Novel organoid models to study non-alcoholic fatty liver disease
Researchers from the Organoid group (former Clevers group, Hubrecht Institute) together with researchers from the Princess Máxima Center for pediatric oncology established novel human Organoids models of fatty liver disease. They used these models to shed light on drug responses, and established a CRISPR-screening platform to identify novel disease mediators and potential therapeutic targets. These models will aid in testing and developing novel medicines to treat fatty liver disease and help to get a better understanding of the disease biology. The results of the study were published in Nature Biotechnology on the 23rd of February, 2023.
Fatty liver
The buildup of fat in the liver is an increasingly common disease worldwide, with over a quarter of the worldwide population affected. Having a fatty liver can lead to inflammation, impairment of liver function, and eventually result in scar tissue formation. Different causes can lead to the development of fatty liver, with diet and lifestyle being the most common contributors. Moreover, genetics can play an important role. For example, genetic lipid disorders make patients more likely to develop fatty liver disease and several mutations heighten the risk to develop the disease.
No therapy
Worryingly, no treatment for fatty liver currently exists that can halt or revert the disease. As the disease progresses, the risk of irreversible liver damage and the need for liver transplantation greatly increases. In addition, individuals with fatty liver are at heightened risk to develop liver cancer. Identifying ways to tackle the disease is very challenging due to the scarcity of model systems. 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.
Figure 1: Modelling a genetic lipid disorder leads to the development of spontaneous fatty liver organoids. Lipids are depth-colored. Credit: Delilah Hendriks & Benedetta Artegiani. Copyright: Hubrecht Institute.
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.
Discovery of novel drug targets
Het onderzoeksteam testte vervolgens een groot aantal mogelijke medicijnen op de nieuwe organoïden om leververvetting te behandelen. De onderzoekers deden de interessante observatie dat de verschillende model-organoïden van leververvetting zeer vergelijkbaar reageerden op de medicijnen. Op deze manier identificeerden ze een aantal medicijnen die heel effectief waren in het verhelpen van de vetophopingen. Opvallend genoeg werkten al deze effectieve medicijnen door een gemeenschappelijk mechanisme waarbij de opbouw van vetten uit suikers voorkomen wordt. Ondanks de overeenkomsten tussen de verschillende modellen waren er ook verschillen. De organoïden met de meest voorkomende risicomutatie bleken anders te reageren op sommige medicijnen dan organoïden zonder deze mutatie. Dit resultaat laat zien dat organoïden gebruikt kunnen worden om gepersonaliseerde therapieën te ontwikkelen.
CRISPR-platform
De onderzoekers gebruikten hun organoïden vervolgens om een CRISPR-platform, genaamd FatTracer, op te zetten waarmee ze nieuwe genen konden ontdekken die een rol spelen bij het ontstaan van leververvetting. Met dit platform bekeken de onderzoekers 20 dagen lang het verloop van leververvetting in de afwezigheid van 35 specifieke genen. Hierdoor ontdekten de onderzoekers dat het gen FADS2 een tot voorheen onbekende en cruciale rol speelt bij leververvetting. Verlies van het gen leidt tot een sterke vervetting van de organoïden. Het team vroeg zich vervolgens af of het tegenovergestelde, een toename van FADS2, juist gunstig is voor het verloop van de ziekte. Na verhoging van de FADS2 niveaus in de organoïden zagen de onderzoekers dat de vervetting inderdaad sterk verminderd was. Dit suggereert dat het gen mogelijk een doelwit kan zijn voor nieuwe therapieën.
Future directions
These novel fatty liver organoid models pave the way for many future directions. For example, the researchers would like to better understand the genetic risks that are linked to the development of fatty liver, as well as to study what factors influence disease progression. The ultimate aim is to use these models to define (personalized) drug therapies that can cure the liver from fat overload.
This work was done together in collaboration with Avans University of Applied Sciences, Maastricht University, and Leiden University Medical Center.
Source: Hubrecht Institute
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