转录因子ChREBP调节果糖代谢的感应机制及其病理作用研究

In mammals, fructose has distinct metabolic pathways and unique metabolic effects compared with glucose. Excess fructose intake is closely correlated with the pathogenesis of metabolic syndromes. ChREBP is a key transcription factor regulating fructose metabolism, however, its sensing and effect mechanism in vivo is poorly defined. Our previous works demonstrate that ChREBP has an unknown fructose-specific nutrition sensing and effect pathway in intestine and liver, by which ChREBP is critically involved in the regulation of cholesterol metabolism. In addition, we identified a novel component named NX in fructose-activated ChREBP functional complex. On the basis of these findings, first we intend to explore the biochemical mechanism underlying the efficient activation of ChREBP by fructose, paying particular attention to the fructose metabolites as well as functional ChREBP complex. Second, we will use tissue-specific knockout mouse model to investigate the cellular and molecular mechanism by which ChREBP regulates fructose and cholesterol homeostasis. Last, to address how ChREBP over-activation disrupts cholesterol homeostasis, we will look into cholesterol synthesis, transport, and disposal in the conditional overexpression models of ChREBP-β. Our proposed researches will not only establish a new model for the activation of ChREBP pathway regulating fructose and cholesterol homeostasis, but also enable us to better understand the mechanisms about fructose tolerance and the pathogenesis of metabolic syndrome, thus paving a way for the prevention and treatment of these related diseases.

果糖具有不同于葡萄糖的独特代谢通路和效应，其摄入过量与代谢综合征的发生发展密切相关。作为调节果糖代谢的关键性转录因子，ChREBP的体内营养感应机制尚不清楚。我们前期发现，ChREBP存在果糖特异性营养感应通路，且具有调节胆固醇代谢的新功能；果糖激活的ChREBP复合物中存在新的互作蛋白NX。在此基础上，本项目拟从果糖特征性代谢产物、ChREBP复合物的结构与功能等角度，解析果糖高效激活ChREBP营养感应通路的生化基础；利用组织特异性基因敲除小鼠模型，揭示ChREBP在维持果糖和胆固醇代谢稳态中的细胞分子机制；利用条件性ChREBP-β过表达小鼠，从胆固醇吸收、合成、转运、清除等环节，阐释ChREBP过度激活导致胆固醇稳态失衡的分子机制，从而提出ChREBP调节果糖感应和胆固醇代谢的新模式，揭示果糖代谢稳态维持及其摄入过多导致糖脂代谢紊乱的新机制，为代谢性疾病的防治提供理论依据和新思路。

果糖具有不同于葡萄糖的独特代谢通路和效应，其摄入过量与代谢综合征等疾病的发生发展密切相关。ChREBP是调节机体果糖代谢的关键性转录因子，然而相关的营养感应机制及其对胆固醇代谢的调节作用尚不清楚。我们研究发现，糖代谢产物ME是果糖激活ChREBP的关键性代谢产物，肠道ChREBP营养感应通路在维持小鼠的果糖偏好中发挥重要生理调节作用； 肝脏ChREBP主要通过靶基因LPK维持果糖和肝糖原代谢稳态，从而保护小鼠免受高果糖诱导的肝脏毒性；ChREBP转录激活因子ZBTB20通过抑制肝脏中LPL的基因转录，协同ChREBP通路维持机体脂代谢稳态；肠道ChREBP通路激活可增强肠道胆固醇吸收，从而参与高胆固醇血症的发生发展。此外，研究揭示了ChREBP对肝脏锰代谢稳态和脂肪产热的调节作用。肝脏ChREBP通过激活锰离子转运蛋白的表达，降低细胞内锰离子浓度，抑制锰离子相关的精氨酸酶和SOD活性。ChREBP过度激活可导致线粒体更新障碍和产热基因UCP1、Dio2下调，从而引起BAT白色化转型、脂肪产热和机体耐寒能力受损。总之，本研究揭示了ChREBP调节果糖感应和胆固醇代谢的新机制，提出了果糖摄入过多导致代谢性疾病的新理论，为代谢性疾病的防治提供理论依据和新思路。