de Assis Leonardo Vinicius Monteiro, Harder Lisbeth, Inderhees Julica, Jöhren Olaf, Mittag Jens, Oster Henrik
Institute of Neurobiology, Center of Brain Behavior & Metabolism, University of Lübeck, Lübeck, Germany.
University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.
NPJ Metab Health Dis. 2024 Aug 13;2(1):21. doi: 10.1038/s44324-024-00023-4.
Thyroid hormones (THs) are critical regulators of systemic energy metabolism and homeostasis. In the liver, high TH action protects against steatosis by enhancing cholesterol and triglyceride turnover, with thyroid hormone receptor beta (THRB) signaling playing a pivotal role. This study probed the potential interaction between THRB action and another critical regulator of liver energy metabolism, the circadian clock. Liver transcriptome analysis of THRB deficient (THRB) mice under normal chow conditions revealed a modest impact of THRB deletion. Temporal transcriptome and lipidome profiling uncovered significant alterations in diurnal metabolic rhythms attributable to THRB deficiency pointing to a pro-steatotic state with elevated levels of cholesterol, tri- and diacylglycerides, and fatty acids. These findings were confirmed by THRB agonization in hepatocytes under steatosis-promoting conditions in vitro. Integration of transcriptome profiles from THRB mice and mice with induced high or low TH action identified a subset of TH responsive but THRB insensitive genes implicated in immune processes. In summary, our study reveals a complex time-of-day dependent interaction of different TH-related signals in the regulation of liver physiology indicating an opportunity for chronopharmacological approaches to TH/THRB manipulation in fatty liver diseases.
甲状腺激素（THs）是全身能量代谢和体内平衡的关键调节因子。在肝脏中，高甲状腺激素作用通过增强胆固醇和甘油三酯的周转来预防脂肪变性，其中甲状腺激素受体β（THRB）信号传导起着关键作用。本研究探讨了THRB作用与肝脏能量代谢的另一个关键调节因子——生物钟之间的潜在相互作用。在正常饮食条件下对THRB缺陷（THRB）小鼠进行肝脏转录组分析，发现THRB缺失的影响较小。时间转录组和脂质组分析发现，由于THRB缺乏，昼夜代谢节律发生了显著改变，表明存在一种促脂肪变性状态，胆固醇、甘油三酯、二酰甘油和脂肪酸水平升高。在体外促进脂肪变性的条件下，肝细胞中的THRB激动作用证实了这些发现。整合THRB小鼠和甲状腺激素作用高或低的诱导小鼠的转录组图谱，确定了一组与免疫过程相关的甲状腺激素反应性但THRB不敏感的基因。总之，我们的研究揭示了不同甲状腺激素相关信号在肝脏生理调节中存在复杂的时间依赖性相互作用，这为在脂肪肝疾病中采用时辰药理学方法调控甲状腺激素/THRB提供了机会。
