EXOSOMAL microRNAs AS POTENTIAL BIOMARKERS OF HEPATIC INJURY AND KIDNEY DISEASE IN GLYCOGEN STORAGE DISEASE TYPE IA PATIENTS.
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PROVIDER: PRJNA780896 | ENA |
REPOSITORIES: ENA
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Project description:Glycogen storage disease type Ia (GSDIa) is an inherited metabolic disorder caused by mutations in the enzyme glucose-6-phosphatase-α (G6Pase-α). Affected individuals develop renal and liver complications, including the development of hepatocellular adenoma/carcinoma and kidney failure. The purpose of this study was to identify potential biomarkers of the evolution of the disease in GSDIa patients. To this end, we analyzed the expression of exosomal microRNAs (Exo-miRs) in the plasma exosomes of 45 patients aged 6 to 63 years. Plasma from age-matched normal individuals were used as controls. We found that the altered expression of several Exo-miRs correlates with the pathologic state of the patients and might help to monitor the progression of the disease and the development of late GSDIa-associated complications.
2022-01-19 | GSE188956 | GEO
Project description:abstract1: Glycogen storage disease type Ia (GSD Ia) is an inborn error of metabolism caused by defective glucose-6-phosphatase (G6PC) activity. GSD Ia patients exhibit severe hepatomegaly due to glycogen and triglyceride (TG) accumulation in the liver. We have previously shown that the activity of Carbohydrate Response Element Binding Protein (ChREBP), a key regulator of glycolysis and de novo lipogenesis, is increased in GSD Ia. In the current study we assessed the contribution of ChREBP to non-alcoholic fatty liver disease (NAFLD) development in a mouse model for hepatic GSD Ia. PMID : 32083759 Abstract2:Glycogen storage disease type 1a (GSD Ia) is an inborn error of metabolism caused by a defect in glucose-6-phosphatase (G6PC) activity, which induces severe hepatomegaly and increases the risk for liver cancer in patients. Hepatic GSD Ia is characterized by constitutive activation of Carbohydrate Response Element Binding Protein (ChREBP), a glucose-sensitive transcription factor that has been proposed as a pro-oncogenic molecular switch that supports tumour progression. Here we studied the contribution of ChREBP signalling on liver disease progression and tumour susceptibility in a mouse model for GSD Ia. Hepatocyte-specific G6pc knockout (L-G6pc-/-) mice were treated with AAV-shChREBP to normalize hepatic ChREBP activity. Hepatic ChREBP normalization induced dysplastic liver growth, massively increased hepatocyte size and sensitized to hepatic inflammation and liver fibrosis in GSD Ia mice. Furthermore, the nuclear levels of the oncoprotein 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 chromosomal instability, cGAS-STING pathway, senescence, and hepatocyte dedifferentiation gene signatures emerged. Upon ChREBP silencing in immortalized human hepatocytes, on the other hand, the induction of YAP target gene expression was paralleled by cell cycle arrest, cell death, and reduced proliferation. In conclusion, our findings indicate that ChREBP activity limits hepatomegaly while protecting against liver disease progression and hepatocellular tumour induction in GSD Ia. These results underline the importance to establish the context-specific roles of ChREBP to define its therapeutic potential. PMID:37085901
2023-04-22 | GSE143357 | GEO
Project description:Glycogen storage disease type III (GSDIII) is a rare genetic disease caused by mutations in the AGL gene, resulting in glycogen debranching enzyme (GDE) deficiency. There is currently no cure. Among various symptoms, skeletal muscle impairment represents a key target for the development of therapies. Identifying reliable biomarkers is crucial for evaluating new therapies, yet muscle-specific biomarkers for GSDIII are lacking. In this study, we generated GSDIII skeletal muscle cells derived from human-induced pluripotent stem cells that recapitulate the glycogen accumulation phenotype. A comparative gene expression analysis was carried out using RNA sequencing to identify novel biomarkers. Our results reports a significant overexpression of galectin-3 in both human and mouse models and patient biopsies, and a significant decrease in mice treated by an AAV gene therapy. Together, our results propose galectin-3 as a biomarker to assess therapeutic efficacy and GSDIII pathological monitoring in the muscle.
