Early diet-induced non-alcoholic steatohepatitis in APOE2 knock-in mice and its prevention by fibrates
Open accessAbstract
Background/aims The molecular mechanisms leading to Non-Alcoholic Steatohepatitis (NASH) are not fully understood. In mice, NASH can be inhibited by fenofibrate, a synthetic agonist for the nuclear receptor peroxisome proliferator activated receptor alpha, which regulates hepatic triglyceride metabolism. This study aimed to elucidate the relation between steatosis and inflammation in NASH in a human-like hyperlipidemic mouse model.Methods Liver phenotype and gene expression were assessed in APOE2 knock-in mice that were fed a western-type high fat diet with or without co-administration of fenofibrate.Results In response to a western diet, APOE2 knock-in mice developed NASH characterized by steatosis and inflammation. Strikingly, macrophage accumulation in the liver preceded the steatosis during progression of the disease. This phenotype was in line with gene expression patterns, which showed regulation of two major groups of genes, i.e. inflammatory and lipid genes. Fenofibrate treatment decreased hepatic macrophage accumulation and abolished steatosis. Moreover, a marked reduction in the expression of inflammatory genes occurred immediately after fenofibrate treatment.Conclusions These data indicate that inflammation might play an instrumental role during the development of NASH in this mouse model. Inhibition of NASH by fenofibrate may be due, at least in part, to its inhibitory effect on pro-inflammatory genes.
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Although fibrates are effective for improvement of NAFLD in animals, their efficacy in clinical settings is not established.
“Although fibrates were effective for improvement of NAFLD in animals [103–105], their efficacy in clinical settings is not established.”
From Pemafibrate, a new selective PPARα modulator: drug concept and its clinical applications for dyslipidemia and metabolic diseases (2020) · cites this paper as [104]
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- Authors
- Shiri-Sverdlov, R., Wouters, K., Gorp, P. J. V., Gijbels, M. J., Noel, B., Buffat, L., Staels, B., Maeda, N., Bilsen, M. V., & Hofker, M. H.
- Affiliations
- Maastricht University (NL)
- Inserm (FR)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Hofker, Marten H.
- ORCID
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2006-04
- Volume
- 44
- Issue
- 4
- Pages
- 732-741
- ISSN
- 0168-8278 (ISSN-L)
- OpenAlex
- W1978805605
- Cited by
- 241
- References
- 35
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2023: 8 · 2022: 11 · 2021: 7 · 2020: 9 · 2019: 6 · 2018: 70 · 2017: 11 · 2016: 15 · 2015: 11 · 2014: 14 · 2013: 8 · 2012: 12
- FWCI
- 4.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, other-oa)
- Pure Amsterdam UMC (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL 42630)
- 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, fenofibrate, fibrates, PPARα, hepatic steatosis, liver inflammation, high-fat diet, hyperlipidemia, inflammatory gene expression, lipid metabolism
- MeSH terms
- Progranulins, Animals, Hypolipidemic Agents, Apolipoproteins E, Clofibric Acid, Dietary Fats, Disease Models, Animal, Fatty Liver, Female, Hyperlipidemias, Immunohistochemistry, Inflammation, Liver, Macrophages, Phospholipases A, Fenofibrate, Stearoyl-CoA Desaturase, Gene Expression, Mice, Knockout, Disease Progression, ATP-Binding Cassette Transporters, Vascular Cell Adhesion Molecule-1, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Intercellular Signaling Peptides and Proteins, Peroxisome Proliferator-Activated Receptors, Mice, Apolipoprotein E2
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