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.