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Glycogen and Liver
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Glycogen and Liver

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (10 December 2022) | Viewed by 16257

Special Issue Editor

Prof. Dr. Francesco Callea

E-Mail Website
Guest Editor
Bugando Medical Centre, Department of Molecular Histopathology, Catholic University Health Allied Sciences, Mwanza, Tanzania
Interests: endoplasmic reticulum storage diseases; metabolic liver diseases; population genetics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The Special Issue “Glycogen and liver” is meant to review the basic knowledge on biochemistry, genetic and morphological aspects of glycogen, starting from its discovery in the liver to the discovery of proteoglycogen/glycogenin and their impact on the emerging knowledge and glycogen biology. The first contribution will be dealing with the histochemical, electron microscopical and immunohistochemical characterization of the organelle-like structure, the glycosome, and its correlation with the life cycle of glycogen granules. The second contribution will refer to the various modalities and causes of both congenital either primary or secondary glycogen disorders (Glycogen Storage Disease (GSD)) and acquired GSD. The issue will provide an update on the hepatic storage of polyglucosans that is becoming a relevant topic in the area of rare diseases and an increase in findings in liver tissue specimens. Antigenic properties, proteomic characterization and morphological aspects will be given special attention, both in experimental animal models and in humans.

Further topics of the issue will be: a) pathomorphogenesis, metabolic pathways and clinical implications of hepatic accumulation of glycogen and polyglucosan bodies (PGb) in refeeding syndrome and parenteral nutrition; b) hepatocytic glycogen bodies in post-transplant livers; c) alleviation of polyglucosan disorders by enhancing the efficiency of degradation systems. These contributions are aimed to clarify whether PGb originates from a defect in the initiation of glycogen synthesis, and, if so, to what extent inactive or mutant glycogenin affects the concerted function of glycogen synthase and the branching enzyme, to generate PGb.

One contribution will be devoted to the comparison of glycogen accumulation in dysfunctional and neoplastic (HCC) hepatocytes.

For the sake of completeness, at least one article will be dealing with abnormal glycogen metabolism in neurodegenerative and neuromuscular disorders.

Prof. Dr. Francesco Callea
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • glycogen
  • liver
  • glycogen metabolism
  • glycogen granules
  • glycogen storage
  • polyglucosan diseases
  • polyglucosan bodies
  • glycogen ground glass hepatocytes
  • eurodegenerative disorders
  • neuromuscolar disorders

Published Papers (6 papers)

