Page 79 - GTM-4-2

Global Translational Medicine

ORIGINAL RESEARCH ARTICLE
Hepatocyte-specific angiotensinogen deficiency

inhibits Western diet-induced liver steatosis with
suppression of cell division in mice

Alex C. Pettey 1,2,3 , Dien Ye 1,2 , Sohei Ito 1,2 , Alan Daugherty 1,2,3 ,
Hong S. Lu 1,2,3 * , and Hisashi Sawada 1,2,3 *
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

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
*Corresponding author: were fed a Western diet (WD, 42% of calories from fat) for 5, 14, or 42 days and
Hong S. Lu evaluated against mice fed a normal laboratory diet. Histological analyses revealed
(hong.lu@uky.edu)
Hisashi Sawada that steatosis was detected as early as 14 days of WD feeding. Bulk RNA sequencing
(hisashi.sawada@uky.edu) demonstrated that WD feeding altered liver transcriptomes related to inflammation
Citation: Pettey AC, Ye D, and cell adhesion consistent with the progression of liver steatosis. Previous studies
Ito S, Daugherty A, Lu HS, determined that hepatocyte-specific deficiency of angiotensinogen (AGT), the
Sawada H. Hepatocyte-specific unique substrate of the renin-angiotensin system (RAS), alleviates WD-induced
angiotensinogen deficiency
inhibits Western diet-induced liver hepatic steatosis in mice. However, the effects of hepatic AGT deficiency were not
steatosis with suppression of cell mimicked by pharmacological inhibition of the RAS, and the molecular mechanisms
division in mice. Global Transl Med. by which AGT deficiency protects against WD-induced steatosis is unknown.
2025;4(2):71-85.
doi: 10.36922/gtm.6027 Therefore, liver transcriptomes were compared between hepatocyte-specific
AGT-deficient mice (hepAGT -/-) and their wild-type littermates (hepAGT +/+) after
Received: November 16, 2024
14 days of WD feeding. Gene ontology analyses showed that upregulated genes in
1st revised: February 12, 2025 hepAGT -/- mice were enriched for metabolic processes and downregulated genes
2nd revised: March 24, 2025 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
Accepted: March 25, 2025
were primarily associated with cell division processes in hepAGT +/+ mice and were
Published online: April 10, 2025 suppressed in hepAGT -/- mice. In conclusion, hepatic AGT deficiency downregulated
Copyright: © 2025 Author(s). genes related to cell division during the progression of liver steatosis.
This is an Open-Access article
distributed under the terms of the
Creative Commons Attribution Keywords: Angiotensinogen; Liver steatosis; Obesity; Transcriptomic analysis
License, permitting distribution,
and reproduction in any medium,
provided the original work is
properly cited.
Publisher’s Note: AccScience 1. Introduction
Publishing remains neutral with Liver steatosis, characterized by excess lipid accumulation within hepatocytes, is a
regard to jurisdictional claims in 1-5
published maps and institutional common hepatic disease that is prevalent worldwide. Liver steatosis represents an
6
affiliations. independent risk factor for chronic liver diseases and many cardiovascular diseases.

Volume 4 Issue 2 (2025) 71 doi: 10.36922/gtm.6027