Dietary exacerbation of metabolic stress leads to accelerated hepatic carcinogenesis in glycogen storage disease type Ia
Author(s): ,
Fabienne Rajas
Affiliations:
Université Lyon I, Villeurbanne F-69622 France
Corresponding author. Address: Inserm U1213, Université Lyon 1 Laennec, 7 rue Guillaume Paradin, 69372 Lyon cedex 08, France. Tel.: +33 478 77 10 28; fax: +33 478 77 87 62.
,
Gilles Mithieux
Affiliations:
Université Lyon I, Villeurbanne F-69622 France
,
Jessica Zucman-Rossi
Affiliations:
Hôpital Européen Georges Pompidou, AP-HP, Assistance Publique-Hôpitaux de Paris, Paris F-75015, France
,
Damien Roussel
Affiliations:
Centre National de la Recherche Scientifique, UMR 5023, Villeurbanne F-69622 France
,
Caroline Romestaing
Affiliations:
Centre National de la Recherche Scientifique, UMR 5023, Villeurbanne F-69622 France
,
Marie Brevet
Affiliations:
Service de Pathologie Lyon Est, Centre hospitalier universitaire de Lyon, Lyon F-69437, France
,
Margaux Raffin
Affiliations:
Université Lyon I, Villeurbanne F-69622 France
,
Marine Silva
Affiliations:
Université Lyon I, Villeurbanne F-69622 France
,
Laure Monteillet
Affiliations:
Université Lyon I, Villeurbanne F-69622 France
,
Julien Calderaro
Affiliations:
APHP, Assistance-Publique Hôpitaux-de-Paris, Département de Pathologie, Hôpital Henri Mondor, Créteil F-94010, France
Monika Gjorgjieva
Affiliations:
Université Lyon I, Villeurbanne F-69622 France
EASL LiverTree™. RAJAS F. Nov 1, 2018; 234542
Dr. Fabienne RAJAS
Dr. Fabienne RAJAS

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Graphical abstract

Graphical abstract

High-calorie diet accelerates tumor incidence and transformation in GSDI livers. A Warburg-like metabolic reprogramming predisposes GSDI livers to HCC development. Metabolic perturbations lead to the loss of cellular defenses in GSDI livers. GSDI livers and tumors exhibit loss of tumor suppressor expression. HCC present a concomitant expression of epithelial and mesenchymal markers.

Background & Aims

Glycogen storage disease type Ia (GSDIa) is a rare genetic disease associated with glycogen accumulation in hepatocytes and steatosis. With age, most adult patients with GSDIa develop hepatocellular adenomas (HCA), which can progress to hepatocellular carcinomas (HCC). In this study, we characterized metabolic reprogramming and cellular defense alterations during tumorigenesis in the liver of hepatocyte-specific G6pc deficient (L.G6pc−/−) mice, which develop all the hepatic hallmarks of GSDIa.

Methods

Liver metabolism and cellular defenses were assessed at pretumoral (four months) and tumoral (nine months) stages in L.G6pc−/− mice fed a high fat/high sucrose (HF/HS) diet.

Results

In response to HF/HS diet, hepatocarcinogenesis was highly accelerated since 85% of L.G6pc−/− mice developed multiple hepatic tumors after nine months, with 70% classified as HCA and 30% as HCC. Tumor development was associated with high expression of malignancy markers of HCC, i.e. alpha-fetoprotein, glypican 3 and β-catenin. In addition, L.G6pc−/− livers exhibited loss of tumor suppressors. Interestingly, L.G6pc−/− steatosis exhibited a low-inflammatory state and was less pronounced than in wild-type livers. This was associated with an absence of epithelial-mesenchymal transition and fibrosis, while HCA/HCC showed a partial epithelial-mesenchymal transition in the absence of TGF-β1 increase. In HCA/HCC, glycolysis was characterized by a marked expression of PK-M2, decreased mitochondrial OXPHOS and a decrease of pyruvate entry in the mitochondria, confirming a “Warburg-like” phenotype. These metabolic alterations led to a decrease in antioxidant defenses and autophagy and chronic endoplasmic reticulum stress in L.G6pc−/− livers and tumors. Interestingly, autophagy was reactivated in HCA/HCC.

Conclusion

The metabolic remodeling in L.G6pc −/− liver generates a preneoplastic status and leads to a loss of cellular defenses and tumor suppressors that facilitates tumor development in GSDI.

Lay summary

Glycogen storage disease type Ia (GSD1a) is a rare metabolic disease characterized by hypoglycemia, steatosis, excessive glycogen accumulation and tumor development in the liver. In this study, we have observed that GSDIa livers reprogram their metabolism in a similar way to cancer cells, which facilitates tumor formation and progression, in the absence of hepatic fibrosis. Moreover, hepatic burden due to overload of glycogen and lipids in the cells leads to a decrease in cellular defenses, such as autophagy, which could further promote tumorigenesis in the case of GSDI.

Keyword(s)
Non-alcoholic fatty liver disease, Hepatocellular adenoma and carcinoma, Cellular defenses, Tumor suppressor, Epithelial-mesenchymal transition
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