Specific features of glycogen metabolism in the liver.
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ABSTRACT:
SUBMITTER: Bollen M
PROVIDER: S-EPMC1219837 | biostudies-other | 1998 Nov
REPOSITORIES: biostudies-other
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Project description:BackgroundDuchenne muscular dystrophy (DMD) is a severe, genetic muscle wasting disorder characterised by progressive muscle weakness. DMD is caused by mutations in the dystrophin (dmd) gene resulting in very low levels or a complete absence of the dystrophin protein, a key structural element of muscle fibres which is responsible for the proper transmission of force. In the absence of dystrophin, muscle fibres become damaged easily during contraction resulting in their degeneration. DMD patients and mdx mice (an animal model of DMD) exhibit altered metabolic disturbances that cannot be attributed to the loss of dystrophin directly. We tested the hypothesis that glycogen metabolism is defective in mdx dystrophic mice.ResultsDystrophic mdx mice had increased skeletal muscle glycogen (79%, (P<0.01)). Skeletal muscle glycogen synthesis is initiated by glycogenin, the expression of which was increased by 50% in mdx mice (P<0.0001). Glycogen synthase activity was 12% higher (P<0.05) but glycogen branching enzyme activity was 70% lower (P<0.01) in mdx compared with wild-type mice. The rate-limiting enzyme for glycogen breakdown, glycogen phosphorylase, had 62% lower activity (P<0.01) in mdx mice resulting from a 24% reduction in PKA activity (P<0.01). In mdx mice glycogen debranching enzyme expression was 50% higher (P<0.001) together with starch-binding domain protein 1 (219% higher; P<0.01). In addition, mdx mice were glucose intolerant (P<0.01) and had 30% less liver glycogen (P<0.05) compared with control mice. Subsequent analysis of the enzymes dysregulated in skeletal muscle glycogen metabolism in mdx mice identified reduced glycogenin protein expression (46% less; P<0.05) as a possible cause of this phenotype.ConclusionWe identified that mdx mice were glucose intolerant, and had increased skeletal muscle glycogen but reduced amounts of liver glycogen.
| S-EPMC3953428 | biostudies-literature
Project description:To investigate the role of Per2 in glucose metabolism in-vivo we used mice bearing a targeted gene mutation in the Per2 gene (Per2brdm) and thus unable to express a functional Per2 protein. Mice were hosted in our standard mouse facility in a 12-hour light and 12-hour dark cycle. Wt and Per2brdm mice were fed with either standard chow diet or high-fat diet for 24 weeks and analyzed for glucose homeostasis. Glucose tolerance test (GTT) and insulin tolerance test (ITT) were performed on mice food deprived for 7 hours. For pyruvate tolerance test (PTT) mice were fasted for 14 hours. Glucose levels were measured over 12 hours starvation time-courses during the light and the dark phase. Fed and fasting blood glucose and hepatic glycogen content were measured over different circadian time-points. To investigate the role of Per2 in the control of liver gene expression we performed DNA-microarray analysis of RNA preparations from liver of Per2brdm and WT mice. We extracted total RNA from liver of four different Per2brdm and WT mice. Mice from the same cohort were sacrificed after 8 hours of starvation. After normalization we performed a fold change comparison selecting probes with a p value < 0.05.
2013-09-02 | E-GEOD-30139 | biostudies-arrayexpress
Project description:Glucose is the main energy fuel for the human brain. Maintenance of glucose homeostasis is therefore, crucial to meet cellular energy demands in both - normal physiological states and during stress or increased demands. Glucose is stored as glycogen primarily in the liver and skeletal muscle with a small amount stored in the brain. Liver glycogen primarily maintains blood glucose levels, while skeletal muscle glycogen is utilized during high-intensity exertion, and brain glycogen is an emergency cerebral energy source. Glycogen and glucose transform into one another through glycogen synthesis and degradation pathways. Thus, enzymatic defects along these pathways are associated with altered glucose metabolism and breakdown leading to hypoglycemia ± hepatomegaly and or liver disease in hepatic forms of glycogen storage disorder (GSD) and skeletal ± cardiac myopathy, depending on the site of the enzyme defects. Overall, defects in glycogen metabolism mainly present as GSDs and are a heterogenous group of inborn errors of carbohydrate metabolism. In this article we review the genetics, epidemiology, clinical and metabolic findings of various types of GSD, and glycolysis defects emphasizing current treatment and implications for future directions.
| S-EPMC6331362 | biostudies-literature
Project description:To investigate the role of Per2 in glucose metabolism in-vivo we used mice bearing a targeted gene mutation in the Per2 gene (Per2brdm) and thus unable to express a functional Per2 protein. Mice were hosted in our standard mouse facility in a 12-hour light and 12-hour dark cycle. Wt and Per2brdm mice were fed with either standard chow diet or high-fat diet for 24 weeks and analyzed for glucose homeostasis. Glucose tolerance test (GTT) and insulin tolerance test (ITT) were performed on mice food deprived for 7 hours. For pyruvate tolerance test (PTT) mice were fasted for 14 hours. Glucose levels were measured over 12 hours starvation time-courses during the light and the dark phase. Fed and fasting blood glucose and hepatic glycogen content were measured over different circadian time-points. To investigate the role of Per2 in the control of liver gene expression we performed DNA-microarray analysis of RNA preparations from liver of Per2brdm and WT mice.
