cover image: Normalization of hepatic ChREBP activity does not protect against liver disease progression in a mouse model for Glycogen Storage Disease type Ia

Normalization of hepatic ChREBP activity does not protect against liver disease progression in a mouse model for Glycogen Storage Disease type Ia

1 Dec 2023

Background Glycogen storage disease type 1a (GSD Ia) is an inborn error of metabolism caused by a defect in glucose-6-phosphatase (G6PC1) activity, which induces severe hepatomegaly and increases the risk for liver cancer. Hepatic GSD Ia is characterized by constitutive activation of Carbohydrate Response Element Binding Protein (ChREBP), a glucose-sensitive transcription factor. Previously, we showed that ChREBP activation limits non-alcoholic fatty liver disease (NAFLD) in hepatic GSD Ia. As ChREBP has been proposed as a pro-oncogenic molecular switch that supports tumour progression, we hypothesized that ChREBP normalization protects against liver disease progression in hepatic GSD Ia. Methods Hepatocyte-specific G6pc knockout (L- G6pc −/− ) mice were treated with AAV-shChREBP to normalize hepatic ChREBP activity. Results Hepatic ChREBP normalization in GSD Ia mice induced dysplastic liver growth, massively increased hepatocyte size, and was associated with increased hepatic inflammation. Furthermore, nuclear levels of the oncoprotein Yes Associated Protein (YAP) were increased and its transcriptional targets were induced in ChREBP-normalized GSD Ia mice. Hepatic ChREBP normalization furthermore induced DNA damage and mitotic activity in GSD Ia mice, while gene signatures of chromosomal instability, the cytosolic DNA-sensing cGAS-STING pathway, senescence, and hepatocyte dedifferentiation emerged. Conclusions In conclusion, our findings indicate that ChREBP activity limits hepatomegaly while decelerating liver disease progression and protecting against chromosomal instability in hepatic GSD Ia. These results disqualify ChREBP as a therapeutic target for treatment of liver disease in GSD Ia. In addition, they underline the importance of establishing the context-specific roles of hepatic ChREBP to define its therapeutic potential to prevent or treat advanced liver disease.

Authors

Martijn Rutten, Yu Lei, Joanne Hoogerland, Vincent Bloks, Hong Yang, Trijnie Bos, Kishore Krishnamurthy, Aycha Bleeker, Mirjam Koster, Rachel Thomas, Justina Wolters, Hilda van den Bos, Gilles Mithieux, Fabienne Rajas, Adil Mardinoglu, Diana Spierings, Alain de Bruin, Bart van de Sluis, Maaike Oosterveer

Related Organizations

European Union
Royal Institute of Technology
Stockholm University
Bibliographic Reference
Martijn Rutten, Yu Lei, Joanne Hoogerland, Vincent Bloks, Hong Yang, et al.. Normalization of hepatic ChREBP activity does not protect against liver disease progression in a mouse model for Glycogen Storage Disease type Ia. Cancer & metabolism / Cancer Metab, 2023, 11 (1), pp.5. ⟨10.1186/s40170-023-00305-3⟩. ⟨inserm-04082460⟩
DOI
https://doi.org/10.1186/s40170-023-00305-3
HAL Collection
['INSERM - Institut national de la santé et de la recherche médicale', 'Université Claude Bernard - Lyon I', 'UDL', 'Université de Lyon']
HAL Identifier
4082460
Institution
['University Medical Center Groningen [Groningen]', 'KTH Royal Institute of Technology [Stockholm]', 'University of Groningen [Groningen]', 'Universiteit Utrecht', 'Utrecht University [Utrecht]', 'Université Claude Bernard Lyon 1', 'Institut National de la Santé et de la Recherche Médicale']
Laboratory
Nutrition, diabète et cerveau
Published in
France

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