Beneficial effects of mineralocorticoid receptor blockade in experimental non‐alcoholic steatohepatitis
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Background: Therapeutic options to treat N on‐alcoholic steatohepatitis (NASH) are limited. Mineralocorticoid receptor (MR) activation could play a role in hepatic fibrogenesis and its modulation could be beneficial for NASH. Aim: To investigate whether eplerenone, a specific MR antagonist, ameliorates liver damage in experimental NASH. Methods: C57bl6 mice were fed a choline‐deficient and amino acid‐defined (CDAA) diet for 22 weeks with or without eplerenone supplementation. Serum levels of aminotransferases and aldosterone were measured and hepatic steatosis, inflammation and fibrosis scored histologically. Hepatic triglyceride content (HTC) and hepatic mRNA levels of pro‐inflammatory pro‐fibrotic, oxidative stress‐associated genes and of MR were also assessed. Results: CDAA diet effectively induced fibrotic NASH, and increased the hepatic expression of pro‐inflammatory, pro‐fibrotic and oxidative stress‐associated genes. Hepatic MR mRNA levels significantly correlated with the expression of pro‐inflammatory and pro‐fibrotic genes and were significantly increased in hepatic stellate cells obtained from CDAA‐fed animals. Eplerenone administration was associated to a reduction in histological steatosis and attenuation of liver fibrosis development, which was associated to a significant decrease in the expression of collagen‐α1, collagen type III, alpha 1 and M atrix metalloproteinase‐2. Conclusion: The expression of MR correlates with inflammation and fibrosis development in experimental NASH. Specific MR blockade with eplerenone has hepatic anti‐steatotic and anti‐fibrotic effects. These data identify eplerenone as a potential novel therapy for NASH. Considering its safety and FDA‐approved status, human studies are warranted.
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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 [30]
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- Authors
- Pizarro, M., Solís, N., Quintero, P., Barrera, F., Cabrera, D., Rojas‐de Santiago, P., Arab, J. P., Padilla, O., Roa, J. C., Moshage, H., Wree, A., Inzaugarat, E., Feldstein, A. E., Fardella, C. E., Baudrand, R., Riquelme, A., & Arrese, M.
- Affiliations
- Pontificia Universidad Católica de Chile (CL)
- Departamento de Gastroenterología Escuela de Medicina Pontificia Universidad Católica de Chile Santiago Chile
- University Medical Center Groningen (NL)
- University of California San Diego (US)
- Department of Pediatrics University of California San Diego CA USA
- Corresponding author
- Arrese, Marco
- ORCID
- Venue
- Liver International
- Publisher
- Wiley
- Published
- 2015-02-23
- Volume
- 35
- Issue
- 9
- Pages
- 2129-2138
- ISSN
- 0106-9543 (ISSN-L)
- 1478-3223
- 1478-3231
- PMC
- PMC4522413
- OpenAlex
- W2136320665
- Cited by
- 66
- References
- 45
- Citations by year
- 2026: 7 · 2025: 5 · 2024: 6 · 2023: 4 · 2022: 6 · 2021: 10 · 2020: 12 · 2019: 3 · 2018: 5 · 2017: 4 · 2016: 2 · 2015: 2
- FWCI
- 3.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Liver International (publishedVersion)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
- PubMed Central (acceptedVersion)
- Americanae (AECID Library) (submittedVersion, other-oa)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- Fondo Nacional de Desarrollo Científico y Tecnológico (1110455)
- Comisión Nacional de Investigación Científica y Tecnológica (PFB 12/2007)
- Basal Centre for Excellence in Science and Technology
- Government of Chile (R01 DK082451)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- nonalcoholic steatohepatitis, mineralocorticoid receptor blockade, eplerenone, liver fibrosis, hepatic steatosis, liver inflammation, hepatic stellate cells, oxidative stress, collagen expression, MMP-2, antifibrotic therapy
- MeSH terms
- Eplerenone, Mineralocorticoid Receptor Antagonists, Animals, Disease Models, Animal, Liver, Liver Cirrhosis, Male, Mice, Inbred C57BL, Spironolactone, Biomarkers, Receptors, Mineralocorticoid, Oxidative Stress, Mice, Non-alcoholic Fatty Liver Disease
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