Glycogen storage disease type Ia mice with less than 2% of normal hepatic glucose-6-phosphatase-α activity restored are at risk of developing hepatic tumors

Kim, Goo-Young; Lee, Young Mock; Kwon, Joon Hyun; Cho, Junho; Pan, Chi-Jiunn; Starost, Matthew F.; Mansfield, Brian C.; Chou, Janice Y.

doi:10.1016/j.ymgme.2017.01.003

Cited by 27 publications

(76 citation statements)

References 26 publications

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“…Of the three rAAV-treated G6pc −/− mice that developed hepatic tumors at age 71–72 weeks, one harbored a HCA nodule and the other two each harbored a single HCC lesion. 36 The non-tumor liver regions of the two HCC-bearing rAAV-treated G6pc −/− mice had 1.5–2.2 units of G6Pase-α activity. However, the HCC lesions of the rAAV-treated G6pc −/− mice had non-detectable G6Pase-α activity.…”

Section: Gsd-i-associated Hcamentioning

confidence: 95%

“…However, the HCC lesions of the rAAV-treated G6pc −/− mice had non-detectable G6Pase-α activity. 36 HCC-1 expressed increased levels of mRNA for Glul and Lgr5 , suggesting that HCC-1 was derived from a bHCA. HCC-2 displayed increased levels of the active p-STAT3-Y705 protein, suggesting that HCC-2 was derived from an IHCA.…”

Section: Gsd-i-associated Hcamentioning

confidence: 98%

“…HCC-2 displayed increased levels of the active p-STAT3-Y705 protein, suggesting that HCC-2 was derived from an IHCA. 36 …”

Section: Gsd-i-associated Hcamentioning

confidence: 99%

“…A variety of gene transfer vectors, including adenovirus vectors, 37 helper-dependent adenovirus vectors, 38 lentivirus vectors, 39–41 and recombinant adeno-associated virus (rAAV) vectors, 26,27,36,42–47 have been developed using animal models of GSD-Ia. The rAAV-mediated gene therapy in both mouse and canine models of GSD-Ia has led to long-term correction of metabolic abnormalities with no detectable toxicity.…”

Section: Treatmentmentioning

confidence: 99%

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Recent development and gene therapy for glycogen storage disease type Ia

2017

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Glycogen storage disease type Ia (GSD-Ia) is an autosomal recessive metabolic disorder caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α or G6PC) that is expressed primarily in the liver, kidney, and intestine. G6Pase-α catalyzes the hydrolysis of glucose-6-phosphate (G6P) to glucose and phosphate in the terminal step of gluconeogenesis and glycogenolysis, and is a key enzyme for endogenous glucose production. The active site of G6Pase-α is inside the endoplasmic reticulum (ER) lumen. For catalysis, the substrate G6P must be translocated from the cytoplasm into the ER lumen by a G6P transporter (G6PT). The functional coupling of G6Pase-α and G6PT maintains interprandial glucose homeostasis. Dietary therapies for GSD-Ia are available, but cannot prevent the long-term complication of hepatocellular adenoma that may undergo malignant transformation to hepatocellular carcinoma. Animal models of GSD-Ia are now available and are being exploited to both delineate the disease more precisely and develop new treatment approaches, including gene therapy.

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Section: Gsd-i-associated Hcamentioning

confidence: 95%

Section: Gsd-i-associated Hcamentioning

confidence: 98%

“…HCC-2 displayed increased levels of the active p-STAT3-Y705 protein, suggesting that HCC-2 was derived from an IHCA. 36 …”

Section: Gsd-i-associated Hcamentioning

confidence: 99%

Section: Treatmentmentioning

confidence: 99%

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Recent development and gene therapy for glycogen storage disease type Ia

2017

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“…Glucose also serves as an important metabolic intermediate of cellular respiration and glucose is stored as glycogen [3].…”

