Endogenous vitamin E metabolites mediate allosteric PPARγ activation with unprecedented co-regulatory interactions.
Allosteric Regulation
/ drug effects
Animals
Benzopyrans
/ chemistry
Binding Sites
Crystallography, X-Ray
Hep G2 Cells
Humans
Ligands
Molecular Dynamics Simulation
PPAR gamma
/ agonists
Pioglitazone
/ chemistry
Protein Binding
Receptors, Cytoplasmic and Nuclear
/ chemistry
Signal Transduction
/ drug effects
Transcriptome
/ drug effects
Vitamin E
/ chemistry
NASH
allosterism
garcinoic acid
metabolic syndrome
natural product
non-alcoholic steatohepatitis
nuclear receptor
peroxisome proliferator-activated receptor
tocopherol
transcription factor
Journal
Cell chemical biology
ISSN: 2451-9448
Titre abrégé: Cell Chem Biol
Pays: United States
ID NLM: 101676030
Informations de publication
Date de publication:
21 10 2021
21 10 2021
Historique:
received:
16
11
2020
revised:
29
03
2021
accepted:
23
04
2021
pubmed:
15
5
2021
medline:
4
1
2022
entrez:
14
5
2021
Statut:
ppublish
Résumé
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 (PPARγ). Co-stimulation of PPARγ with GA and the orthosteric agonist pioglitazone resulted in additive transcriptional activity. In line with this, the PPARγ-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 PPARγ compared with canonical PPARγ agonists and gene expression analysis revealed different effects of GA and pioglitazone on PPAR signaling in hepatocytes. These observations reveal allosteric mechanisms of PPARγ modulation as an alternative avenue to PPARγ targeting and suggest contributions of PPARγ activation by α-13-tocopherolcarboxylate to the pharmacological effects of vitamin E.
Identifiants
pubmed: 33989565
pii: S2451-9456(21)00212-9
doi: 10.1016/j.chembiol.2021.04.019
pii:
doi:
Substances chimiques
Benzopyrans
0
Ligands
0
PPAR gamma
0
Receptors, Cytoplasmic and Nuclear
0
garcinoic acid
0
Vitamin E
1406-18-4
Pioglitazone
X4OV71U42S
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1489-1500.e8Informations de copyright
Copyright © 2021 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests O.W. is an inventor of the patent WO/2017/032881 on tocotrienole derivatives related to 5-LOX. The authors declare no other competing interests.