The Role of TCF7L2 in Hepatic Metabolic Zonation

Background and Aims: The molecular mechanisms regulating the zonal distribution of metabolism in liver are incompletely understood. Here we used multimodal single nuclei genomics techniques to examine the spatial transcriptional function of the transcription factor 7-like 2 (TCF7L2) in rodent liver. We also determined whether inactivation of TCF7L2 disrupted the normal metabolic architecture of the liver and influenced the development of fibrotic liver diseases. Methods: Multimodal single nuclei RNA- and ATAC-Seq were used to examine the spatial expression and DNA binding activity of TCF7L2 across the liver lobule. The transcriptional activity of TCF7L2 was targeted by removing exon 11 of Tcf7l2, which encodes part of the DNA binding domain (DBD). The effect of TCF7L2 inactivation on transcriptional regulators of zonation, hepatic metabolism, and the development of fibrosis was investigated in Hep-TCF7L2ΔDBD mice fed the Gubra Amylin Nash (GAN) or choline-deficient amino acid-defined high fat (CDAHFD) diet for 24- and 8-weeks, respectively. Results: Tcf7l2 mRNA expression was ubiquitous across the liver lobule, but the presence of the consensus TCF/LEF DNA binding motif in open chromatin was enriched in pericentral (PC) hepatocytes in zone 3, but not periportal (PP) or mid-lobular hepatocytes in zones 1 and 2. Consistent with this, PC hepatocyte gene expression was lost in Hep-TCF7L2ΔDBD mice, which we link to alterations in the transcriptional activity of zonal repressors Tbx3 and Tcf7l1. The absence of PC hepatocyte gene expression resulted in impaired bile acid synthesis and hepatic cholesterol accumulation, and disrupted metabolic pathways linked to ammonia detoxification, most notably glutamine/glutamate homeostasis. Following the CDAHFD, Hep-TCF7L2ΔDBD mice developed more severe hepatic fibrosis. Finally, TCF7L2 expression declined in human livers as the severity of fibrosis progressed. Conclusion: TCF7L2 is an important transcriptional regulator of PC hepatocytes in zone 3, and regulates multiple zonated metabolic pathways that may contribute to the development of fibrotic liver diseases.