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

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.

Nonalcoholic fatty liver disease (NAFLD) is a condition in which fat builds up in your liver, resulting in inflammation and liver cell damage. A healthy lifestyle and exercise is the best prescription to prevent this from happening, but NAFLD is on the rise worldwide. Currently, there are no drug therapies for this condition. Drugs that target a protein called peroxisome proliferator-activated receptor (PPAR) have potential to improve liver function and reduce fat build up, but the drugs currently available are associated with undesirable side effects in other tissues. We generated a zebrafish model that can identify new tissue-selective potential drugs to weakly target PPAR with fewer toxic effects. We found a drug, idebenone, with structural similarities to coenzyme Q 10 , which has weak activity against two forms of the PPAR protein, PPARα and PPARγ. Testing idebenone in a mouse model of type 2 diabetes revealed the ability to reverse fatty liver development. This partial activity of idebenone against both PPARα and PPARγ, combined with its excellent safety profile in humans, demonstrates that it could be a good treatment option for nonalcoholic fatty liver disease (NAFLD). "In vivo [zebrafish] screens allow the identification of tissue-selective bioactive small molecules with good permeability, uptake, stability and delivery." What are the potential implications of these results for your field of research?
In drug discovery, the key challenge is selecting the right assay and finding compounds that can reach, and function specifically, within the intended cells, considering drug absorption, distribution and metabolism. Commonly used assays in cells or in silico cannot assess these properties. We developed a whole-animal assay that allows identification of selective compounds and provides information on a drug's effectiveness, selectivity and toxicology, as well being highly cost-effective in a live vertebrate model. We validated our zebrafish ligand trap technology and tested our findings in a mouse model of type 2 diabetes. Our results will hopefully encourage other researchers to perform screens in wholeanimal models and test their findings in rodent or clinical studies. We hope that this will identify drugs that have better chances of success in clinical trials.
What are the main advantages and drawbacks of the model system you have used as it relates to the disease you are investigating?
The zebrafish (Danio rerio) is an emerging vertebrate model for drug discovery that allows whole-animal drug screening. There are many advantages of the model. In vivo screens allow the identification of tissue-selective bioactive small molecules with good permeability, uptake, stability and delivery. Embryos develop ex utero and are optically clear, which allows the use of fluorescent reporters to pinpoint receptor activity in live animals. Embryogenesis is completed after 3 days of development and the cost to maintain zebrafish is a fraction of that of rodents or other mammalian organisms. The zebrafish model also has some disadvantages. Several mammalian organs are not present in the zebrafish, including breast tissue, lungs What has surprised you the most while conducting your research? I was most surprised by how powerful small molecules are in biology. Of course, this seems obvious, but when you study small molecules in a live transparent zebrafish embryo with fluorescent reporters you can monitor their influence on your target receptor almost in real time. Using a potent agonist in picomole concentrations, you might be under the impression there is nothing left of that compound after you did the serial dilution, but then you obtain a strong tissue-selective response. Compared to results from luciferase assays, which give you numbers, looking at the glowing embryo and monitoring the tissue-selective response is very impressive and can be surprising.
Describe what you think is the most significant challenge impacting your research at this time and how will this be addressed over the next 10 years?
The most significant challenge in drug development is to advance discovery in a way that leads to more FDA-approved drugs. Next to regulatory aspects of this timely process, I believe that selecting a drug candidate from a whole-animal model will help to improve success rates and reduce cost and time. In addition, access to good small molecule libraries is key. Purchasing drug libraries or analog molecules can be very expensive, which can delay research or result in termination of projects. Drug development would also benefit from a pooling of resources in, for example, an international drug resource center, and more open interactions between pharma labs and academic labs.
What changes do you think could improve the professional lives of early-career scientists? I think early professionals would benefit from more funding and fellowship programs granted to them directly. The application process is good training for their later careers and it would allow them to develop their own innovative ideas and try new technologies in their projects. Universities should also train scientists for a life outside academia. Mentoring throughout their training is important and will help them to find the right path for their future.

"[…]
when you study small molecules in a live transparent zebrafish embryo with fluorescent reporters you can monitor their influence on your target receptor almost in real time." What's next for you?
In addition to my interest in metabolic syndromes, I am interested in the relationship between health, lifestyle, sleep and circadian rhythm in the development of human diseases. Novel drug-discovery techniques targeting cellular circadian rhythm in a specific disease background are needed to improve the treatment options for many major diseases such as depression, autism and drug addiction, as well as certain types of cancer. Recently, I developed assays that relate, in part, to the discovery that the activity of a clock protein is surprisingly impaired under conditions of disrupted circadian rhythm when compared with its activity levels under normal conditions. This discovery was transferred into screening assays in our fish model. Initial screens identified drugs that work under either normal or disrupted rhythm. I now have completed my term at the University of Toronto and incorporated a life science company with a focus on chronobiology disorders. My aim is to discover selective drugs for clock protein-related diseases to help provide solutions for the treatment of autism, addiction and other neurological disorders.