The Role of Tcf7l2 in maintaining liver zonation and metabolic homeostasis

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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.