The Role of Tcf7l2 in maintaining liver zonation and metabolic homeostasis

摘要 15年前，遗传学研究确定了TCF7L2与糖尿病之间的联系；最近， 与非酒精性脂肪性肝病(NAFLD)相关。然而，TCF7L2的作用，特别是 在肝脏中，仍然存在争议。我们认为，迄今为止的进展受到以下因素的阻碍：(1)使用支配性 阐明TCF7L2功能的负面策略；(2)对糖代谢的有限关注；(3)缺乏 肝细胞异质性的评价。也就是说，肝细胞在转录水平和功能上有所不同。 取决于它们所在的解剖带。这项提案的首要目标是确定 TCF7L2在调节肝脏基因表达和代谢中的作用我们用小鼠进行的初步研究 随着TCF7L2在肝脏中的急性缺失，显示(1)TCF7L2对基因表达具有区带特异性影响； 胰高血糖素抑制TCF7L2；和(3)TCF7L2的破坏导致氨基酸、胆汁酸和血脂的改变 新陈代谢。因此，作为对西方饮食的反应，肝脏TCF7L2缺失的小鼠表现出 脂滴的大小和带状明显破坏，肝细胞损伤增加。我们 因此，假设TCF7L2是肝脏中的区域守卫者，对于维持体内平衡是必要的 禁食/进食转变以及在营养过剩期间脂质的安全储存。为了检验这一假设，我们 将利用单核测序、新颖的小鼠模型来检测TCF7L2染色质在不同 区域和新陈代谢方法。我们希望这些研究将扩大我们对 糖尿病，并为开发个性化的基于基因的策略来预防NAFLD和 其他糖尿病后遗症。

Abstract Fifteen years ago, genetic studies identified an association between TCF7L2 and diabetes; more recently an association with non-alcoholic fatty liver disease (NAFLD) was identified. Yet, the role of TCF7L2, particularly in the liver, remains controversial. We think that progress to date has been hindered by (1) use of dominant negative strategies to elucidate TCF7L2 function; (2) a restricted focus on glucose metabolism; (3) a lack of appreciation of hepatocyte heterogeneity. That is, hepatocytes differ in transcriptional profile and function depending on the anatomic zone in which they reside. The overarching goal of this proposal is to determine the role of TCF7L2 in regulating hepatic gene expression and metabolism. Our preliminary studies using mice with acute deletion of Tcf7l2 in the liver show (1) TCF7L2 has zone-specific effects on gene expression; (2) glucagon inhibits TCF7L2; and (3) disruption of TCF7L2 leads to alterations in amino acid, bile acid, and lipid metabolism. Consequently, in response to a Western diet, mice with hepatic deletion of TCF7L2 show a marked disruption in the size and zonation of lipid droplets, as well as an increase in hepatocyte injury. We therefore hypothesize that TCF7L2 is a zone-keeper in the liver, necessary for maintaining homeostasis during fasting/feeding transitions as well as the safe storage of lipids during overnutrition. To test this hypothesis, we will use single-nuclei sequencing, novel mouse models to examine TCF7L2 chromatin binding in different zones, and metabolomic approaches. We expect that these studies will broaden our understanding of diabetes, and forge the way for developing personalized genotype-based strategies to prevent NAFLD and other diabetic sequelae.