PUBLICATION
Idebenone and coenzyme Q10 are novel PPARα/γ ligands, with potential for treatment of fatty liver diseases.
- Authors
- Tiefenbach, J., Magomedova, L., Liu, J., Reunov, A.A., Tsai, R., Eappen, N.S., Jockusch, R.A., Nislow, C., Cummins, C.L., Krause, H.M.
- ID
- ZDB-PUB-180902-5
- Date
- 2018
- Source
- Disease models & mechanisms 11(9): (Journal)
- Registered Authors
- Krause, Henry, Tiefenbach, Jens
- Keywords
- Drug discovery, Fatty liver disease, Idebenone, Nuclear receptors, Zebrafish
- MeSH Terms
-
- 3T3-L1 Cells
- Animals
- Animals, Genetically Modified
- Benzoquinones/chemistry
- Benzoquinones/pharmacology
- Benzoquinones/therapeutic use
- Drug Evaluation, Preclinical
- HEK293 Cells
- Humans
- Ligands
- Lipid Metabolism/drug effects
- Liver/drug effects
- Liver/metabolism
- Liver/pathology
- Male
- Mice
- Mice, Inbred C57BL
- Non-alcoholic Fatty Liver Disease/drug therapy*
- PPAR alpha/agonists
- PPAR alpha/metabolism*
- PPAR gamma/agonists
- PPAR gamma/metabolism*
- Ubiquinone/analogs & derivatives*
- Ubiquinone/chemistry
- Ubiquinone/pharmacology
- Ubiquinone/therapeutic use
- Zebrafish
- PubMed
- 30171034 Full text @ Dis. Model. Mech.
Citation
Tiefenbach, J., Magomedova, L., Liu, J., Reunov, A.A., Tsai, R., Eappen, N.S., Jockusch, R.A., Nislow, C., Cummins, C.L., Krause, H.M. (2018) Idebenone and coenzyme Q10 are novel PPARα/γ ligands, with potential for treatment of fatty liver diseases.. Disease models & mechanisms. 11(9):.
Abstract
Current peroxisome proliferator-activated receptor (PPAR)-targeted drugs, such as the PPARγ-directed diabetes drug rosiglitazone, are associated with undesirable side effects due to robust agonist activity in non-target tissues. To find new PPAR ligands with fewer toxic effects, we generated transgenic zebrafish that can be screened in high throughput for new tissue-selective PPAR partial agonists. A structural analog of coenzyme Q10 (idebenone) that elicits spatially restricted partial agonist activity for both PPARα and PPARγ was identified. Coenzyme Q10 was also found to bind and activate both PPARs in a similar fashion, suggesting an endogenous role in relaying the states of mitochondria, peroxisomes and cellular redox to the two receptors. Testing idebenone in a mouse model of type 2 diabetes revealed the ability to reverse fatty liver development. These findings indicate new mechanisms of action for both PPARα and PPARγ, and new potential treatment options for nonalcoholic fatty liver disease (NAFLD) and steatosis.This article has an associated First Person interview with the first author of the paper.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping