转录因子FOXQ1调节机体糖脂代谢

Hepatic gluconeogenesis is essential for maintaining normal blood glucose levels in the fasted state in mammals. However, hepatic gluconeogenesis is abnormal activated and a main factor contributing to high blood glucose levels in diabetic patients. .Our preliminary data suggest that hepatic transcription factor Foxq1 is regulated by pathophysiological and nutritional status. Fasting decreases expression of Foxq1 in liver of normal mice. Moreover, Foxq1 expression is decreased in db/db mice compared to normal mice. Adenovirus-mediated overexpression of Foxq1 in db/db mice reduced expression of gluconeogenic genes, including PGC-1α, PEPCK and G6pc, thereby reducing hepatic gluconeogenesis, decreasing fasting blood glucose level, improving glucose tolerance and enhancing insulin sensitivity. In contrast, knockdown of Foxq1 expression in normal mice modestly increased blood glucose levels, impairing glucose tolerance and insulin sensitivity. .FOXO1 is a well-known factor activating hepatic gluconeogenesis. Our CoIP and GST-pull down experiments suggest that Foxq1 directly interacts with FOXO1, forming a complex in vivo and in vitro. .Based on these data, we propose a model of the mechanism of Foxq1 action on hepatic gluconeogenesis. In this model, Foxq1 protein levels decrease under certain pathophysiological conditions (insulin resistance and diabetes) or fasting state,, allowing FOXO1 binding to gluconeogenic genes, contributing to hepatic glucose production. However, under feeding condition Foxq1 proteins are increased and form complex with FOXO1, blocking FOXO1 activity on hepatic gluconeogenesis and maintaining glucose homeostasis..However, more studies are required to test this model. We plan to generate liver and adipose –specific Foxq1 knockout mice to explore the role of Foxq1 in regulating systemic glucose and lipid metabolism. .In addition, we will study the role of Foxq1 in regulating preadipocyte differentiation and adipose tissue development using Foxq1-deficient MEF cells and Foxq1-deficient mice. .Studying of factors controlling hepatic and adipose metabolism may contribute to identification of a potential therapeutic target for treating metabolic disease.

哺乳动物的肝脏糖异生对维持饥饿血糖水平及其重要，但是，糖尿病人肝脏中糖异生被过度激活，这是糖尿病人高血糖的一个重要原因。我们前期研究工作表明，肝脏转录因子Foxq1受到营养状态和病理状态调控，db/db糖尿病小鼠肝脏中Foxq1的表达明显下降。在db/db糖尿病小鼠肝脏中激活Foxq1，明显抑制肝脏糖异生，降低血糖水平，改善葡萄糖耐受和胰岛素敏感性。CoIP，GST-pull down实验表明，Foxq1可以与FOXO1直接相互作用。这些结果表明Foxq1是一个重要的调节机体糖脂代谢的因子。本申请拟从分子水平，细胞水平及动物整体水平，系统研究Foxq1如果调控肝脏的糖脂代谢，构建肝脏组织和脂肪组织特意敲除Foxq1小鼠模型，研究Foxq1在这些组织中的功能。研究肝脏的糖脂代谢网络，鉴定新的可行的治疗靶点，对预防和治疗2型糖尿病极其关键。

哺乳动物维持机体血糖稳定对于保证机体正常的生理功能至关重要，在病生理状态下,比如2 型糖尿病,其胰岛素信号通路受到伤害,最终导致血糖升高。阐明机体血糖血脂调控机制,可以为治疗2 型糖尿病提供有效的治疗靶点。我们的前期工作表明，FOX 家族成员FOXP1 参与了肝脏糖脂代谢。在此基础上，我们进一步系统研究了FOX家族其他成员是否参与了机体的糖脂代谢。在该项目的支持下我们取得了以下研究成果：肝脏中FOXQ1受到病理状态和营养状态调控。我们发现FOXQ1能抑制肝脏糖异生，降低血糖，改善葡萄糖耐受和胰岛素敏感性，并且阐明了其作用分子机制，FOXQ1可以和FOXO1竞争性相互作用，阻止其结合到IRE转录元件上，进而阻止了FOXO1引起的糖异生相关基因的表达增高，尤其是G6Pase，从而调节肝脏糖代谢平衡,但是FOXQ1并没有影响脂肪细胞分化。该研究成果发表在(Diabetologia, 2016, 59 (10), p2229-2239)。.在该项目的支持下，我们还开展了其他研究，关于脂肪中的KLF9通过PGC1A调控脂肪组织产热的相关研究成果发表在Diabetes (2020), 关于肝脏中的KLF9通过调控肝脏糖异生调节机体血糖的相关研究成果发表在JCI (2019), 关于脂肪中SITR6通过结合和磷酸化ATF2调节其结合PGC1α启动子的作用，从而调节脂肪产热功能的相关研究成果发表在Cell Reports (2017), 研究KLF10调节肝脏糖代谢的研究成果发表在Diabetologia (2017),研究肝脏中的SIRT1通过去乙酰化FOXA2从而调节机体的胆汁酸代谢的相关研究成果发表在 BBA (2017),研究骨骼肌中SIRT6通过调节AMPK的活性从而调节肌肉组织的糖脂代谢，脂肪酸氧化以及线粒体氧化磷酸化的相关研究成果发表在 Am J Physiol- Endocrinol Metab (2017)上。