Scientists have created new models of human organoid fatty liver. They used these models to elucidate drug responses and created a CRISPR screening platform to find new disease mediators and potential therapeutic targets. These models will aid in the testing and development of new treatments for fatty liver disease, as well as a better understanding of the biology of the disease.
Researchers from the Organoid Group (formerly the Clevers Group, Hubrecht Institute) together with researchers from the Princess Maxima Center for Children’s Oncology and the conclusions of the study published in Nature Biotechnology.
Fatty liver
Fatty liver is an increasingly common disease worldwide, affecting more than a quarter of the global population. Fatty liver can lead to inflammation, damage to liver function and eventually scarring. A variety of causes can lead to fatty liver, with diet and lifestyle being the most common. In addition, genetics can play an important role. For example, genetic disorders of lipids in patients increase the likelihood of developing fatty liver, and several mutations increase the risk of developing the disease.
No therapy
Worryingly, there is currently no treatment for fatty liver that can stop or reverse the disease. As the disease progresses, the risk of irreversible liver damage and the need for a liver transplant increases significantly. In addition, individuals with fatty liver are at increased risk of developing liver cancer. Identifying ways to deal with this disease is very challenging due to the lack of model systems.
Mice vary widely in their metabolism and therefore cannot be used as a representative model system for human disease. In addition, current human-based in vitro models have several drawbacks. Genetic modification of these models is difficult and currently it is not possible to rapidly generate large numbers of cells.
Fatty liver organoids
Now, the researchers turned to organoids to create three models that capture different triggers for the development of fatty liver disease. First, they “fed” the organoids a mixture of fatty acids to mimic a Western diet and witnessed the rapid development of fatty liver organoids. As a second model, the team introduced the mutation with the highest risk for fatty liver disease into their organoid system using a new CRISPR tool called prime editing.
Organoids with this mutation showed much more severe fat accumulation than organoids without it. Finally, the researchers also modeled genetic disorders of lipids using CRISPR-Cas9 to investigate how these disorders affect the development of fatty liver disease. These mutant organoids spontaneously developed a severe fatty liver due to the accumulation of sugar-derived fats.
Discovery of new drug targets
The team then screened a large number of drug candidates for the treatment of fatty liver in the newly developed organoid models. Interestingly, the researchers observed that different models of fatty liver organoids responded to the drugs in very comparable ways. In doing so, they identified a subset of drugs that were effective across all models. Interestingly, these effective drugs worked by a common mechanism in which the formation of lipids from sugars was blocked.
Importantly, the team also observed that organoids with the highest risk of the fatty liver mutation did not respond to all drugs in the same way as organoids without the mutation. This shows that organoids can be used as a tool for personalized medicine.
The researchers went on to use their organoid models to create a genetic screening platform to identify new genes with roles in fatty liver disease. The researchers turned their organoids into a CRISPR screening platform called FatTracer.
These new fatty liver organoid models pave the way for many future directions. For example, scientists would like to better understand the genetic risks that are associated with the development of fatty liver, as well as investigate what factors influence the progression of the disease. The ultimate goal is to use these models to define (personalized) drug therapies that can cure the liver of fat overload.
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