Eplerenone ameliorates the phenotypes of metabolic syndrome with NASH in liver-specific SREBP-1c Tg mice fed high-fat and high-fructose diet
Abstract
Because the renin-angiotensin-aldosterone system has been implicated in the development of insulin resistance and promotion of fibrosis in some tissues, such as the vasculature, we examined the effect of eplerenone, a selective mineralocorticoid receptor (MR) antagonist, on nonalcoholic steatohepatitis (NASH) and metabolic phenotypes in a mouse model reflecting metabolic syndrome in humans. We adopted liver-specific transgenic (Tg) mice overexpressing the active form of sterol response element binding protein-1c (SREBP-1c) fed a high-fat and fructose diet (HFFD) as the animal model in the present study. When wild-type (WT) C57BL/6 and liver-specific SREBP-1c Tg mice grew while being fed HFFD for 12 wk, body weight and epididymal fat weight increased in both groups with an elevation in blood pressure and dyslipidemia. Glucose intolerance and insulin resistance were also observed. Adipose tissue hypertrophy and macrophage infiltration with crown-like structure formation were also noted in mice fed HFFD. Interestingly, the changes noted in both genotypes fed HFFD were significantly ameliorated with eplerenone. HFFD-fed Tg mice exhibited the histological features of NASH in the liver, including macrovesicular steatosis and fibrosis, whereas HFFD-fed WT mice had hepatic steatosis without apparent fibrotic changes. Eplerenone effectively ameliorated these histological abnormalities. Moreover, the direct suppressive effects of eplerenone on lipopolysaccharide-induced TNFα production…
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Several genes were previously connected with fatty liver disease such as Nr3c1, Nr3c2, Zbtb16, Dnmt1, and Keap1, but most of the top genes had no connections with liver disease or NASH.
“Several genes were previously connected with fatty liver disease such as the glucocorticoid receptor Nr3c128,29, the mineralocorticoid receptor Nr3c230,31, the transcription factor Zbtb1632, the DNA methyltransferase Dnmt133, and the E3 ubiquitin ligase adaptor Keap134,35, but most of the top genes had no connections with liver disease or NASH.”
From Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease (2023) · cites this paper as [31]
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- Authors
- Wada, T., Miyashita, Y., Sasaki, M., Aruga, Y., Nakamura, Y., Ishii, Y., Sasahara, M., Kanasaki, K., Kitada, M., Koya, D., Shimano, H., Tsuneki, H., & Sasaoka, T.
- Affiliations
- Department of Clinical Pharmacology and
- University of Toyama (JP)
- Kanazawa Medical University (JP)
- University of Tsukuba (JP)
- Corresponding author
- Sasaoka, Toshiyasu
- ORCID
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2013-12-01
- Volume
- 305
- Issue
- 11
- Pages
- E1415-E1425
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- OpenAlex
- W2170063399
- Cited by
- 79
- References
- 41
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 6 · 2023: 4 · 2022: 7 · 2021: 7 · 2020: 9 · 2019: 8 · 2018: 3 · 2017: 5 · 2016: 6 · 2015: 10 · 2014: 5
- FWCI
- 5.08
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (23790381, 25293093)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- eplerenone, nonalcoholic steatohepatitis, metabolic syndrome, SREBP-1c, high-fat high-fructose diet, mineralocorticoid receptor antagonists, insulin resistance, hepatic steatosis, liver fibrosis, Kupffer cells, macrophages, TNF-α, lipopolysaccharide, inflammation, adipose tissue hypertrophy, renin-angiotensin-aldosterone system
- MeSH terms
- Eplerenone, Mineralocorticoid Receptor Antagonists, Animals, Cells, Cultured, Dietary Carbohydrates, Fatty Liver, Fructose, Liver, Male, Mice, Inbred C57BL, Mice, Transgenic, Phenotype, Spironolactone, Rats, Wistar, Metabolic Syndrome, Mice, Rats, Sterol Regulatory Element Binding Protein 1, Diet, High-Fat, Non-alcoholic Fatty Liver Disease
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