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Research

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11 pages, 3315 KiB  
Article
Pathomorphogenesis of Glycogen-Ground Glass Hepatocytic Inclusions (Polyglucosan Bodies) in Children after Liver Transplantation
by Francesco Callea, Paola Francalanci, Chiara Grimaldi, Francesca Diomedi Camassei, Rita Devito, Fabio Facchetti, Rita Alaggio and Emanuele Bellacchio
Int. J. Mol. Sci. 2022, 23(17), 9996; https://doi.org/10.3390/ijms23179996 - 02 Sep 2022
Cited by 2 | Viewed by 1654
Abstract
Seventeen out of 764 liver biopsies from transplanted (Tx) livers in children showed glycogen-ground glass (GGG) hepatocytic inclusions. The inclusions were not present in pre-Tx or in the explanted or donor’s liver. Under the electron microscope (EM), the stored material within the cytosol [...] Read more.
Seventeen out of 764 liver biopsies from transplanted (Tx) livers in children showed glycogen-ground glass (GGG) hepatocytic inclusions. The inclusions were not present in pre-Tx or in the explanted or donor’s liver. Under the electron microscope (EM), the stored material within the cytosol appeared as non-membrane-bound aggregates of electron-lucent globoid or fibrillar granules, previously described as abnormally structured glycogen and identified as Polyglucosan bodies (PB). The appearance of GGG in our children was analogous to that of PB-GGG occurring in a number of congenital diseases due to gene mutations such as Lafora’s d., Andersen’s d., Adult Polyglucosan Body Disease and glycogenin deficiency. The same type of GGG was previously reported in the liver of patients undergoing transplants, immunosuppressive or antiblastic treatment. To explore the potential mechanism of GGG formation, we examined whether the drugs after whose treatment this phenomenon was observed could have a role. By carrying out molecular docking, we found that such drugs somehow present a high binding affinity for the active region of glycogenin, implicating that they can inactivate the protein, thus preventing its interaction with glycogen synthase (GS), as well as the maturation of the nascent glycogen towards gamma, beta or alfa glycogen granules. We could also demonstrate that PG inclusions consist of a complex of PAS positive material (glycogen) and glycogen-associated proteins, i.e., glicogenin-1 and -2 and ubiquitin. These features appear to be analogous to congenital GGG, suggesting that, in both cases, they result from the simultaneous dysregulation of glycogen synthesis and degradation. Drug-induced GGG appear to be toxic to the cell, despite their reversibility. Full article
(This article belongs to the Special Issue Glycogen and Liver)
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12 pages, 4100 KiB  
Article
A Mouse Model of Glycogen Storage Disease Type IX-Beta: A Role for Phkb in Glycogenolysis
by Charles J. Arends, Lane H. Wilson, Ana Estrella, Oh Sung Kwon, David A. Weinstein and Young Mok Lee
Int. J. Mol. Sci. 2022, 23(17), 9944; https://doi.org/10.3390/ijms23179944 - 01 Sep 2022
Cited by 3 | Viewed by 1720
Abstract
Glycogen storage disease type IX (GSD-IX) constitutes nearly a quarter of all GSDs. This ketotic form of GSD is caused by mutations in phosphorylase kinase (PhK), which is composed of four subunits (α, β, γ, δ). PhK is required for the activation of [...] Read more.
Glycogen storage disease type IX (GSD-IX) constitutes nearly a quarter of all GSDs. This ketotic form of GSD is caused by mutations in phosphorylase kinase (PhK), which is composed of four subunits (α, β, γ, δ). PhK is required for the activation of the liver isoform of glycogen phosphorylase (PYGL), which generates free glucose-1-phosphate monomers to be used as energy via cleavage of the α -(1,4) glycosidic linkages in glycogen chains. Mutations in any of the PhK subunits can negatively affect the regulatory and catalytic activity of PhK during glycogenolysis. To understand the pathogenesis of GSD-IX-beta, we characterized a newly created PHKB knockout (Phkb−/−) mouse model. In this study, we assessed fasting blood glucose and ketone levels, serum metabolite concentrations, glycogen phosphorylase activity, and gene expression of gluconeogenic genes and fibrotic genes. Phkb−/− mice displayed hepatomegaly with lower fasting blood glucose concentrations. Phkb−/− mice showed partial liver glycogen phosphorylase activity and increased sensitivity to pyruvate, indicative of partial glycogenolytic activity and upregulation of gluconeogenesis. Additionally, gene expression analysis demonstrated increased lipid metabolism in Phkb−/− mice. Gene expression analysis and liver histology in the livers of old Phkb−/− mice (>40 weeks) showed minimal profibrogenic features when analyzed with age-matched wild-type (WT) mice. Collectively, the Phkb−/− mouse recapitulates mild clinical features in patients with GSD-IX-beta. Metabolic and molecular analysis confirmed that Phkb−/− mice were capable of sustaining energy homeostasis during prolonged fasting by using partial glycogenolysis, increased gluconeogenesis, and potentially fatty acid oxidation in the liver. Full article
(This article belongs to the Special Issue Glycogen and Liver)
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12 pages, 1537 KiB  
Article
Dynamics of the Glycogen β-Particle Number in Rat Hepatocytes during Glucose Refeeding
by Natalia N. Bezborodkina, Andrei V. Stepanov, Mikhail L. Vorobev, Grigory I. Stein, Sergey V. Okovityi and Boris N. Kudryavtsev
Int. J. Mol. Sci. 2022, 23(16), 9263; https://doi.org/10.3390/ijms23169263 - 17 Aug 2022
Viewed by 1146
Abstract
Glycogen is an easily accessible source of energy for various processes. In hepatocytes, it can be found in the form of individual molecules (β-particles) and their agglomerates (α-particles). The glycogen content in hepatocytes depends on the physiological state and can vary due to [...] Read more.
Glycogen is an easily accessible source of energy for various processes. In hepatocytes, it can be found in the form of individual molecules (β-particles) and their agglomerates (α-particles). The glycogen content in hepatocytes depends on the physiological state and can vary due to the size and number of the particles. Using biochemical, cytofluorometric, interferometric and morphometric methods, the number of β-particles in rat hepatocytes was determined after 48 h of fasting at different time intervals after glucose refeeding. It has been shown that after starvation, hepatocytes contain ~1.6 × 108 β-particles. During refeeding, their number of hepatocytes gradually increases and reaches a maximum (~5.9 × 108) at 45 min after glucose administration, but then quickly decreases. The data obtained suggest that in cells there is a continuous synthesis and degradation of particles, and at different stages of life, one or another process predominates. It has been suggested that in the course of glycogenesis, pre-existing β-particles are replaced by those formed de novo. The main contribution to the deposition of glycogen is made by an increase in the glucose residue number in its molecules. The average diameter of β-particles of glycogen during glycogenesis increases from ~11 nm to 21 nm. Full article
(This article belongs to the Special Issue Glycogen and Liver)
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Review

