Gene therapy for murine glycerol kinase deficiency: Importance of murine ortholog

Kuwada, Naruo; Nagano, Kei; MacLennan, Nicole K.; Havens, James J.; Kumar, Manish; Dipple, Katrina M.; McCabe, Edward R.B.

doi:10.1016/j.bbrc.2005.07.066

Cited by 12 publications

(8 citation statements)

References 24 publications

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“…Three-day-old mice were chosen for this study because this is the first day that the mice have statistically significant clinical symptoms including hypoglycemia, lower pH, lower bicarbonate, and lower base excess, which mimics the human disease. 35 It was felt that on day of life two the important changes from glycerol kinase deficiency would not be present without the clinical changes seen in mice (and humans). We believe that the majority of the changes seen on day 3 will be owing to the effects of GKD, however one cannot rule out the possibility that some will be due to the perimortum state of the mice as they die on DOL4.…”

Section: Resultsmentioning

confidence: 99%

Glycerol kinase deficiency alters expression of genes involved in lipid metabolism, carbohydrate metabolism, and insulin signaling

et al. 2007

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Glycerol kinase (GK) is at the interface of fat and carbohydrate metabolism and has been implicated in insulin resistance and type 2 diabetes mellitus. To define GK's role in insulin resistance, we examined gene expression in brown adipose tissue in a glycerol kinase knockout (KO) mouse model using microarray analysis. Global gene expression profiles of KO mice were distinct from wild type with 668 differentially expressed genes. These include genes involved in lipid metabolism, carbohydrate metabolism, insulin signaling, and insulin resistance. Real-time polymerase chain reaction analysis confirmed the differential expression of selected genes involved in lipid and carbohydrate metabolism. PathwayAssist analysis confirmed direct and indirect connections between glycerol kinase and genes in lipid metabolism, carbohydrate metabolism, insulin signaling, and insulin resistance. Network component analysis (NCA) showed that the transcription factors (TFs) PPAR-gamma, SREBP-1, SREBP-2, STAT3, STAT5, SP1, CEBPalpha, CREB, GR and PPAR-alpha have altered activity in the KO mice. NCA also revealed the individual contribution of these TFs on the expression of genes altered in the microarray data. This study elucidates the complex network of glycerol kinase and further confirms a possible role for glycerol kinase deficiency, a simple Mendelian disorder, in insulin resistance, and type 2 diabetes mellitus, a common complex genetic disorder.

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Section: Resultsmentioning

confidence: 99%

Glycerol kinase deficiency alters expression of genes involved in lipid metabolism, carbohydrate metabolism, and insulin signaling

et al. 2007

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“…We used bioinformatics tools (TargetScan, MiRanda, and DIANA microT-CDS) to predict the targets of miR-451. Among the putative targets, Cab39, 14-3-3z, and Gyk are all involved in glucose metabolism (26,29,30,39). Although Cab39 and 14-3-3z have been reported to mediate miR-451 functions other than gluconeogenesis (25-27,40), the relationship between miR-451 and Gyk is unknown.…”

Section: Gyk Is a Target Of Mir-451mentioning

confidence: 99%

“…Gyk is a rate-limiting enzyme that converts glycerol to glycerol 3-phosphate, which is the first step on the glycerol gluconeogenesis axis (39,41,42). After we identified Gyk as a target of miR-451 and found that miR-451 regulated the hepatic AKT-FOXO1-PEPCK/G6Pase pathway, we investigated whether Gyk could regulate both the glycerol gluconeogenesis axis and the AKT-FOXO1-PEPCK/G6Pase pathway.…”

