Comparative Evaluation of Gemcabene and Peroxisome Proliferator–Activated Receptor Ligands in Transcriptional Assays of Peroxisome Proliferator–Activated Receptors
| Autor: | Bisgaier Cl, Srivastava Rak, Oniciu Dc |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
PPAR-δ
0301 basic medicine Agonist PPAR-γ medicine.drug_class Peroxisome Proliferator-Activated Receptors nuclear hormone receptors Peroxisome proliferator-activated receptor Hyperlipidemias Pharmacology Ligands Transfection GW0742 Cell Line Muraglitazar Mice 03 medical and health sciences Transactivation 0302 clinical medicine Species Specificity transactivation medicine Animals Humans Receptor Caproates Hypolipidemic Agents chemistry.chemical_classification Dose-Response Relationship Drug Chemistry Lipids Rats gemcabene 030104 developmental biology Mechanism of action Cardiovascular Diseases 030220 oncology & carcinogenesis Original Article lipids (amino acids peptides and proteins) medicine.symptom Cardiology and Cardiovascular Medicine Rosiglitazone PPAR-α Signal Transduction medicine.drug |
| Zdroj: | Journal of Cardiovascular Pharmacology |
| ISSN: | 0160-2446 |
| Popis: | Gemcabene, a late-stage clinical candidate, has shown efficacy for LDL-C, non-HDL cholesterol, apoB, triglycerides, and hsCRP reduction, all risk factors for cardiovascular disease. In rodents, gemcabene showed changes in targets, including apoC-III, apoA-I, peroxisomal enzymes, considered regulated through peroxisome proliferator–activated receptor (PPAR) gene activation, suggesting a PPAR-mediated mechanism of action for the observed hypolipidemic effects observed in rodents and humans. In the current study, the gemcabene agonist activity against PPAR subtypes of human, rat, and mouse were compared with known lipid lowering PPAR activators. Surprisingly, gemcabene showed no or little PPAR-α transactivation compared with reference agonists, which showed concentration-dependent transactivation against human PPAR-α of 2.4- to 30-fold (fenofibric acid), 17-fold (GW590735), and 2.3- to 25-fold (WY-14643). These agents also showed robust transactivation of mouse and rat PPAR-α in a concentration-dependent manner. The known PPAR-δ agonists, GW1516, L165041, and GW0742, showed potent agonist activity against human, mouse, and rat receptors (ranging from 165- to 396-fold). By contrast, gemcabene at the highest concentration tested (300 μM) showed no response in mouse and rat and a marginal response against human PPAR-δ receptors (3.2-fold). For PPAR-γ, gemcabene showed no agonist activity against all 3 species at 100 μM and marginal activity (3.6- to 5-fold) at 300 μM. By contrast, the known agonists, rosiglitazone, indomethacin, and muraglitazar showed strong activation against the mouse, rat, and human PPAR-γ receptors. No clear antagonist activity was observed with gemcabene against any PPAR subtypes for all 3 species over a wide range of concentrations. In summary, the transactivation studies rule out gemcabene as a direct agonist or antagonist of PPAR-α, PPAR-γ, and PPAR-δ receptors of these 3 species. These data suggest that the peroxisomal effects observed in rodents and the lipid regulating effects observed in rodents and humans are not related to a direct activation of PPAR receptors by gemcabene. |
| Databáze: | OpenAIRE |
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