Endocrine Abstracts

Background: Thyroid hormones (THs) stimulate hepatic de-novo lipid biosynthesis but also lipolysis and beta-oxidation. Similarly, they simultaneously enhance cholesterol uptake, biosynthesis, and degradation. Thyroid hormone receptor beta (THRβ) is the main hepatic thyroid hormone receptor. Mammals have developed a circadian timekeeping system that controls physiological processes to adapt to time-of-day.HypothesisWe hypothesized that TH effects are subject to circadian regulation via an interaction of THRβ with hepatocyte clocks.

Results: Approximately 9000 rhythmic mRNAs were identified in THRβWT and THRβKO livers. Differential rhythm analysis identified 1446, 314, and 369 genes with changes in mesor (baseline expression), amplitude (rhythm strength), and acrophase (time of peak expression), respectively. Gene set enrichment analysis followed by predictive exploration suggested elevated levels of triglycerides and cholesterol in THRBKO livers. A total of 148 rhythmic lipids were identified and 33 lipids showed rhythm parameter differences. Phosphatidylcholines (42:2, 18:0_22:5, 20:0_20:4, 22:0_20:4, 31:1) and phosphatidylinositols (18:0_22:6, 20:0_20:4) had reduced mesor while cholesterol esters (18:1), ceramides (42:3;2O and 18:1;2O/23:0), triglycerides (58:8, 55:5, 53:4, 52:5, 51:4), diacylglycerides (18:1_22:6, 18:2_20:2, 18:2_20:4, 18:1_18:2, 18:0_18:2, 16:0_18:2), phosphatidylglycerol (18:1_18:1, 18:1_18:2, 18:1_22:6, 18:2_22:6) and free fatty acids (18:2) showed increased mesor. Interestingly, the diacylglycerides 18:2_20:4 and 18:0_18:2 showed a phase advance of 3 and 6 h, respectively. An integrative pipeline was implemented to match the identified rhythmic transcriptome changes with lipidome alterations, thus providing a resource for further experimentation.

Conclusions: Our findings show that loss of THRβ contributes to metabolic changes resembling early-stage hepatic steatosis.