Profiling of hepatic gene expression in rats treated with fibric acid analogs
| Autor: | Angus T. De Souza, Paul D. Cornwell, Roger G. Ulrich |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Male
medicine.medical_specialty Peroxisome proliferator-activated receptor gamma medicine.drug_class Health Toxicology and Mutagenesis Peroxisome proliferator-activated receptor Peroxisome Proliferation Fibrate Biology Fenofibrate Internal medicine Genetics medicine Animals Receptor Molecular Biology chemistry.chemical_classification Gene Expression Profiling Body Weight Fatty acid Organ Size Rats Endocrinology chemistry Liver Peroxisome proliferator-activated receptor alpha medicine.drug |
| Zdroj: | Mutation research. 549(1-2) |
| ISSN: | 0027-5107 |
| Popis: | Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptors whose ligands include fatty acids, eicosanoids and the fibrate class of drugs. In humans, fibrates are used to treat dyslipidemias. In rodents, fibrates cause peroxisome proliferation, a change that might explain the observed hepatomegaly. In this study, rats were treated with multiple dose levels of six fibric acid analogs (including fenofibrate) for up to two weeks. Pathological analysis identified hepatocellular hypertrophy as the only sign of hepatotoxicity, and only one compound at the highest dose caused any significant increase in serum ALT or AST activity. RNA profiling revealed that the expression of 1288 genes was related to dose or length of treatment and correlated with hepatocellular hypertrophy. This gene list included expression changes that were consistent with increased mitochondrial and peroxisomal β-oxidation, increased fatty acid transport, increased hepatic uptake of LDL-cholesterol, decreased hepatic uptake of glucose, decreased gluconeogenesis and decreased glycolysis. These changes are likely linked to many of the clinical benefits of fibrate drugs, including decreased serum triglycerides, decreased serum LDL-cholesterol and increased serum HDL-cholesterol. In light of the fact that all six compounds stimulated similar or identical changes in the expression of this set of 1288 genes, these results indicate that hepatomegaly is due to PPARα activation, although signaling through other receptors (e.g. PPARγ, RXR) or through non-receptor pathways cannot be excluded. |
| Databáze: | OpenAIRE |
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