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Global Translational Medicine Angiotensinogen in liver steatosis

However, in vitro studies investigating the role of Dtl, The present study used a ketamine/xylazine cocktail
Cdc6, Top2a, and Mki67 in lipid-treated hepatocytes are to euthanize mice that has the potential to impact
needed to investigate their potential causative roles in liver metabolic organs, such as the liver. However, in the
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steatosis. present study, mice were rapidly perfused with cold
Elevated mRNA abundances of Dtl, Top2a, Cdc6, saline by left ventricular puncture, and livers were
and Mki67 are associated with highly proliferative immediately processed for RNA extraction. Furthermore,
phenotypes in HCC, a disease that can emerge as a long- all study mice were euthanized and processed in the same
term consequence of liver steatosis. 48,50,59-63 We detected manner in a random order. Therefore, we infer that any
increased mRNA abundance of Dtl, Top2a, Cdc6, and variation in liver transcriptomes due to the euthanasia
Mki67 in liver before development of macrovesicular method would not interfere with data analyses and
steatosis in hepAGT +/+ mice, suggesting that cell interpretation.
proliferation precedes WD-induced liver pathology. 5. Conclusion
This observation is consistent with several recent reports
which indicate that early liver proliferation is a key driver Our integrated transcriptomic analyses identified five
of hepatic steatosis. 56,64,65 Expression of Top2a, Cdc6, and target genes related to cell division that may contribute to
Mki67 is dynamically regulated within the cell cycle, 57,66,67 the development of liver steatosis mediated by WD and
suggesting that the upregulation of these genes by WD AGT. This study provides insights into the role of the RAS
feeding may occur subsequent to proliferative intracellular in WD-induced hepatic steatosis.
signaling. Dtl relieves transcriptional repression through
ubiquitination of several transcriptional modulators. 47,68 Acknowledgments
These data suggest that Dtl may promote cell proliferation None.
and downstream upregulation of Top2a, Cdc6, and
Mki67. Interestingly, Smpd3 is often reported as a tumor- Funding
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suppressing gene in HCC. Overexpression of Smpd3 in
HCC reduced cell proliferation. In vitro, overexpression This research work is supported by the National
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of Smpd3 has been shown to promote palmitate-induced Institutes of Health (R01HL139748, R35HL155649, and
insulin resistance. Disruption of PI3K/Akt signaling and TL1TR001997) and a MERIT award from the American
39
enhanced stress responses resulting from insulin resistance Heart Association (23MERIT1036341). The content in this
suggest a potential opposing relationship between Smpd3 article is solely the responsibility of the authors and does
and Dtl in the context of WD-induced steatosis. While not necessarily represent the official views of the National
our findings and previous literature suggest potential Institutes of Health.
mechanisms by which Smpd3, Dtl, Cdc6, Top2a, and Mki67 Conflict of interest
contribute to liver steatosis, further study is needed to
clarify their precise roles. Taken together, it is important to Alan Daugherty is an Honorary Editor-in-Chief, and
understand the complex interplay between WD, AGT, and Hong S. Lu is an Editorial Board Member of this journal,
hepatocyte proliferation in the pathophysiology of liver but they were not in any way involved in the editorial and
steatosis. peer-review process conducted for this paper, directly or
In the present study, bulk RNA sequencing was indirectly. Separately, other authors declared that they
performed to determine transcriptomic alterations in livers. have no known competing financial interests or personal
A key limitation of bulk RNA sequencing is its inability relationships that could have influenced the work reported
to resolve cellular heterogeneity, which precludes the in this paper.
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identification of cell-specific changes in gene expression. Author contributions
The responses of heterogenous liver cell populations to
WD-feeding, particularly in respect to hepatocyte zonality Conceptualization: Alan Daugherty, Hong S. Lu, Hisashi
and the regulatory roles of parenchymal cells, remain Sawada
critical areas of interest in understanding the link between Formal analysis: Alex C. Pettey, Hisashi Sawada
AGT and liver steatosis. As such, single-cell, single-nuclei, Investigation: Alex C. Pettey, Dien Ye, Sohei Ito
and spatial transcriptomic approaches represent promising Methodology: Alan Daugherty, Hong S. Lu, Hisashi Sawada
tools for future investigations into the relationship between Writing–original draft: Alex C. Pettey
the target genes identified in this study and their potential Writing–review & editing: Dien Ye, Sohei Ito, Alan
contributions to AGT-mediated liver steatosis. Daugherty, Hong S. Lu, Hisashi Sawada

Volume 4 Issue 2 (2025) 80 doi: 10.36922/gtm.6027