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

ABSTRACT: Current peroxisome proliferator-activated receptor (PPAR)-targeted drugs, such as the PPAR?-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 PPAR? and PPAR? 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 PPAR? and PPAR?, 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.

SUBMITTER: Tiefenbach J

PROVIDER: S-EPMC6177011 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Idebenone and coenzyme Q<sub>10</sub> are novel PPARα/γ ligands, with potential for treatment of fatty liver diseases.

Tiefenbach Jens J Magomedova Lilia L Liu Jiabao J Liu Jiabao J Reunov Arkadiy A AA Tsai Ricky R Eappen Neena S NS Jockusch Rebecca A RA Nislow Corey C Cummins Carolyn L CL Krause Henry M HM

Disease models & mechanisms 20180831 9

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 Q<sub>10</sub> (idebenone) that elicits spatially restricted parti ...[more]

PMID: 30171034

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Project description:ObjectiveA role for mitochondrial dysfunction has been proposed in the immune dysregulation and organ damage characteristic of systemic lupus erythematosus (SLE). Idebenone is a coenzyme Q10 synthetic quinone analog and an antioxidant that has been used in humans to treat diverse diseases in which mitochondrial function is impaired. This study was undertaken to assess whether idebenone ameliorates lupus in murine models.MethodsIdebenone was administered orally to MRL/lpr mice at 2 different doses (1 gm/kg or 1.5 gm/kg idebenone-containing diet) for 8 weeks. At peak disease activity, clinical, immunologic, and metabolic parameters were analyzed and compared to those in untreated mice (n = 10 per treatment group). Results were confirmed in the lupus-prone NZM2328 mouse model.ResultsIn MRL/lpr mice, idebenone-treated mice showed a significant reduction in mortality incidence (P < 0.01 versus untreated mice), and the treatment attenuated several disease features, including glomerular inflammation and fibrosis (each P < 0.05 versus untreated mice), and improved renal function in association with decreased renal expression of interleukin-17A (IL-17A) and mature IL-18. Levels of splenic proinflammatory cytokines and inflammasome-related genes were significantly decreased (at least P < 0.05 and some with higher significance) in mice treated with idebenone, while no obvious drug toxicity was observed. Idebenone inhibited neutrophil extracellular trap formation in neutrophils from lupus-prone mice (P < 0.05) and human patients with SLE. Idebenone also improved mitochondrial metabolism (30% increase in basal respiration and ATP production), reduced the extent of heart lipid peroxidation (by one-half that of untreated mice), and significantly improved endothelium-dependent vasorelaxation (P < 0.001). NZM2328 mice exposed to idebenone also displayed improvements in renal and systemic inflammation, reducing the kidney pathology score (P < 0.05), IgG/C3 deposition (P < 0.05), and the gene expression of interferon, proinflammatory, and inflammasome-related genes (at least P < 0.05 and some with higher significance).ConclusionIdebenone ameliorates murine lupus disease activity and the severity of organ damage, supporting the hypothesis that agents that modulate mitochondrial biologic processes may have a therapeutic role in human SLE.

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

Publications

Idebenone and coenzyme Q<sub>10</sub> are novel PPARα/γ ligands, with potential for treatment of fatty liver diseases.

Similar Datasets

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