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

Non-alcoholic Fatty Liver Disease/drug therapy*
Animals
PPAR gamma/agonists
PPAR gamma/metabolism*
Animals, Genetically Modified
PPAR alpha/agonists
PPAR alpha/metabolism*
Ligands
Mice
HEK293 Cells
Liver/drug effects
Liver/metabolism
Liver/pathology
Drug Evaluation, Preclinical
Mice, Inbred C57BL
Lipid Metabolism/drug effects
Zebrafish
3T3-L1 Cells
Humans
Ubiquinone/analogs & derivatives*
Ubiquinone/chemistry
Ubiquinone/pharmacology
Ubiquinone/therapeutic use
Benzoquinones/chemistry
Benzoquinones/pharmacology
Benzoquinones/therapeutic use
Male

(all 27)

PubMed

30171034 Full text @ Dis. Model. Mech.

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

Figures

Show all Figures

Expression

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
zf2021Tg	chemical treatment by environment: coenzyme Q10	Long-pec	whole organism EGFP expression increased amount, abnormal	Fig. 3
zf2021Tg	chemical treatment by environment: idebenone	Long-pec	whole organism EGFP expression increased amount, abnormal	Fig. 3
zf225Tg	chemical treatment by environment: 10-Hydroxycamptothecin	Long-pec	whole organism EGFP expression increased amount, abnormal	Fig. 2
zf225Tg	chemical treatment by environment: bexarotene	Long-pec	whole organism EGFP expression increased amount, abnormal	Fig. 2
zf225Tg	chemical treatment by environment: capsaicin	Long-pec	whole organism EGFP expression increased amount, abnormal	Fig. 2
zf225Tg	chemical treatment by environment: coenzyme Q10	Long-pec	blood EGFP expression increased amount, abnormal	Fig. 3
zf225Tg	chemical treatment by environment: coenzyme Q10	Long-pec	central nervous system EGFP expression increased amount, abnormal	Fig. 3
zf225Tg	chemical treatment by environment: coenzyme Q10	Long-pec	epidermis EGFP expression increased amount, abnormal	Fig. 3
zf225Tg	chemical treatment by environment: coenzyme Q10	Long-pec	spinal cord posterior region EGFP expression increased amount, abnormal	Fig. 3
zf225Tg	chemical treatment by environment: ubiquinone-2	Long-pec	blood EGFP expression increased amount, abnormal	Fig. 3

1 - 10 of 46

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
a9		Complex	mpv17
w2		Point Mutation	mitfa
zf225Tg	Tg(hsp70l:GAL4-Hsa.PPARG,14xUAS-E1B:NLS-EGFP)	Transgenic Insertion
zf2021Tg	Tg(hsp70l:GAL4-Hsa.PPARA,14xUAS-E1B:NLS-EGFP)	Transgenic Insertion
zf2022Tg	Tg(hsp70l:GAL4-Hsa.PPARD,14xUAS-E1B:NLS-EGFP)	Transgenic Insertion

1 - 5 of 5

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Human Disease / Model

Sequence Targeting Reagents

Fish

Fish
zf225Tg
zf2021Tg
zf2022Tg

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP
GAL4	EFG	GAL4

Mapping

Tiefenbach et al., 2018 ZDB-PUB-180902-5 PMID:30171034

Idebenone and coenzyme Q10 are novel PPARα/γ ligands, with potential for treatment of fatty liver diseases.

Tiefenbach et al., 2018

ZDB-PUB-180902-5
PMID:30171034

Idebenone and coenzyme Q₁₀ are novel PPARα/γ ligands, with potential for treatment of fatty liver diseases.