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Normalization of he...
Normalization of hepatic ChREBP activity does not protect against liver disease progression in a mouse model for Glycogen Storage Disease type Ia
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- Rutten, Martijn G. S. (författare)
- Univ Groningen, Univ Med Ctr Groningen, Dept Pediat, Groningen, Netherlands.
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- Lei, Yu (författare)
- Univ Groningen, Univ Med Ctr Groningen, Dept Pediat, Groningen, Netherlands.
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- Hoogerland, Joanne H. H. (författare)
- Univ Groningen, Univ Med Ctr Groningen, Dept Pediat, Groningen, Netherlands.
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- Bloks, Vincent W. W. (författare)
- Univ Groningen, Univ Med Ctr Groningen, Dept Pediat, Groningen, Netherlands.
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- Yang, Hong (författare)
- KTH,Science for Life Laboratory, SciLifeLab
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- Bos, Trijnie (författare)
- Univ Groningen, Univ Med Ctr Groningen, Dept Lab Med, Groningen, Netherlands.
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- Krishnamurthy, Kishore A. A. (författare)
- Univ Groningen, Univ Med Ctr Groningen, Dept Pediat, Groningen, Netherlands.
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- Bleeker, Aycha (författare)
- Univ Groningen, Univ Med Ctr Groningen, Dept Pediat, Groningen, Netherlands.
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- Koster, Mirjam H. H. (författare)
- Univ Groningen, Univ Med Ctr Groningen, Dept Pediat, Groningen, Netherlands.
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- Thomas, Rachel E. E. (författare)
- Univ Utrecht, Fac Vet Med, Dept Biomol Hlth Sci, Utrecht, Netherlands.
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- Wolters, Justina C. C. (författare)
- Univ Groningen, Univ Med Ctr Groningen, Dept Pediat, Groningen, Netherlands.
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- van den Bos, Hilda (författare)
- Univ Groningen, Univ Med Ctr Groningen, European Res Inst Biol Ageing ERIBA, Groningen, Netherlands.
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- Mithieux, Gilles (författare)
- INSERM, U1213 Lyon, Lyon, France.;Univ Lyon, Lyon, France.;Univ Lyon 1, Villeurbanne, France.
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- Rajas, Fabienne (författare)
- INSERM, U1213 Lyon, Lyon, France.;Univ Lyon, Lyon, France.;Univ Lyon 1, Villeurbanne, France.
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- Mardinoglu, Adil (författare)
- KTH,Science for Life Laboratory, SciLifeLab
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- Spierings, Diana C. J. (författare)
- Univ Groningen, Univ Med Ctr Groningen, European Res Inst Biol Ageing ERIBA, Groningen, Netherlands.
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- de Bruin, Alain (författare)
- Univ Groningen, Univ Med Ctr Groningen, Dept Pediat, Groningen, Netherlands.;Univ Utrecht, Fac Vet Med, Dept Biomol Hlth Sci, Utrecht, Netherlands.
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- van de Sluis, Bart (författare)
- Univ Groningen, Univ Med Ctr Groningen, Dept Pediat, Groningen, Netherlands.
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- Oosterveer, Maaike H. H. (författare)
- Univ Groningen, Univ Med Ctr Groningen, Dept Pediat, Groningen, Netherlands.;Univ Groningen, Univ Med Ctr Groningen, Dept Lab Med, Groningen, Netherlands.
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Univ Groningen, Univ Med Ctr Groningen, Dept Pediat, Groningen, Netherlands Science for Life Laboratory, SciLifeLab (creator_code:org_t)
- Springer Nature, 2023
- 2023
- Engelska.
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Ingår i: Cancer & Metabolism. - : Springer Nature. - 2049-3002. ; 11:1
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- BackgroundGlycogen 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.MethodsHepatocyte-specific G6pc knockout (L-G6pc−/−) mice were treated with AAV-shChREBP to normalize hepatic ChREBP activity.ResultsHepatic 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.ConclusionsIn 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Nyckelord
- Glycogen Storage Disease type 1a
- Carbohydrate Response Element Binding Protein
- Hepatomegaly
- Yes Associated Protein
- Cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING)
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Rutten, Martijn ...
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Lei, Yu
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Hoogerland, Joan ...
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Bloks, Vincent W ...
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Yang, Hong
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Bos, Trijnie
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Krishnamurthy, K ...
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Bleeker, Aycha
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Koster, Mirjam H ...
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Thomas, Rachel E ...
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Wolters, Justina ...
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van den Bos, Hil ...
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Mithieux, Gilles
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Rajas, Fabienne
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Mardinoglu, Adil
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Spierings, Diana ...
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de Bruin, Alain
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van de Sluis, Ba ...
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Oosterveer, Maai ...
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