肝脏c-Jun对糖脂代谢和能量稳态的调控作用与分子机制研究

In recent years, there has been an increase in the reported global prevalence of metabolism syndrome (MS) including diabetes, NAFLD (Non Alcoholic Fatty Liver Disease) and obesity. Dysregulation of glucose, lipid and energy metabolism is the most fundamental pathophysiological features of MS. The liver is a vital organ that plays an important role in the whole-body physiology including glucose, lipid and energy metabolism. Over the years, although many regulatory mechanisms regarding these processes have been identified, detailed molecular causes for the hepatic regulation of glucose, lipid and energy metabolism remain elusive. Previously, we observed increased blood glucose levels in the mice injected with adenoviruses knocking down c-Jun. We then generated liver-specific c-Jun knock-out mice, which showed decreased hepatic lipid accumulation, reduced body weight and increased oxygen consumption. These results suggest a possible role of hepatic c-Jun in regulating glucose, lipid and energy metabolism. The objectives of this research are to investigate the involvement of hepatic c-Jun in regulating glucose, lipid and energy metabolism and elucidate the underlying mechanisms. We will explore these in various cell models, db/db mice and liver-specific c-Jun knock-out mice. Studies at the levels of molecule, cell and animals will be utilized to address these specific aims in order to provide a comprehensive understanding about the impact of inter-organ crosstalk on the regulation of whole body metabolic homeostasis. This work will reveal the novel function of c-Jun in regulating glucose, lipid and energy metabolism, and greatly enhance our understanding about the pathogenesis of diabetes, NAFLD and obesity.

糖脂代谢紊乱和能量失衡是导致糖尿病、非酒精性脂肪肝和肥胖等重大慢性代谢性疾病发生的内在原因。肝脏是以代谢功能为主的器官，在机体的糖脂代谢和能量稳态调控过程中扮演了重要角色。申请人前期研究发现，尾静脉注射腺病毒降低小鼠肝脏c-Jun表达后，小鼠血糖升高，提示肝脏c-Jun表达降低将导致小鼠糖代谢紊乱。之后申请人构建了肝脏c-Jun特异性敲除小鼠。该小鼠肝脏脂质积累减少，体重降低，氧耗增加，多个脑区神经元活性发生改变。这一现象表明肝脏c-Jun表达降低将导致小鼠脂质和能量代谢紊乱。因此，我们提出假设：肝脏c-Jun具有调控糖脂代谢和能量稳态的功能。本项目将利用多种细胞和动物模型，从多个层次研究肝脏c-Jun对糖脂代谢及全身能量稳态的调控作用与机制。该研究将加深人们对c-Jun生理功能及各个器官交互作用调节机体代谢稳态的认识，有助于理解糖尿病、非酒精性脂肪肝和肥胖等代谢疾病发生发展的分子机制。

本项目探讨了肝脏c-Jun对糖脂代谢和能量稳态的调控作用与机制。利用肝脏特异性敲除c-Jun小鼠c-jun△li，我们发现肝脏特异敲除c-Jun使小鼠糖异生能力显著升高，体外细胞实验也证明了这一点。进一步研究发现，肝脏c-Jun敲除后抑制了FGF21的表达，尾静脉注射FGF21过表达腺病毒可以减缓肝脏c-Jun敲除小鼠的糖异生能力。此外，我们发现c-jun△li小鼠体温显著升高，而这种高体温可能是通过增加了褐脂中UCP1表达实现的。利用30度高温抑制褐脂的功能后，c-jun△li小鼠不再表现出高体温的现象。我们发现c-jun△li小鼠的交感神经活性升高，而注射肾上腺素受体抑制剂后可以阻断c-jun△li小鼠的高体温。最后，我们发现c-jun△li小鼠神经活性的激活和体温的升高可能是肝脏通过迷走神经影响了脑而实现的：肝脏迷走神经切除后脑中反应神经活性的因子c-FOS表达显著回复，且体温不再升高。以上工作发现了肝脏c-Jun在调控糖代谢和体温方面的新功能，增加了人们对于器官互作调控机体生理功能的新认识。在本项目资助下，我们还探讨了c-Jun的上游BTG1在脂肪组织中的作用与机制。我们发现地塞米松处理小鼠的褐脂会发生白色化，自噬及其相关基因ATG7参与调控这一过程。进一步检测发现，地塞米松对于ATG7表达的调控依赖BTG1/CREB1信号通路。脂肪组织特异性过表达BTG1小鼠褐脂发生白色化，全身脂肪含量增加。利用病毒降低褐脂BTG1表达能够阻止地塞米松诱导的褐脂白色化以及全身脂肪含量的增加。该工作证明了抑制自噬作用可有效缓解糖皮质激素诱导的肥胖，加深了人们对于糖皮质激素作用机制以及褐脂白色化过程的理解和认识。