Ayala Iriscilla, Hebbale Skanda K, Mononen Juho, Brearley-Sholto Madelaine C, Shannon Christopher E, Valdez Ivan, Fourcaudot Marcel, Bakewell Terry M, Zagorska Anna, Romero Giovanna, Asmis Mara, Musa Fatima A, Sily Jonah T, Smelter Annie A, Hinostroza Edgar A, Freitas Lima Leandro C, de Aguiar Vallim Thomas Q, Heikkinen Sami, Norton Luke
Diabetes Division, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA.
Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland.
Nat Commun. 2025 Apr 10;16(1):3408. doi: 10.1038/s41467-025-58714-5.
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.
调节肝脏代谢区域分布的分子机制尚未完全明确。在此，我们运用单核基因组学技术来研究转录因子7样2（TCF7L2）在小鼠肝脏中的空间转录功能，并确定TCF7L2转录失活对肝脏代谢结构及区域化代谢途径功能的影响。我们发现，虽然Tcf7l2 mRNA在整个肝小叶中普遍表达，但共有的TCF/LEF DNA结合基序的可及性仅限于3区的中央周围（PC）肝细胞。在肝脏中表达功能失活的TCF7L2的小鼠中，缺乏PC肝细胞特异性基因表达，我们证明这会促进肝脏胆固醇积累、胆汁酸合成受损、谷氨酰胺/谷氨酸稳态破坏以及明显的饮食诱导性肝纤维化。总之，TCF7L2是肝脏区域基因表达的关键调节因子，并调节多种可能导致纤维化肝病发展的区域化代谢途径。
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