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

Iriscilla Ayala, Skanda K. Hebbale, Juho Mononen, Madelaine C. Brearley-Sholto, Christopher E. Shannon, Ivan Valdez, Marcel Fourcaudot, Terry M. Bakewell, Anna Zagorska, Giovanna Romero, Mara Asmis, Fatima A. Musa, Jonah T. Sily, Annie A. Smelter, Edgar A. Hinostroza, Leandro C. Freitas Lima, Thomas Q. Aguiar Vallim, Sami Heikkinen and Luke Norton ()
Additional contact information
Iriscilla Ayala: University of Texas Health San Antonio
Skanda K. Hebbale: University of Texas Health San Antonio
Juho Mononen: University of Eastern Finland
Madelaine C. Brearley-Sholto: University of California Los Angeles
Christopher E. Shannon: University of Texas Health San Antonio
Ivan Valdez: University of Texas Southwestern Medical Center
Marcel Fourcaudot: University of Texas Health San Antonio
Terry M. Bakewell: University of Texas Health San Antonio
Anna Zagorska: Gilead Sciences
Giovanna Romero: University of Texas Health San Antonio
Mara Asmis: University of Texas Health San Antonio
Fatima A. Musa: University of Texas Health San Antonio
Jonah T. Sily: University of Texas Health San Antonio
Annie A. Smelter: University of Texas Health San Antonio
Edgar A. Hinostroza: University of Texas Health San Antonio
Leandro C. Freitas Lima: University of Texas Health San Antonio
Thomas Q. Aguiar Vallim: University of California Los Angeles
Sami Heikkinen: University of Eastern Finland
Luke Norton: University of Texas Health San Antonio

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-58714-5

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