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Project description:Circulating exosomal microRNA as potential biomarkers of hepatic injury and inflammation in glycogen storage disease type 1a
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Project description:Glycogen and lipid are major storage forms of energy that are tightly regulated by hormones and metabolic signals. Here, we evaluate the role of the glycogenic scaffolding protein PTG/R5 in energy homeostasis. We demonstrate that feeding mice a high-fat diet (HFD) increases hepatic glycogen, corresponding to increased PTG levels, increased activity of the mechanistic target of rapamycin complex 1 (mTORC1) and induced expression of sterol regulatory element binding protein 1c (SREBP1c). PTG promoter activity was increased by activation of mTORC1 and SREBP1, and PTG and glycogen levels were augmented in mice and cells in which mTORC1 is constitutively active. HFD-dependent increases in hepatic glycogen were prevented by deletion of the PTG gene in mice. Interestingly, PTG knockout mice fed HFD exhibited improved liver steatosis and decreased lipid levels in muscle, in coordination with decreased glycogen, suggesting possible crosstalk between glycogen and lipid stores in the overall control of energy metabolism. Together, these data suggest that transcriptional regulation of PTG by dietary and nutritional cues has profound effects on energy storage and metabolism.fi
2014-06-13 | GSE45319 | GEO
Project description:Glycogen and lipid are major storage forms of energy that are tightly regulated by hormones and metabolic signals. Here, we evaluate the role of the glycogenic scaffolding protein PTG/R5 in energy homeostasis. We demonstrate that feeding mice a high-fat diet (HFD) increases hepatic glycogen, corresponding to increased PTG levels, increased activity of the mechanistic target of rapamycin complex 1 (mTORC1) and induced expression of sterol regulatory element binding protein 1c (SREBP1c). PTG promoter activity was increased by activation of mTORC1 and SREBP1, and PTG and glycogen levels were augmented in mice and cells in which mTORC1 is constitutively active. HFD-dependent increases in hepatic glycogen were prevented by deletion of the PTG gene in mice. Interestingly, PTG knockout mice fed HFD exhibited improved liver steatosis and decreased lipid levels in muscle, in coordination with decreased glycogen, suggesting possible crosstalk between glycogen and lipid stores in the overall control of energy metabolism. Together, these data suggest that transcriptional regulation of PTG by dietary and nutritional cues has profound effects on energy storage and metabolism.fi RNA-Seq analysis was used to characterize hepatic diet-associated gene expression changes between wild-type and PTG KO mice. Mice were maintained on a normal chow diet or a high-fat diet as indicated. 2-3 biological replicates per genotype/diet.
2014-06-13 | E-GEOD-45319 | biostudies-arrayexpress
Project description:Most patients affected by glycogen storage disease type 1a (GSD-1a), an inherited metabolic disorder caused by mutations in the enzyme glucose-6-phosphatase-alpha (G6Pase- α), develop renal and liver complications, including development of hepatocellular adenoma/carcinoma. The purpose of this study was to identify potential biomarkers of the pathophysiology of the GSD1a affected liver. To this end, we utilized the plasma exosomes of a murine model of GSD-1a, LS-G6pc-/- mice, to uncover microRNA expression modulation associated with the disease. Differentially expressed microRNA between LS-G6pc-/- and wild type mice, LS-G6pc-/- mice with hepatocellular adenoma and LS-G6pc-/- mice without adenoma, and LS-G6pc-/- mice with amyloidosis and LS-G6pc-/- mice without amyloidosis were identified. Pathway analysis demonstrated that the target genes of the differentially expressed miRNAs were significantly enriched for insulin signaling pathway, glucose and lipid metabolism, Wnt-beta catenin, telomere maintenance and hepatocellular carcinoma, and chemokine and immune regulation signaling pathways. While some microRNA were common to the different pathologic conditions, others were unique to cancerous or inflammatory status of the animals. Therefore, the altered expression of several microRNA correlates with various pathologic liver statuses and may help discriminate during the progression of the disease and the development of late GSD1-associated complications.
2020-09-09 | GSE157656 | GEO
Project description:Hepatic ChREBP activation limits NAFLD development in a mouse model for Glycogen Storage Disease type Ia/ Normalization of ChREBP activity in hepatic GSD Ia accelerates liver disease progression and sensitizes towards hepatocellular tumour formation.
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Project description:Glycogen is the largest soluble cytosolic macromolecule and considered as the principal storage form of glucose. Cancer cells generally increase their glucose consumption and rewire their metabolism towards aerobic glycolysis to promote growth. Here we report that glycogen accumulation is a key initiating oncogenic event and essential for malignant transformation. RNA-sequencing analysis reveals that G6PC, an enzyme catalyzing the last step of glycogenolysis, is frequently downregulated to augment glucose storage in pro-tumor cells. Accumulated glycogen undergoes liquid-liquid phase separation undergoes liquid-liquid phase separation, which results in the assembly of the laforin-Mst1/2 complex and consequently traps Hippo kinases Mst1/2 in glycogen liquid droplets to relieve their inhibition on Yap. Moreover, G6PC or another glycogenolysis enzyme PYGL deficiency in both human and mice result in glycogen storage disease with enlarged liver size and cancer development, phenocopying Hippo deficiency. Consistently, elimination of glycogen accumulation abrogates liver enlargement and cancer incidence, whereas increasing glycogen storage accelerates tumorigenesis. Thus, we concluded that glycogen not only provides nutrition and energy to the cells but also functions as a key initiating oncogenic metabolite, which physically blocks Hippo signaling through glycogen phase separation to augment pro-tumor cell initiation and progression.
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