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

Abstract

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.

Global metabolic effects of glycerol kinase overexpression in rat hepatoma cells

“…Gene expression of GK, G6PDH, fructose-1,6-bisphosphatase (F16bPase), pyruvate kinase (PyK), phosphoenolpyruvate carboxykinase (PEPCK), and citrate synthase (CS) was assayed by real time (RT)-PCR, as described previously [18] with 18s rRNA (Applied Biosystems, Foster City, CA) used as an endogenous control. Briefly, mRNA extracted from the cell lines was used to synthesize cDNA by using Superscript III reverse transcriptase (Invitrogen) and random primers.…”

A Novel Splice-Site Mutation of the Gk Gene in a Chinese Patient with Isolate Glycerol Kinase Deficiency

“…Only one patient from the literature (IVS9-1G>T) who had a history of metabolic and CNS crises at the age 6 years and 3 months, indicating the symptomatic form of GKD, but he was uneventful in the neonatal period and early childhood [10]. Previous studies showed that there was no genotype-phenotype correlation in GKD [1,11,12]. Our patient presented no symptoms, excepting no weight gain.…”

“…Only one patient from the literature (IVS9-1G>T) who had a history of metabolic and CNS crises at the age 6 years and 3 months, indicating the symptomatic form of GKD, but he was uneventful in the neonatal period and early childhood [10]. Figure 3: (1) Sequencing results blast of the products a and b, query is a, and the other is b; (2) Sequencing results blast of the products a and c, the above one is a, the other is c; (3) Sequencing results blast of the products b and d, the above is b, the below is d. Mei L, Tan H, Li H, Lv W, et al (2017) Previous studies showed that there was no genotype-phenotype correlation in GKD [1,11,12]. Our patient presented no symptoms, excepting no weight gain.…”

Argininosuccinic aciduria: from a monogenic to a complex disorder

“…24 Such sophisticated methods are required to deal adequately with environmental input while maintaining homeostasis, as well as with the complexities of eukaryotic organisms, which result from eukaryotes' multicellularity, compartmentalization of metabolites into organelles, and complex transport mechanisms. [25][26][27][28] In the liver, ASL is one of the enzymes that participates in the urea cycle. A number of studies have attempted to draw a correlation between the genotype, which determines the level of ASL enzyme activity, and the phenotype severity of patients with ASA, with limited success.…”