Liver Glycogen Phosphorylase Deficiency Leads to Profibrogenic Phenotype in a Murine Model of Glycogen Storage Disease Type VI
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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wolters Kluwer Health/LWW
2019-11-01
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| Series: | Hepatology Communications |
| Online Access: | https://doi.org/10.1002/hep4.1426 |
| _version_ | 1797713725304602624 |
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| author | Lane H. Wilson Jun‐Ho Cho Ana Estrella Joan A. Smyth Rong Wu Tayoot Chengsupanimit Laurie M. Brown David A. Weinstein Young Mok Lee |
| author_facet | Lane H. Wilson Jun‐Ho Cho Ana Estrella Joan A. Smyth Rong Wu Tayoot Chengsupanimit Laurie M. Brown David A. Weinstein Young Mok Lee |
| author_sort | Lane H. Wilson |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T07:41:03Z |
| format | Article |
| id | doaj.art-eb094ee5286e491c88069ed9a8d697ac |
| institution | Directory Open Access Journal |
| issn | 2471-254X |
| language | English |
| last_indexed | 2024-03-12T07:41:03Z |
| publishDate | 2019-11-01 |
| publisher | Wolters Kluwer Health/LWW |
| record_format | Article |
| series | Hepatology Communications |
| spelling | doaj.art-eb094ee5286e491c88069ed9a8d697ac2023-09-02T21:19:00ZengWolters Kluwer Health/LWWHepatology Communications2471-254X2019-11-013111544155510.1002/hep4.1426Liver Glycogen Phosphorylase Deficiency Leads to Profibrogenic Phenotype in a Murine Model of Glycogen Storage Disease Type VILane H. Wilson0Jun‐Ho Cho1Ana Estrella2Joan A. Smyth3Rong Wu4Tayoot Chengsupanimit5Laurie M. Brown6David A. Weinstein7Young Mok Lee8Glycogen Storage Disease Program Department of Pediatrics University of Connecticut School of Medicine Farmington CTGlycogen Storage Disease Program Department of Pediatrics University of Connecticut School of Medicine Farmington CTGlycogen Storage Disease Program Department of Pediatrics University of Connecticut School of Medicine Farmington CTConnecticut Veterinary Medical Diagnostic Laboratory Department of Pathobiology and Veterinary Science University of Connecticut Storrs CTBiostatistics Center Connecticut Convergence Institute for Translation in Regenerative Engineering University of Connecticut Health Center Farmington CTGlycogen Storage Disease Program University of Florida College of Medicine Gainesville FLGlycogen Storage Disease Program University of Florida College of Medicine Gainesville FLGlycogen Storage Disease Program Department of Pediatrics University of Connecticut School of Medicine Farmington CTGlycogen Storage Disease Program Department of Pediatrics University of Connecticut School of Medicine Farmington CTMutations 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.https://doi.org/10.1002/hep4.1426 |
| spellingShingle | Lane H. Wilson Jun‐Ho Cho Ana Estrella Joan A. Smyth Rong Wu Tayoot Chengsupanimit Laurie M. Brown David A. Weinstein Young Mok Lee Liver Glycogen Phosphorylase Deficiency Leads to Profibrogenic Phenotype in a Murine Model of Glycogen Storage Disease Type VI Hepatology Communications |
| title | Liver Glycogen Phosphorylase Deficiency Leads to Profibrogenic Phenotype in a Murine Model of Glycogen Storage Disease Type VI |
| title_full | Liver Glycogen Phosphorylase Deficiency Leads to Profibrogenic Phenotype in a Murine Model of Glycogen Storage Disease Type VI |
| title_fullStr | Liver Glycogen Phosphorylase Deficiency Leads to Profibrogenic Phenotype in a Murine Model of Glycogen Storage Disease Type VI |
| title_full_unstemmed | Liver Glycogen Phosphorylase Deficiency Leads to Profibrogenic Phenotype in a Murine Model of Glycogen Storage Disease Type VI |
| title_short | Liver Glycogen Phosphorylase Deficiency Leads to Profibrogenic Phenotype in a Murine Model of Glycogen Storage Disease Type VI |
| title_sort | liver glycogen phosphorylase deficiency leads to profibrogenic phenotype in a murine model of glycogen storage disease type vi |
| url | https://doi.org/10.1002/hep4.1426 |
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