2013-09-02 | GSE30139 | GEO
Project description:BACKGROUNDLiver disease in urea cycle disorders (UCDs) ranges from hepatomegaly and chronic hepatocellular injury to cirrhosis and end-stage liver disease. However, the prevalence and underlying mechanisms are unclear.METHODSWe estimated the prevalence of chronic hepatocellular injury in UCDs using data from a multicenter, longitudinal, natural history study. We also used ultrasound with shear wave elastography and FibroTest to evaluate liver stiffness and markers of fibrosis in individuals with argininosuccinate lyase deficiency (ASLD), a disorder with high prevalence of elevated serum alanine aminotransferase (ALT). To understand the human observations, we evaluated the hepatic phenotype of the AslNeo/Neo mouse model of ASLD.RESULTSWe demonstrate a high prevalence of elevated ALT in ASLD (37%). Hyperammonemia and use of nitrogen-scavenging agents, 2 markers of disease severity, were significantly (P < 0.001 and P = 0.001, respectively) associated with elevated ALT in ASLD. In addition, ultrasound with shear wave elastography and FibroTest revealed increased echogenicity and liver stiffness, even in individuals with ASLD and normal aminotransferases. The AslNeo/Neo mice mimic the human disorder with hepatomegaly, elevated aminotransferases, and excessive hepatic glycogen noted before death (3-5 weeks of age). This excessive hepatic glycogen is associated with impaired hepatic glycogenolysis and decreased glycogen phosphorylase and is rescued with helper-dependent adenovirus expressing Asl using a liver-specific (ApoE) promoter.CONCLUSIONOur results link urea cycle dysfunction and impaired hepatic glucose metabolism and identify a mouse model of liver disease in the setting of urea cycle dysfunction.TRIAL REGISTRATIONThis study has been registered at ClinicalTrials.gov (NCT03721367, NCT00237315).FUNDINGFunding was provided by NIH, Burroughs Wellcome Fund, NUCDF, Genzyme/ACMG Foundation, and CPRIT.
| S-EPMC7101134 | biostudies-literature
Project description:Glycogen plays essential roles in glucose metabolism. Imaging glycogen in the liver, the major glycogen reservoir in the body, may shed new light on many metabolic disorders. 13C magnetic resonance spectroscopy (MRS) has become the mainstream method for monitoring glycogen in the body. However, the equipment of special hardware to standard clinical magnetic resonance imaging (MRI) scanners limits its clinical applications. Herein, we utilized endogenous glycogen as a T 2-based relaxation contrast agent for imaging glycogen metabolism in the liver in vivo. The in vitro results demonstrated that the transverse relaxation rate of glycogen strongly correlates with the concentration, pH, and field strength. Based on the Swift-Connick theory, we characterized the exchange property of glycogen and measured the exchange rate of glycogen as 31,847 Hz at 37 °C. Besides, the viscosity and echo spacing showed no apparent effect on the transverse relaxation rate. This unique feature enables visualization of glycogen signaling in vivo through T 2-weighted MRI. Two hours-post intraperitoneal injection of glucagon, a clinical drug to promote glycogenolysis and gluconeogenesis, the signal intensity of the mice's liver increased by 1.8 times from the T 2-weighted imaging experiment due to the decomposition of glycogen. This study provides a convenient imaging strategy to non-invasively investigate glycogen metabolism in the liver, which may find clinical applications in metabolic diseases.
| S-EPMC11197538 | biostudies-literature
Project description:IntroductionThe p.(Arg85Trp) variant-specific phenotype of hepatocyte nuclear factor 4 alpha shows a complex clinical picture affecting three different organ systems and their corresponding metabolisms. Little is known about the molecular mechanisms involved and their relationship with the diverse symptoms seen in the context of this specific variant. Here, we present data of a new patient that expand the clinical phenotype, suggesting possible disease mechanisms.Case presentationClinical data were extracted from the patient's charts. The liver, kidney, and muscle were analyzed with routine histology and electron microscopy. Mitochondrial function was assessed by respirometric analyses and enzymatic activity assays. Structure and sequence analyses of this specific variant were investigated by in silico analyses. Our patient showed the known features of the variant-specific phenotype, including macrosomia, congenital hyperinsulinism, transient hepatomegaly, and renal Fanconi syndrome. In addition to that, she showed liver cirrhosis, chronic kidney failure, and altered mitochondrial morphology and function. The clinical and biochemical phenotype had features of a new type of glycogen storage disease.DiscussionThis case expands the p.(Arg85Trp) variant-specific phenotype. Possible pathomechanistic explanations for the documented multiorgan involvement and changes of symptoms and signs during development of this ultra-rare but instructive disorder are discussed.