Section: Gyk Regulates the Hepatic Glycerol Gluconeogenesis Axis And mentioning

confidence: 99%

MicroRNA-451 Negatively Regulates Hepatic Glucose Production and Glucose Homeostasis by Targeting Glycerol Kinase–Mediated Gluconeogenesis

et al. 2016

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MicroRNAs (miRNAs) are a new class of regulatory molecules implicated in type 2 diabetes, which is characterized by insulin resistance and hepatic glucose overproduction. We show that miRNA-451 (miR-451) is elevated in the liver tissues of dietary and genetic mouse models of diabetes. Through an adenovirus-mediated gain- and loss-of-function study, we found that miR-451 negatively regulates hepatic gluconeogenesis and blood glucose levels in normal mice and identified glycerol kinase (Gyk) as a direct target of miR-451. We demonstrate that miR-451 and Gyk regulate hepatic glucose production, the glycerol gluconeogenesis axis, and the AKT-FOXO1-PEPCK/G6Pase pathway in an opposite manner; Gyk could reverse the effect of miR-451 on hepatic gluconeogenesis and AKT-FOXO1-PEPCK/G6Pase pathway. Moreover, overexpression of miR-451 or knockdown of Gyk in diabetic mice significantly inhibited hepatic gluconeogenesis, alleviated hyperglycemia, and improved glucose tolerance. Further studies showed that miR-451 is upregulated by glucose and insulin in hepatocytes; the elevation of hepatic miR-451 in diabetic mice may contribute to inhibiting Gyk expression. This study provides the first evidence that miR-451 and Gyk regulate the AKT-FOXO1-PEPCK/G6Pase pathway and play critical roles in hepatic gluconeogenesis and glucose homeostasis and identifies miR-451 and Gyk as potential therapeutic targets against hyperglycemia in diabetes.

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“…For example, analysis of adipose tissue from glycerol kinase knockout mice revealed altered expression levels of genes involved in the insulin signaling pathway in addition to lipid and carbohydrate metabolism [13], [14]. However, glycerol kinase knockout mice die at postnatal day 3 or 4, making this a challenging animal model to study [15], [16]. Drosophila is an alternative animal model and possesses a wide array of classical and molecular genetic techniques available for investigating gene function [17], [18].…”

Section: Introductionmentioning

confidence: 99%

Glycerol Hypersensitivity in a Drosophila Model for Glycerol Kinase Deficiency Is Affected by Mutations in Eye Pigmentation Genes

2012

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Glycerol kinase plays a critical role in metabolism by converting glycerol to glycerol 3-phosphate in an ATP dependent reaction. In humans, glycerol kinase deficiency results in a wide range of phenotypic variability; patients can have severe metabolic and CNS abnormalities, while others possess hyperglycerolemia and glyceroluria with no other apparent phenotype. In an effort to help understand the pathogenic mechanisms underlying the phenotypic variation, we have created a Drosophila model for glycerol kinase deficiency by RNAi targeting of dGyk (CG18374) and dGK (CG7995). As expected, RNAi flies have reduced glycerol kinase RNA expression, reduced phosphorylation activity and elevated glycerol levels. Further investigation revealed these flies to be hypersensitive to fly food supplemented with glycerol. Due to the hygroscopic nature of glycerol, we predict glycerol hypersensitivity is a result of greater susceptibility to desiccation, suggesting glycerol kinase to play an important role in desiccation resistance in insects. To evaluate a role for genetic modifier loci in determining severity of the glycerol hypersensitivity observed in knockdown flies, we performed a preliminary screen of lethal transposon insertion mutant flies using a glycerol hypersensitive survivorship assay. We demonstrate that this type of screen can identify both enhancer and suppressor genetic loci of glycerol hypersensitivity. Furthermore, we found that the glycerol hypersensitivity phenotype can be enhanced or suppressed by null mutations in eye pigmentation genes. Taken together, our data suggest proteins encoded by eye pigmentation genes play an important role in desiccation resistance and that eye pigmentation genes are strong modifiers of the glycerol hypersensitive phenotype identified in our Drosophila model for glycerol kinase deficiency.

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Gene therapy for murine glycerol kinase deficiency: Importance of murine ortholog

Cited by 12 publications

References 24 publications

Glycerol kinase deficiency alters expression of genes involved in lipid metabolism, carbohydrate metabolism, and insulin signaling

Glycerol kinase deficiency alters expression of genes involved in lipid metabolism, carbohydrate metabolism, and insulin signaling

MicroRNA-451 Negatively Regulates Hepatic Glucose Production and Glucose Homeostasis by Targeting Glycerol Kinase–Mediated Gluconeogenesis

Glycerol Hypersensitivity in a Drosophila Model for Glycerol Kinase Deficiency Is Affected by Mutations in Eye Pigmentation Genes

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