Monika Gjorgjieva1, Julien Calderaro2, Laure Monteillet1, Marine Silva1, Margaux Raffin1, Marie Brevet3, Caroline Romestaing4, Damien Roussel4, Jessica Zucman-Rossi5, Gilles Mithieux1, Fabienne Rajas6. 1. Institut National de la Santé et de la Recherche Médicale, U1213, Lyon F-69008, France; Université de Lyon, Lyon F-69008 France; Université Lyon I, Villeurbanne F-69622 France. 2. Inserm UMR-1162, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, Paris, France; Université Paris Est Créteil, Créteil, France; APHP, Assistance-Publique Hôpitaux-de-Paris, Département de Pathologie, Hôpital Henri Mondor, Créteil F-94010, France. 3. Université de Lyon, Lyon F-69008 France; Université Lyon I, Villeurbanne F-69622 France; Service de Pathologie Lyon Est, Centre hospitalier universitaire de Lyon, Lyon F-69437, France. 4. Université de Lyon, Lyon F-69008 France; Université Lyon I, Villeurbanne F-69622 France; Centre National de la Recherche Scientifique, UMR 5023, Villeurbanne F-69622 France. 5. Inserm UMR-1162, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, Paris, France; Hôpital Européen Georges Pompidou, AP-HP, Assistance Publique-Hôpitaux de Paris, Paris F-75015, France. 6. Institut National de la Santé et de la Recherche Médicale, U1213, Lyon F-69008, France; Université de Lyon, Lyon F-69008 France; Université Lyon I, Villeurbanne F-69622 France. Electronic address: fabienne.rajas@univ-lyon1.fr.
Abstract
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.
BACKGROUND & AIMS:Glycogenstorage 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:Glycogenstorage 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.
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