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14 pages, 2840 KiB  
Review
The Liver and Glycogen: In Sickness and in Health
by Gwyneth S. T. Soon and Michael Torbenson
Int. J. Mol. Sci. 2023, 24(7), 6133; https://doi.org/10.3390/ijms24076133 - 24 Mar 2023
Cited by 11 | Viewed by 6106
Abstract
The liver is a major store of glycogen and is essential in maintaining systemic glucose homeostasis. In healthy individuals, glycogen synthesis and breakdown in the liver are tightly regulated. Abnormal glycogen metabolism results in prominent pathological changes in the liver, often manifesting as [...] Read more.
The liver is a major store of glycogen and is essential in maintaining systemic glucose homeostasis. In healthy individuals, glycogen synthesis and breakdown in the liver are tightly regulated. Abnormal glycogen metabolism results in prominent pathological changes in the liver, often manifesting as hepatic glycogenosis or glycogen inclusions. This can occur in genetic glycogen storage disease or acquired conditions with insulin dysregulation such as diabetes mellitus and non-alcoholic fatty liver disease or medication effects. Some primary hepatic tumors such as clear cell hepatocellular carcinoma also demonstrate excessive glycogen accumulation. This review provides an overview of the pathological manifestations and molecular mechanisms of liver diseases associated with abnormal glycogen accumulation. Full article
(This article belongs to the Special Issue Glycogen and Liver)
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11 pages, 956 KiB  
Review
Glycogen—Endoplasmic Reticulum Connection in the Liver
by József Mandl
Int. J. Mol. Sci. 2023, 24(2), 1074; https://doi.org/10.3390/ijms24021074 - 05 Jan 2023
Cited by 2 | Viewed by 2180
Abstract
Glycogen, the branched polymer of glucose is found mainly in the liver and muscle in mammals. Along with several other proteins, glycogen forms separate cellular organelles, and particles in cells. Glycogen particles in the liver have a special metabolic and also regulatory connection [...] Read more.
Glycogen, the branched polymer of glucose is found mainly in the liver and muscle in mammals. Along with several other proteins, glycogen forms separate cellular organelles, and particles in cells. Glycogen particles in the liver have a special metabolic and also regulatory connection to the intracellular endomembrane system, particularly the endoplasmic reticulum. This connection is part of the organelle homeostasis in hepatocytes and forms a “glycogenoreticular system”. The actual size of hepatic glycogen stores and the rate of glycogenolysis determines several essential liver-specific metabolic processes, such as glucose secretion for the maintenance of blood glucose levels or the glucuronidation of certain vital endo-, and xenobiotics, and are also related to liver antioxidant defense. In starvation, and in certain physiological and pathological states, where glycogen stores are depleted, functions of the glycogenoreticular system are altered. The starvation-induced depletion of hepatic glycogen content changes the biotransformation of various endo- and xenobiotics. This can be observed especially in acute DILI (drug-induced liver injury) due to paracetamol overdose, which is the most common cause of acute liver failure in the West. Full article
(This article belongs to the Special Issue Glycogen and Liver)
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16 pages, 1537 KiB  
Review
Role of Glycogen Synthase Kinase-3 in Interferon-γ-Mediated Immune Hepatitis
by Chia-Ling Chen, Po-Chun Tseng, Rahmat Dani Satria, Thi Thuy Nguyen, Cheng-Chieh Tsai and Chiou-Feng Lin
Int. J. Mol. Sci. 2022, 23(9), 4669; https://doi.org/10.3390/ijms23094669 - 23 Apr 2022
Cited by 1 | Viewed by 2559
Abstract
Glycogen synthase kinase-3 (GSK-3), a serine/threonine kinase, is a vital glycogen synthase regulator controlling glycogen synthesis, glucose metabolism, and insulin signaling. GSK-3 is widely expressed in different types of cells, and its abundant roles in cellular bioregulation have been speculated. Abnormal GSK-3 activation [...] Read more.
Glycogen synthase kinase-3 (GSK-3), a serine/threonine kinase, is a vital glycogen synthase regulator controlling glycogen synthesis, glucose metabolism, and insulin signaling. GSK-3 is widely expressed in different types of cells, and its abundant roles in cellular bioregulation have been speculated. Abnormal GSK-3 activation and inactivation may affect its original bioactivity. Moreover, active and inactive GSK-3 can regulate several cytosolic factors and modulate their diverse cellular functional roles. Studies in experimental liver disease models have illustrated the possible pathological role of GSK-3 in facilitating acute hepatic injury. Pharmacologically targeting GSK-3 is therefore suggested as a therapeutic strategy for liver protection. Furthermore, while the signaling transduction of GSK-3 facilitates proinflammatory interferon (IFN)-γ in vitro and in vivo, the blockade of GSK-3 can be protective, as shown by an IFN-γ-induced immune hepatitis model. In this study, we explored the possible regulation of GSK-3 and the potential relevance of GSK-3 blockade in IFN-γ-mediated immune hepatitis. Full article
(This article belongs to the Special Issue Glycogen and Liver)
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