Patients with Glycogen Storage Disease type 1a (GSD Ia) primarily present with life-threatening hypoglycemia and display severe liver disease characterized by hepatomegaly. Despite strict dietary management, long-term complications still occur, amongst which liver tumor development. Variations in residual glucose-6-phosphatase (G6PC1) activity likely contribute to phenotypic heterogeneity in biochemical symptoms and complications between patients. However, lack of insight into the relationship between G6PC1 activity and symptoms/complications, and poor understanding of the underlying disease mechanisms pose major challenges to provide optimal healthcare and quality of life for GSD Ia patients. Currently available GSD Ia animal models are not suitable to systematically investigate the relationship between hepatic G6PC activity and phenotypic heterogeneity, or the contribution of gene-gene interactions in the liver. To meet these needs, we generated and characterized a novel hepatocyte-specific GSD Ia mouse model using somatic CRISPR/Cas9-mediated gene editing. Hepatic G6pc editing reduced hepatic G6PC activity up to 98% and resulted in failure to thrive, fasting hypoglycemia, hypertriglyceridemia, hepatomegaly, hepatic steatosis, and increased liver tumor incidence. This approach was furthermore successful to simultaneously modulate hepatic G6PC and ChREBP, a transcription factor that is activated in GSD Ia and protects against hepatic steatosis under these conditions. Importantly, it also allowed to model a spectrum of GSD Ia phenotypes in terms of hepatic G6PC activity, fasting hypoglycemia, hypertriglyceridemia, hepatomegaly and hepatic steatosis.
In conclusion, we show that somatic CRISPR/Cas9-mediated gene editing allows to model a spectrum of hepatocyte-borne GSD Ia disease symptoms in mice, and to efficiently study gene-gene interactions in the liver. This approach opens new perspectives for translational research and will likely contribute to novel and personalized treatments for GSD Ia and other genetic liver diseases.
Read more : Hepatology: https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.32022
There is plenty of work, and yet people with a disability are still often sidelined. One plus one is two, or so you’d think: this is the perfect time to help this group of workers find a job. The intention is there, also within the University, but...
The Dutch science funding agency NWO recently awarded a large research project into new concepts for energy-efficient information technology of no less than ten million euros
On the recommendation of the Board of the University of Groningen, Dr Frans J. Sijtsma has been appointed as academic director of the Rudolf Agricola School for Sustainable Development with effect from 1 February 2023. This concerns a 0.5 FTE...
The UG website uses functional and anonymous analytics cookies. Please answer the question of whether or not you want to accept other cookies (such as tracking cookies).
If no choice is made, only basic cookies will be stored. More information