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Spatial hepatocyte plasticity of gluconeogenic gene expression and gluconeogenic activity during the metabolic transitions between fed, fasted and starvation states [RNA-Seq]

ABSTRACT: Single cell analyses of hepatocytes across the liver lobule demonstrated that gluconeogenic gene expression (Pck1 and G6pc) is relatively low in the fed state and gradually increase first in the periportal hepatocytes during the initial fasting period. As the time of fasting progresses, pericentral hepatocyte gluconeogenic gene expression increases and following entry into the starvation state the pericentral hepatocytes are not significantly different than the periportal hepatocytes. Similarly, pyruvate-dependent gluconeogenic activity is approximately 10-fold higher in the periportal hepatocytes during the initial fasting states but with only 1.5-fold different between the pericentral and periportal hepatocytes in the starvation state. In parallel, starvation induced a reduction of canonical beta-catenin signaling and redistribution of pericentral and periportal glutamine synthetase and glutaminase resulting in an enhanced pericentral glutamine-dependent gluconeogenesis. These data demonstrate that hepatocyte gluconeogenic gene expression and gluconeogenic activity are highly spatially and temporally plastic across the liver lobule and underscore the critical importance of using well-defined feeding and fasting times to define the basis of hepatic insulin resistance and glucose production.

ORGANISM(S): Mus musculus

PROVIDER: GSE263415 | GEO | 2025/01/23

REPOSITORIES: GEO

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Project description: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.

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Spatial hepatocyte plasticity of gluconeogenic gene expression and gluconeogenic activity during the metabolic transitions between fed, fasted and starvation states [RNA-Seq]

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