Section: Introductionmentioning

confidence: 99%

The relationship between ultraviolet, vitamin d and blood glucose, in vivo study

Bukhari

Khorshid²

2017

Trauma Emerg Care

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This study is carried on to investigate the effect of (UV) on the estimate of vitamin D production and the correlation ratio of vitamin D and its impact on the increase of blood glucose finally to prove the relationship via biochemical analysis of Vitamin D and glucose level. 90 adult rats were randomly divided into three groups. G1 (-ve control): This group contains 30 rats that were not exposed to the ultraviolet. Rats were eating daily/4 months. G2 (+ve control): This group contains 30 rats that were not exposed to the ultraviolet. Rats were fasting 2 days and eat the third day frequently (4 months). G3: Test group: To examine the exposed to the ultraviolet for 10 second to simulate sunrise and another 10 second to simulate sunset (using prototype cage). This group contains 30 rats, which were fasting 2 days and eat the third day frequently (4 months). Weights were recorder every week. The blood samples were collected through retro-orbital venous plexus in the zero time, every month, and at the end of four months and the obtained sera were subjected to the Glucose and D3 tests. The results showed that the body weights were reducing significantly in G1 compared with G3 at all measured periods (P < 0.000). Whereas no significant differences between G3 and G2 in all weeks. The Glucose levels in G1 and G3 were raised significantly in (1 st , 2 nd , 3 rd and 4 th month) (P< 0 .035), (P< 0 .036), (P< 0.030) and (P< 0.023). Also blood level of Glucose was raised significantly between G3 and G2 in all periods (P< 0 .008), (P< 0 .009), (P< 0.002) and (P< 0.001). Moreover the blood levels of Vitamin D between G1 and G3 were raised significantly in all tested periods (P< 0 .001), (P< 0 .000), (P< 0.000) and (P< 0.003). Also Vitamin D was raised significant (P< 0.000) in G3 compared with G2. This study was proved that vitamin D level was affected by the exposure to ultraviolet that intern affect the glucose level. Also ultraviolet (UV) extend to preservation of glucose homeostasis by raising glucose level. Accordingly ultraviolet (UV) raising vitamin D should be considered since this may help reduce the risk of glucose disorders.

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Modeling Phenotypic Heterogeneity of Glycogen Storage Disease Type 1a Liver Disease in Mice by Somatic CRISPR/CRISPR‐associated protein 9–Mediated Gene Editing

et al. 2021

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BaCKgRoUND aND aIMS: Patients with glycogen storage disease type 1a (GSD-1a) primarily present with lifethreatening hypoglycemia and display severe liver disease characterized by hepatomegaly. Despite strict dietary management, long-term complications still occur, such as liver tumor development. Variations in residual glucose-6-phosphatase (G6PC1) activity likely contribute to phenotypic heterogeneity in biochemical symptoms and complications between patients. However, lack of insight into the relationship between G6PC1 activity and symptoms/complications and poor understanding of the underlying disease mechanisms pose major challenges to provide optimal health care and quality of life for GSD-1a patients. Currently available GSD-1a animal models are not suitable to systematically investigate the relationship between hepatic G6PC activity and phenotypic heterogeneity or the contribution of gene-gene interactions (GGIs) in the liver.appRoaCH aND ReSUltS: To meet these needs, we generated and characterized a hepatocyte-specific GSD-1a mouse model using somatic CRISPR/CRISPR-associated protein 9 (Cas9)-mediated gene editing. Hepatic G6pc editing reduced hepatic G6PC activity up to 98% and resulted in failure to thrive, fasting hypoglycemia, hypertriglyceridemia, hepatomegaly, hepatic steatosis (HS), and increased liver tumor incidence. This approach was furthermore successful in simultaneously modulating hepatic G6PC and carbohydrate response element-binding protein, a transcription factor that is activated in GSD-1a and protects against HS under these conditions. Importantly, it also allowed for the modeling of a spectrum of GSD-1a phenotypes in terms of hepatic G6PC activity, fasting hypoglycemia, hypertriglyceridemia, hepatomegaly and HS. CoNClUSIoNS:In conclusion, we show that somatic CRISPR/Cas9-mediated gene editing allows for the modeling of a spectrum of hepatocyte-borne GSD-1a disease symptoms in mice and to efficiently study GGIs in the liver. This approach opens perspectives for translational research and will likely contribute to personalized treatments for GSD-1a and other genetic liver diseases.

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Glycogen storage disease type Ia mice with less than 2% of normal hepatic glucose-6-phosphatase-α activity restored are at risk of developing hepatic tumors

Cited by 27 publications

References 26 publications

Recent development and gene therapy for glycogen storage disease type Ia

Recent development and gene therapy for glycogen storage disease type Ia

The relationship between ultraviolet, vitamin d and blood glucose, in vivo study

Modeling Phenotypic Heterogeneity of Glycogen Storage Disease Type 1a Liver Disease in Mice by Somatic CRISPR/CRISPR‐associated protein 9–Mediated Gene Editing

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