Search for biomarkers and prognostic indicators of liver degeneration in glycogen storage disease type Ia

Background and aims: Glycogen storage disease type Ia (GSDIa) is an inherited metabolic disorder caused by mutations in the enzyme glucose-6-phosphatase-alpha (G6Pase-alpha).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.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.In addition, the Exo-miRs expression profile obtained from the patients was correlated with the liver-specific Exo-miRs profile obtained from a mouse model for GSDIa we have generated (LS-G6pc -/-), to derive a common signature that could be specific and prognostic of liver degeneration and connected with biological pathways associated with tumor development and progression.Method: 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.microRNAs were purified with exoRNeasy Serum/Plasma Midi kit (Qiagen) from plasma exosomes.TaqMan Array Human microRNA A cards (Thermo Fisher Scientific), enabling the quantification of 381 microRNAs each, were used to analyze exosomes-derived microRNA (ExomiR) expression.Results: We found several deregulated Exo-miRs that correlate with the pathologic state of the liver patients.We identified microRNAs associated with liver disease and metabolic alterations of glucose and lipid pathways.We also found deregulation of microRNAs relevant in liver tumor development and, finally, several microRNAs whose altered expression has been associated with diabetic and chronic kidney diseases.Interestingly, we found that deregulated Exo-miR profiles correlate with the altered proteome profile and the altered Exo-miR profile identified in LS-G6pc -/-.Conclusion: The altered expression of several Exo-miRs correlated with various pathologic liver states associated with the progression of the disease.Thus, our results provide evidence that the Exo-miRs profiles identified may relate to the specific affected organ gene expression and that the long-term consequences of GSDIa can be monitored through Exo-miRs assessment.In conclusion, our results may evolve into protocols to counteract both the progression of liver degeneration leading to HCA and HCC onset as well as kidney disease and failure using circulating microRNAs as biomarkers.