| Autor: |
Willems, S., Gellrich, L., Chaikuad, A., Kluge, S., Werz, O., Heering, J., Knapp, S., Lorkowski, S., Schubert-Zsilavecz, M., Merk, D. |
| Přispěvatelé: |
Publica |
| Jazyk: |
angličtina |
| Rok vydání: |
2021 |
| Popis: |
Vitamin E exhibits pharmacological effects beyond established antioxidant activity suggesting involvement of unidentified mechanisms. Here, we characterize endogenously formed tocopherol carboxylates and the vitamin E mimetic garcinoic acid (GA) as activators of the peroxisome proliferator-activated receptor gamma (PPARg). Co-stimulation of PPARg with GA and the orthosteric agonist pioglitazone resulted in additive transcriptional activity. In line with this, the PPARg-GA complex adopted a fully active conformation and interestingly contained two bound GA molecules with one at an allosteric site. A co-regulator interaction scan demonstrated an unanticipated co-factor recruitment profile for GA-bound PPARg compared with canonical PPARg agonists and gene expression analysis revealed different effects of GA and pioglitazone on PPAR signaling in hepatocytes. These observations reveal allosteric mechanisms of PPARg modulation as an alternative avenue to PPARg targeting and suggest contributions of PPARg activation by a-13-tocopherolcarboxylate to the pharmacological effects of vitamin E. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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