Liver Glycogen Phosphorylase Deficiency Leads to Profibrogenic Phenotype in a Murine Model of Glycogen Storage Disease Type VI

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.

Glycogen storage disease type VI can progress to cirrhosis: ten Chinese patients with GSD VI and a literature review

“…Hepatic fibrosis is caused by chronic liver injury because of viral infection, drugs, toxins, or metabolic disorders [32]. Activated hepatic stellate cells (HSCs) play an important role in pathogenesis of hepatic fibrosis [8,32]. Under the stimulation of cytokines and chemokines released by immune cells and damaged hepatocytes, HSCs can be activated, which then differentiate into myofibroblasts that secrete various extracellular matrix proteins causing hepatic fibrosis [32].…”

“…Thus, we cannot rule out the possibility that hepatic fibrosis and even cirrhosis may present over time. A recently constructed GSD VI murine model also revealed that the damage, inflammation, and fibrosis of hepatocytes aggravated with aging [8]. So far, no cirrhosis was reported in patients with GSD VI, and this may be a result of the lower number of liver biopsy that has been investigated.…”

“…Molecular genetic testing can accurately diagnose GSD VI, and invasive liver biopsy may be avoided [2]. Although a GSD VI murine model recapitulating the phenotypes of human GSD VI was generated, there is a paucity of patients with GSD VI confirmed by molecular genetic testing in the literature including only one patient in Hong Kong, China [8,9]. Considering the full genotypic and phenotypic spectrum of GSD VI continue to evolve, we reported 10 Chinese patients with GSD VI confirmed by next-generation sequencing (NGS) and reviewed literature to give a systematic description of patients with GSD VI in Chinese population.…”

Novel PYGL mutations in Chinese children leading to glycogen storage disease type VI: two case reports

“…According to a retrospective study of six GSD VI patients treated with small, frequent meals as well as cornstarch in the evening, three younger patients showed persistent hyperglyceridemia and the youngest patient (2.5 years old) simultaneously showed obvious elevated transaminases (ALT = 344 U/L, AST = 266 U/L) even after 1.5 years' follow up [10]. A murine model of GSD VI revealed that elevated liver enzymes could increase the risk of liver damage, inflammation, and fibrosis [15]. We speculate that for younger patients, more frequent and intensive UCS treatment for the initial one year should be used to ensure the better metabolic control and catch-up growth.…”

SnapshotDx Quiz: October 2020

“…Two differentially expressed genes, in particular, were found to be directly involved in glycogen metabolism (Gu et al, 2020). One of those genes was PYGL, which is responsible for encoding the liver enzyme glycogen phosphorylase that is involved in glycogen degradation (Wilson et al, 2019). This enzyme degrades glycogen to glucose-1-phosphate, which is an irreversible process.…”