG at 4 h was consistent with TSH,which was in accordance with results in TSH inhibited mouse model.These results suggest that these lipid changes may be directly induced by TSH stimulation.In order to verify the above results,rh TSH was employed to stimulate hepatocellular carcinoma cell model Hep G2 and human TSH receptor transgenic cell model TSHR-HEK 293 cell line with different TSHR expression.Lipidomics showed that triglycerides and sphingolipids were significantly up-regulated,while phospholipids were down-regulated,similar to the results in the above animal models.Transcriptome analysis after rh TSH stimulation showed that genes enriched in signal transduction,energy metabolism,endoplasmic reticulum and lipid metabolism.Further analysis showed that fatty acid and related synthesis genes were stimulated,and genes participated in de novo TG synthesis pathway were also upregulated,which was also confirmed by the inhibition of Acyl-Co A:Diacylglycerol Acyltransferase 1(DGAT1)and Acyl-Co A:Diacylglycerol Acyltransferase 1(DGAT2),suggesting the potential mechanisms of TG synthesis after TSH stimulation.This study provides a more comprehensive understanding of the relationship between TSH,thyroid hormones,and lipid metabolism.rh TSH stimulates lipids directly,and induces fatty acid metabolism and de novo synthesis of TG,which has implications for the control of dyslidemia in thyroid diseases.