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ORIGINAL RESEARCH ARTICLE

Hepatocyte-specific angiotensinogen deficiency inhibits Western diet-induced liver steatosis with suppression of cell division in mice

Alex C. Pettey1,2,3 ,  Dien Ye1,2 ,  Sohei Ito1,2 ,  Alan Daugherty1,2,3 ,  Hong S. Lu1,2,3* ,  Hisashi Sawada1,2,3*
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1 Saha Cardiovascular Research Center, College of Medicine, University of Kentucky, Lexington, Kentucky, United States of America
2 Saha Aortic Center, College of Medicine, University of Kentucky, Lexington, Kentucky, United States of America
3 Department of Physiology, College of Medicine, University of Kentucky, Lexington, Kentucky, United States of America
Global Translational Medicine, 6027 https://doi.org/10.36922/gtm.6027
Submitted: 16 November 2024 | Revised: 24 March 2025 | Accepted: 25 March 2025 | Published: 10 April 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Liver steatosis is a common cause of chronic liver disease. To investigate the molecular basis of hepatic steatosis, low-density lipoprotein receptor-deficient (LDLR -/-) mice were fed a Western diet (WD, 42% of calories from fat) for 5, 14, or 42 days and evaluated against mice fed a normal laboratory diet. Histological analyses revealed that steatosis was detected as early as 14 days of WD feeding. Bulk RNA sequencing demonstrated that WD feeding altered liver transcriptomes related to inflammation and cell adhesion consistent with the progression of liver steatosis. Previous studies determined that hepatocyte-specific deficiency of angiotensinogen (AGT), the unique substrate of the renin-angiotensin system (RAS), alleviates WD-induced hepatic steatosis in mice. However, the effects of hepatic AGT deficiency were not mimicked by pharmacological inhibition of the RAS, and the molecular mechanisms by which AGT deficiency protects against WD-induced steatosis is unknown. Therefore, liver transcriptomes were compared between hepatocyte-specific AGT-deficient mice (hepAGT -/-) and their wild-type littermates (hepAGT +/+) after 14 days of WD feeding. Gene ontology analyses showed that upregulated genes in hepAGT -/- mice were enriched for metabolic processes and downregulated genes were enriched for cell division pathways. The integration analysis of the two RNA sequencing data identified 5 key genes, Smpd3, Dtl, Cdc6, Mki67, and Top2a, which were primarily associated with cell division processes in hepAGT +/+ mice and were suppressed in hepAGT -/- mice. In conclusion, hepatic AGT deficiency downregulated genes related to cell division during the progression of liver steatosis.

Keywords
Angiotensinogen
Liver steatosis
Obesity
Transcriptomic analysis
Funding
This research work is supported by the National Institutes of Health (R01HL139748, R35HL155649, and TL1TR001997) and a MERIT award from the American Heart Association (23MERIT1036341). The content in this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Conflict of interest
Alan Daugherty is an Honorary Editor-in-Chief, and Hong S. Lu is an Editorial Board Member of this journal, but they were not in any way involved in the editorial and peer-review process conducted for this paper, directly or indirectly. Separately, other authors declared that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.
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