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Iron Overload Reprograms Glul+ Hepatocyte Fate to Induce Steatosis and Fibrosis via WNT-signaling pathway in Mice

ABSTRACT: Background & Aims Hepatic iron overload is associated with non-alcoholic fatty liver disease (NAFLD) and cirrhosis in lean individuals. We aimed to explore the underlying mechanism through which excessive iron induces fatty liver and cirrhosis at single-cell resolution. Methods Mouse models were established through feeding a high iron or high fat diet to mimic the condition of iron overload and obesity. Iron overload and obesity induced NAFLD models were confirmed by biochemistry measurements and histological sections. Single-cell RNA-seq (scRNA-seq) and single-nucleus ATAC-seq (snATAC-seq) were conducted to provide insights to the molecular effects of iron overload or obesity on major liver cell types. Pseudo-time analysis and motif activity analysis were performed to gain insight of the differentiation trajectory and the underlying regulatory mechanisms. Cell-cell interaction analysis was utilized to evaluate the hepatic microenvironment in mice with iron overload. Results Iron overload-induced fatty liver is characterized by down-regulation of PPAR signaling pathway. Ghr+ pericentral hepatocytes, expressing key regulator PPARα, are perturbed by iron, in contrast to the increased population in HFD mice. Iron overload and obesity induced distinctive hepatocyte differentiation trajectories. Differentiation of iron-overloaded hepatocytes mitigates oxidative damage but leads to the downregulation of the PPAR signaling pathway. Glul+ pericentral hepatocytes, serves as transit-amplifying cells (TACs) in liver lobule, lose their differentiation ability under high iron diet. The motif analysis of the transcription factors indicated the role of TCF7L2/LEF1 in governing the differentiation of Glul+ hepatocytes through WNT pathway. Reprogrammed Glul+ pericentral hepatocytes under iron overload also established an inflammatory micro-environment involving increased interactions between hepatocytes and non-parenchymal cells (NPCs), contributing to the formation of liver fibrosis. Conclusions This study offers comprehensive evidence elucidating the distinctive molecular and cellular mechanism of iron overload-induced NAFLD and fibrosis. PPARA and TCF7L2 agonists should be considered in developing effective therapeutic strategies for iron overload-induced lean NAFLD.

ORGANISM(S): Mus musculus

PROVIDER: GSE268613 | GEO | 2026/02/11

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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Iron Overload Reprograms Glul+ Hepatocyte Fate to Induce Steatosis and Fibrosis via WNT-signaling pathway in Mice

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