甲状腺激素通过调节胆汁酸组成参与组织间的互作及代谢稳态维持的研究

机体代谢器官之间的交流对话形成了复杂的协同调控网络，对于糖脂代谢的调控和稳态维持至关重要。甲状腺激素（TH）及其受体TR对代谢的调控极其复杂，既往及我们的前期研究都提示TH有可能通过组织间互作的模式，间接调控肝脏和脂肪组织代谢从而参与代谢稳态的维持。胆汁酸作为一类小分子代谢物，可通过核受体FXR、膜受体TGR5、以及受体下游众多的调节因子（如FGF15/19），作用于肝、肠、脂肪等组织器官，在代谢调控网络中发挥重要作用。我们的前期研究提示，TH不但能通过调控胆汁酸合成影响胆汁酸池的大小，而且会调节胆汁酸的组成，从而影响受体活性及受体下游调节因子的表达，进而对肝脏和脂肪的代谢调控产生影响。本项目将以肝肠胆汁酸代谢为切入点，利用多种体内外模型和多组学技术，借助肝脏特异性TRβ激动剂，发现TH通过特定胆汁酸组分参与肝、肠、及脂肪组织间的互作并调控糖脂代谢的新机制，并探索肥胖及脂肪肝防治的新策略。

The communication and crosstalk among key metabolic tissues give a rise to complex, integrated regulatory network, thereby playing a vital role in the regulation of glucose and lipid metabolism and maintenance of metabolic homeostasis. The role of thyroid hormone (TH) in metabolic regulation is profound. Previous studies and our recent findings all suggest that TH may regulate the metabolism in liver and adipose tissues indirectly through metabolic crosstalk among tissues, thereby maintaining the metabolic homeostasis. Bile acids, as bioactive metabolites, regulate glucose, lipid, and energy metabolism by targeting liver, intestine, adipose tissues, and skeletal muscle through its nuclear receptor FXR, membrane receptor TGR5, as well as their downstream regulators such as FGF15/19. Our preliminary data indicate that TH not only regulates the bile acid pool size by controlling bile acid synthetic pathways, but also regulates the bile acid composition, which may greatly impact the metabolism in liver and adipose tissues through the receptors of bile acids and/or their downstream regulators. In this study, to further understand the enterohepatic bile acid signaling in the metabolic regulation by TH, we will take advantage of a variety of in vivo and in vitro models, quantitative metabolomics, and liver-targeted TH mimetics to identify particular bile acids involved and investigate the molecular mechanisms involved; establish the critical role of TH-regulated enterohepatic bile acid signaling in metabolic crosstalk among liver, intestine, and adipose tissues and integrated regulatory network of glucose and lipid metabolism; and explore the new strategies of precaution and therapy for metabolic diseases such as obesity and fatty liver.