| S-EPMC10521240 | biostudies-literature
Project description:In the human body, glycogen is a branched polymer of glucose stored mainly in the liver and the skeletal muscle that supplies glucose to the blood stream during fasting periods and to the muscle cells during muscle contraction. Glycogen has been identified in other tissues such as brain, heart, kidney, adipose tissue, and erythrocytes, but glycogen function in these tissues is mostly unknown. Glycogen synthesis requires a series of reactions that include glucose entrance into the cell through transporters, phosphorylation of glucose to glucose 6-phosphate, isomerization to glucose 1-phosphate, and formation of uridine 5'-diphosphate-glucose, which is the direct glucose donor for glycogen synthesis. Glycogenin catalyzes the formation of a short glucose polymer that is extended by the action of glycogen synthase. Glycogen branching enzyme introduces branch points in the glycogen particle at even intervals. Laforin and malin are proteins involved in glycogen assembly but their specific function remains elusive in humans. Glycogen is accumulated in the liver primarily during the postprandial period and in the skeletal muscle predominantly after exercise. In the cytosol, glycogen breakdown or glycogenolysis is carried out by two enzymes, glycogen phosphorylase which releases glucose 1-phosphate from the linear chains of glycogen, and glycogen debranching enzyme which untangles the branch points. In the lysosomes, glycogen degradation is catalyzed by α-glucosidase. The glucose 6-phosphatase system catalyzes the dephosphorylation of glucose 6-phosphate to glucose, a necessary step for free glucose to leave the cell. Mutations in the genes encoding the enzymes involved in glycogen metabolism cause glycogen storage diseases.
| S-EPMC4802397 | biostudies-literature
Project description:Background: Glycogen storage disease type Ia (GSD Ia), also known as von Gierke disease, is the most common glycogen storage disorder. It is caused by the deficiency of glucose-6-phosphatase, the enzyme that catalyzes the final step of gluconeogenesis and glycogenolysis. The accumulation of glucose-6-phosphate leads to increased glycogen and triglyceride levels in the liver. Patients with GSD Ia can develop steatohepatitis, cirrhosis, and increased risk for hepatocellular adenomas and carcinomas. We previously showed that animal models of GSD Ia had defective autophagy and dysfunctional mitochondria. In this study, we examined the effect of VK2809, a liver-specific thyroid hormone receptor ? agonist, on hepatic steatosis, autophagy, and mitochondrial biogenesis in a mouse model of GSD Ia. Methods: G6pc-/--deficient (GSD Ia) mice were treated with VK2809 or vehicle control by daily intraperitoneal injection for four days. The hepatic triglyceride and glycogen were determined by biochemical assays. Autophagy and mitochondrial biogenesis were measured by Western blotting for key autophagy and mitochondrial markers. Results: VK2809 treatment decreased hepatic mass and triglyceride content in GSD Ia mice. VK2809 stimulated hepatic autophagic flux as evidenced by increased microtubule-associated protein light chain 3-II (LC3B-II), decreased p62 protein levels, activation of AMP-activated protein kinase (AMPK), inhibition of the mammalian target of rapamycin (mTOR) signaling, enhancement of protein levels of ATG5-ATG12, and increased lysosomal protein expression. VK2809 also increased the expression of carnitine palmitoyltransferase 1a (CPT1?) and fibroblast growth factor 21 (FGF21), as well as mitochondrial biogenesis to promote mitochondrial ?-oxidation. Conclusions: In summary, VK2809 treatment decreased hepatic triglyceride levels in GSD Ia mice through its simultaneous restoration of autophagy, mitochondrial biogenesis, and ?-oxidation of fatty acids. Liver-specific thyromimetics represent a potential therapy for hepatosteatosis in GSD Ia as well as nonalcoholic fatty liver disease.
| S-EPMC6707038 | biostudies-literature
Project description:Background/Aims: The storage amount of liver glycogen could affect the liver fibrosis assessment made by MRI-based methods. However, it remained unclear whether glycogen amount could bias the estimation of liver fat content by proton density fat fraction. In this study, we aimed to investigate whether glycogen metabolism gene variants could contribute to the bias of PDFF by genetic association. Methods: We conducted an association study of the glycogen metabolism genes based on the PDFF data of 11,129 participants in the UK Biobank. The effect of the SNPs in these genes on non-alcoholic fatty liver disease was estimated by a meta-analysis of the available NAFLD case-control studies. Results: We identified significant associations of the SNPs near the genes encoding glycogen phosphorylase (PYGM and PYGL) and synthase (GYS2) with PDFF (FDR-corrected p value < 0.05). The genes encoding the regulatory proteins of glycogenolysis (PHKB, CALM2/3), glucose transporter (SLC2A1), and glucose kinase (GCK) were also associated with PDFF. The SNP rs5402 of SLC2A2 and rs547066 of PYGM were associated with NAFLD (p < 0.05) with others being insignificant. Except for the PYGM gene, the PDFF-associated SNPs showed no associations with NAFLD. In addition, the burden tests of rare variants in these genes were not significant after FDR correction. Conclusion: Liver glycogen metabolism genes associated with PDFF were not associated with NAFLD, which implicated a potential bias effect of glycogen storage on the quantification of liver fat content by PDFF.
| S-EPMC9019352 | biostudies-literature