Perturbed liver gene zonation in a mouse model of non-alcoholic steatohepatitis
Abstract
Liver zonation characterizes the separation of metabolic pathways along the lobules and is required for optimal hepatic function. Wnt signaling is a master regulator of spatial liver zonation. A perivenous-periportal Wnt activity gradient orchestrates metabolic zonation by activating gene expression in perivenous hepatocytes, while suppressing gene expression in their periportal counterparts. However, the understanding as to the liver gene zonation and zonation regulators in diseases is limited. Non-alcoholic steatohepatitis (NASH) is a chronic liver disease characterized by fat accumulation, inflammation, and fibrosis. Here, we investigated the perturbation of liver gene zonation in a mouse NASH model by combining spatial transcriptomics, bulk RNAseq and in situ hybridization. Wnt-target genes represented a major subset of genes showing altered spatial expression in the NASH liver. The altered Wnt-target gene expression levels and zonation spatial patterns were in line with the up regulation of Wnt regulators and the augmentation of Wnt signaling. Particularly, we found that the Wnt activator Rspo3 expression was restricted to the perivenous zone in control liver but expanded to the periportal zone in NASH liver. AAV8-mediated RSPO3 overexpression in controls resulted in zonation changes, and further amplified the disturbed zonation of Wnt-target genes in NASH, similarly Rspo3 knockdown in Rspo3 +/- mice resulted in zonation changes of Wnt-target genes in both chow and HFD m…
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Previous studies using global knockout or overexpression found that RSPO3 is an important regulator of liver zonation and hepatocyte proliferation, but did not dissect its cell-specific functions and its key role in HSC-hepatocyte cross-talk.
“Previous studies, using global knockout or overexpression, have found that RSPO3 is an important regulator of liver zonation and hepatocyte proliferation, but did not dissect its cell-specific functions and its key role in the HSC–hepatocyte cross-talk24,41,55.”
From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [55]
Liver zonation is perturbed in CLD, including MASLD.
“Accordingly, liver zonation is perturbed in CLD, including MASLD54,55.”
From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [55]
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- Authors
- Zhou, Y., Zhao, Y., Carbonaro, M., Chen, H., Germino, M., Adler, C., Ni, M., Zhu, Y. O., Kim, S. Y., Altarejos, J., Li, Z., Burczynski, M. E., Glass, D. J., Sleeman, M. W., Lee, A.-H., Halasz, G., & Cheng, X.
- Affiliations
- Regeneron (United States) (US)
- Corresponding author
- Chen, Helen
- Cheng, Xiping
- ORCID
- Venue
- Metabolism
- Publisher
- Elsevier BV
- Published
- 2024-05
- Volume
- 154
- Pages
- 155830
- ISSN
- 0026-0495 (ISSN-L)
- OpenAlex
- W4392245613
- Cited by
- 24
- References
- 51
- Citations by year
- 2026: 13 · 2025: 9 · 2024: 2
- FWCI
- 7.28
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- liver zonation, nonalcoholic steatohepatitis, Wnt signaling, RSPO3, periportal zone, perivenous zone, hepatic lobule, spatial gene expression, high-fat diet, hepatocyte heterogeneity
- MeSH terms
- Animals, Disease Models, Animal, Fibrosis, Inflammation, Liver, Mice, Inbred C57BL, Hepatocytes, Mice, Non-alcoholic Fatty Liver Disease
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