New Organoid Models Shed Insights into Non-alcoholic Fatty Liver Disease

Mice differ greatly in their metabolism and can therefore not be used as a representative model system of the human disease. Moreover, current human-based in vitro models possess several drawbacks. Genetic modification of these models is difficult and it is currently impossible to quickly generate large numbers of cells.

Fatty Liver Organoids

Now, the researchers turned to organoids to establish three models that capture different triggers of fatty liver development. Firstly, they “fed” the organoids with 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 top risk mutation for fatty liver disease into their organoid system using a new CRISPR tool named prime editing. Organoids with this mutation displayed much more severe fat accumulation than organoids without it.

Finally, the researchers also modeled genetic lipid disorders using CRISPR-Cas9 to investigate how these disorders influence the development of fatty liver disease. These mutant organoids spontaneously developed severe fatty livers as a result of a build-up of sugar-derived fats.

The team then screened a large number of drug candidates to treat fatty liver disease on the newly developed organoid models. Interestingly, the researchers observed that the different fatty liver organoid models responded to the drugs in a very comparable manner.

Doing so, they identified a subset of drugs that were effective across all models. Interestingly, these effective drugs functioned by a common mechanism in which the generation of lipids from sugars was blocked. Importantly, the team also observed that organoids having the top risk mutation for fatty liver disease did not react to all drugs in the same way as organoids without the mutation. This shows the organoids can be used as a tool for personalized medicine.

CRISPR Platform

The researchers went on to use their organoid models to establish a genetic screening platform to identify novel genes with roles in fatty liver disease. The researchers turned their organoids into a CRISPR-screening platform, named FatTracer.

They used this platform to investigate the effect of loss of specific genes on the fatty liver phenotype, which could be visualized in real-time over 20 days. After screening of 35 candidates, a novel and critical role for the FADS2 gene (fatty acid desaturase 2) in fatty liver disease was discovered. Disruption of FADS2 made the organoids much more fatty.

The team wondered whether the opposite condition, having more FADS2, would instead be beneficial to the disease. Indeed, when overexpressing FADS2, the fatty liver that the organoids once displayed was severely reduced, suggesting it is a potential novel therapeutic target.

The ultimate aim is to use these models to define (personalized) drug therapies that can cure the liver from fat overload.

Source: Eurekalert