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Liver Glycogen Phosphorylase Deficiency Leads to Profibrogenic Phenotype in a Murine Model of Glycogen Storage Disease Type VI
- Source :
- Hepatology Communications, Hepatology Communications, Vol 3, Iss 11, Pp 1544-1555 (2019)
- Publication Year :
- 2019
-
Abstract
- Mutations in the liver glycogen phosphorylase (Pygl) gene are associated with the diagnosis of glycogen storage disease type VI (GSD-VI). To understand the pathogenesis of GSD-VI, we generated a mouse model with Pygl deficiency (Pygl -/-). Pygl -/- mice exhibit hepatomegaly, excessive hepatic glycogen accumulation, and low hepatic free glucose along with lower fasting blood glucose levels and elevated blood ketone bodies. Hepatic glycogen accumulation in Pygl -/- mice increases with age. Masson's trichrome and picrosirius red staining revealed minimal to mild collagen deposition in periportal, subcapsular, and/or perisinusoidal areas in the livers of old Pygl -/- mice (>40 weeks). Consistently, immunohistochemical analysis showed the number of cells positive for alpha smooth muscle actin (α-SMA), a marker of activated hepatic stellate cells, was increased in the livers of old Pygl -/- mice compared with those of age-matched wild-type (WT) mice. Furthermore, old Pygl -/- mice had inflammatory infiltrates associated with hepatic vessels in their livers along with up-regulated hepatic messenger RNA levels of C-C chemokine ligand 5 (Ccl5/Rantes) and monocyte chemoattractant protein 1 (Mcp-1), indicating inflammation, while age-matched WT mice did not. Serum levels of aspartate aminotransferase and alanine aminotransferase were elevated in old Pygl -/- mice, indicating liver damage. Conclusion: Pygl deficiency results in progressive accumulation of hepatic glycogen with age and liver damage, inflammation, and collagen deposition, which can increase the risk of liver fibrosis. Collectively, the Pygl-deficient mouse recapitulates clinical features in patients with GSD-VI and provides a model to elucidate the mechanisms underlying hepatic complications associated with defective glycogen metabolism.
- Subjects :
- Chemokine
medicine.medical_specialty
Hepatology
biology
Chemistry
Glycogen storage disease type VI
Inflammation
Original Articles
medicine.disease
Hepatic Complication
Pathogenesis
Glycogen phosphorylase
Endocrinology
Internal medicine
medicine
biology.protein
Ketone bodies
Hepatic stellate cell
lcsh:Diseases of the digestive system. Gastroenterology
Original Article
lcsh:RC799-869
medicine.symptom
Subjects
Details
- ISSN :
- 2471254X
- Volume :
- 3
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Hepatology communications
- Accession number :
- edsair.doi.dedup.....82dae2e44eb7c0a2a2b15313199bbdad