Journal Article

The Spatial Transcriptional Activity of Hepatic TCF7L2 Regulates Zonated Metabolic Pathways that Contribute to Liver Fibrosis

Hinostroza, Edgar A., Ayala, Iriscilla, Hebbale, Skanda K., Sily, Jonah T., Musa, Fatima A., Romero, Giovanna, Mononen, Juho, Freitas Lima, Leandro C., Asmis, Mara, Smelter, Annie A., Heikkinen, Sami, Valdez, Ivan, Bakewell, Terry M., Shannon, Christopher E., Norton, Luke, de Aguiar Vallim, Thomas Q., Fourcaudot, Marcel, Brearley-Sholto, Madelaine C., Zagorska, Anna

2025

Overview

The molecular mechanisms regulating the zonal distribution of metabolism in liver are incompletely understood. Here we use single nuclei genomics techniques to examine the spatial transcriptional function of transcription factor 7-like 2 (TCF7L2) in mouse liver, and determine the consequences of TCF7L2 transcriptional inactivation on the metabolic architecture of the liver and the function of zonated metabolic pathways. We report that while Tcf7l2 mRNA expression is ubiquitous across the liver lobule, accessibility of the consensus TCF/LEF DNA binding motif is restricted to pericentral (PC) hepatocytes in zone 3. In mice expressing functionally inactive TCF7L2 in liver, PC hepatocyte-specific gene expression is absent, which we demonstrate promotes hepatic cholesterol accumulation, impaired bile acid synthesis, disruption to glutamine/glutamate homeostasis and pronounced dietary-induced hepatic fibrosis. In summary, TCF7L2 is a key regulator of hepatic zonal gene expression and regulates several zonated metabolic pathways that may contribute to the development of fibrotic liver disease. This study identifies transcription factor 7-like 2 (TCF7L2) as a key regulator of hepatic metabolic zonation, and demonstrates that disruption to the transcriptional activity of TCF7L2 exacerbates the development of dietary-induced hepatic fibrosis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45/15 / 45/91 / 631/337/572/2102 / 631/443/319/1642 / 64/60 / 692/4020/1503/1607/1605 / 692/4020/4021/288 / 692/699/1503/1607/2750 / Animals / Bile Acids and Salts - biosynthesis / Bile Acids and Salts - metabolism / Cholesterol / Disruption / Fibrosis / Gene expression / Gene Expression Regulation / Glutamine / Hepatocytes / Hepatocytes - metabolism / Homeostasis / Humanities and Social Sciences / LEF/TCF protein / Liver / Liver - metabolism / Liver - pathology / Liver cirrhosis / Liver Cirrhosis - genetics / Liver Cirrhosis - metabolism / Liver Cirrhosis - pathology / Liver diseases / Male / Metabolic Networks and Pathways - genetics / Metabolic pathways / Metabolism / Mice / Mice, Inbred C57BL / Molecular modelling / multidisciplinary / Science / Science (multidisciplinary) / Transcription Factor 7-Like 2 Protein - genetics / Transcription Factor 7-Like 2 Protein - metabolism / Transcription factors / Transcription, Genetic / Zonal distribution / Zonation