Circulating exosomal microRNAs as potential biomarkers of hepatic injury and inflammation in a murine model of glycogen storage disease type 1a.

Roberta Resaz,Daniela Segalerba,Luca Mastracci,Federica Grillo,Alessandra Eva,Davide Cangelosi,Cristina Bottino,Maria Carla Bosco,Martina Morini,Irma Colombo

doi:10.1242/dmm.043364

Abstract

ABSTRACTMost patients affected by glycogen storage disease type 1a (GSD1a), an inherited metabolic disorder caused by mutations in the enzyme glucose-6-phosphatase-α (G6Pase-α), develop renal and liver complications, including the 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 used the plasma exosomes of a murine model of GSD1a, the LS-G6pc−/− mouse, to uncover the modulation in microRNA expression associated with the disease. The microRNAs differentially expressed 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 microRNA were significantly enriched for the insulin signaling pathway, glucose and lipid metabolism, Wnt/β-catenin, telomere maintenance and hepatocellular carcinoma, and chemokine and immune regulation signaling pathways. Although some microRNAs were common to the different pathologic conditions, others were unique to the cancerous or inflammatory status of the animals. Therefore, the altered expression of several microRNAs is correlated with various pathologic liver states and might help to distinguish them during the progression of the disease and the development of late GSD1a-associated complications.

Highlights

Glycogen storage disease type 1a (GSD1a) is an autosomal rare metabolic disorder caused by a mutation in the catalytic subunit of glucose-6-phosphatase-α (G6Pase-α), a key enzyme in glucose homeostasis
Persistent liver dysmetabolism results in a progressive worsening of the clinical parameters and the formation of hepatocellular adenomas (HCAs), which progress to hepatocellular carcinomas (HCCs) in 10% of cases (Labrune et al, 1997)
Analysis of Exo-miR and data normalization We searched for Exo-miR biomarkers for pathologic manifestations of GSD1a in plasma exosomes of LS-G6pc−/− mice of different ages by comparing the Exo-miR expression profiles of diseased versus control wild-type (WT) mice

Summary

Introduction

Glycogen storage disease type 1a (GSD1a) is an autosomal rare metabolic disorder caused by a mutation in the catalytic subunit of glucose-6-phosphatase-α (G6Pase-α), a key enzyme in glucose homeostasis. Patients with GSD1a are unable to maintain glucose homeostasis and show growth retardation, hypoglycemia, hepatomegaly, kidney enlargement, hyperlipidemia, hyperuricemia and lactic acidemia. The control of hypoglycemia cannot prevent the progressive deterioration of the liver and kidney. Persistent liver dysmetabolism results in a progressive worsening of the clinical parameters and the formation of hepatocellular adenomas (HCAs), which progress to hepatocellular carcinomas (HCCs) in 10% of cases (Labrune et al, 1997). The elevated percentage of adenomas with β-catenin-activating mutations might explain the risk of malignant transformation of HCA to HCC in GSD1a patients. Liver transplant is the only option in the most severe cases

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