Glycerol kinase deficiency in adults: Description of 4 novel cases, systematic review and development of a clinical diagnostic score

Lamíquiz-Moneo, Itziar; Mateo-Gállego, Rocío; Fernández-Pardo, Jacinto; López-Ariño, C.; Marco-Benedí, Victoria; Bea, Ana M.; Ferraro, L.; Jarauta, Estíbaliz; Cenarro, Ana; Civeira, Fernando

doi:10.1016/j.atherosclerosis.2020.10.897

Cited by 5 publications

(2 citation statements)

References 31 publications

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“…Disruptions in the GK gene can lead to metabolic disturbances, emphasizing its critical importance in health preservation and disease intervention. In the context of liver cancer, changes in GK activity can be detected at the disease's early stages and continue throughout its advancement, which suggests that the GK gene is a potential therapeutic target in developing treatments for HCC [ 78 , 79 ]. In conclusion, our study demonstrates the stability of TADs in the goose liver genomes induced by an HFD, except for the two genes PRODH and GK , which have the potential as a therapeutic target for HCC.…”

Section: Discussionmentioning

confidence: 99%

Exploring the dynamic three-dimensional chromatin architecture and transcriptional landscape in goose liver tissues underlying metabolic adaptations induced by a high-fat diet

Gao,

Liu,

et al. 2024

J Animal Sci Biotechnol

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Background Goose, descendants of migratory ancestors, have undergone extensive selective breeding, resulting in their remarkable ability to accumulate fat in the liver and exhibit a high tolerance for significant energy intake. As a result, goose offers an excellent model for studying obesity, metabolic disorders, and liver diseases in mammals. Although the impact of the three-dimensional arrangement of chromatin within the cell nucleus on gene expression and transcriptional regulation is widely acknowledged, the precise functions of chromatin architecture reorganization during fat deposition in goose liver tissues still need to be fully comprehended. Results In this study, geese exhibited more pronounced changes in the liver index and triglyceride (TG) content following the consumption of the high-fat diet (HFD) than mice without significant signs of inflammation. Additionally, we performed comprehensive analyses on 10 goose liver tissues (5 HFD, 5 normal), including generating high-resolution maps of chromatin architecture, conducting whole-genome gene expression profiling, and identifying H3K27ac peaks in the livers of geese and mice subjected to the HFD. Our results unveiled a multiscale restructuring of chromatin architecture, encompassing Compartment A/B, topologically associated domains, and interactions between promoters and enhancers. The dynamism of the three-dimensional genome architecture, prompted by the HFD, assumed a pivotal role in the transcriptional regulation of crucial genes. Furthermore, we identified genes that regulate chromatin conformation changes, contributing to the metabolic adaptation process of lipid deposition and hepatic fat changes in geese in response to excessive energy intake. Moreover, we conducted a cross-species analysis comparing geese and mice exposed to the HFD, revealing unique characteristics specific to the goose liver compared to a mouse. These chromatin conformation changes help elucidate the observed characteristics of fat deposition and hepatic fat regulation in geese under conditions of excessive energy intake. Conclusions We examined the dynamic modifications in three-dimensional chromatin architecture and gene expression induced by an HFD in goose liver tissues. We conducted a cross-species analysis comparing that of mice. Our results contribute significant insights into the chromatin architecture of goose liver tissues, offering a novel perspective for investigating mammal liver diseases.

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Section: Discussionmentioning

confidence: 99%

Exploring the dynamic three-dimensional chromatin architecture and transcriptional landscape in goose liver tissues underlying metabolic adaptations induced by a high-fat diet

Gao,

Liu,

et al. 2024

J Animal Sci Biotechnol

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“…Thus, glycerol kinase deficiency in humans is an X-chromosome linked disease and is reported to be associated with abnormalities in lipid metabolism, susceptibility to diabetes, metabolic acidosis, etc. (55). Glycerol kinase knockout mice were found to have severely disturbed fat metabolism, hyperglycerolemia and postnatal growth retardation and death by 3-4 days of age (56).…”

Section: G3pp In Human Diseasesmentioning

confidence: 99%

New Mammalian Glycerol-3-Phosphate Phosphatase: Role in β-Cell, Liver and Adipocyte Metabolism

Possik¹,

Al‐Mass

Peyot³

et al. 2021

Front. Endocrinol.

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Cardiometabolic diseases, including type 2 diabetes, obesity and non-alcoholic fatty liver disease, have enormous impact on modern societies worldwide. Excess nutritional burden and nutri-stress together with sedentary lifestyles lead to these diseases. Deranged glucose, fat, and energy metabolism is at the center of nutri-stress, and glycolysis-derived glycerol-3-phosphate (Gro3P) is at the crossroads of these metabolic pathways. Cellular levels of Gro3P can be controlled by its synthesis, utilization or hydrolysis. The belief that mammalian cells do not possess an enzyme that hydrolyzes Gro3P, as in lower organisms and plants, is challenged by our recent work showing the presence of a Gro3P phosphatase (G3PP) in mammalian cells. A previously described phosphoglycolate phosphatase (PGP) in mammalian cells, with no established physiological function, has been shown to actually function as G3PP, under physiological conditions, particularly at elevated glucose levels. In the present review, we summarize evidence that supports the view that G3PP plays an important role in the regulation of gluconeogenesis and fat storage in hepatocytes, glucose stimulated insulin secretion and nutri-stress in β-cells, and lipogenesis in adipocytes. We provide a balanced perspective on the pathophysiological significance of G3PP in mammals with specific reference to cardiometabolic diseases.

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In vivo glycerol metabolism in patients with glycerol kinase deficiency

Shah,

Xu,

Kwon

et al. 2024

JIMD Reports

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Glycerol kinase deficiency (GKD) is an X‐linked recessive disorder due to glycerol kinase (GK) gene mutations resulting in hyperglycerolermia, hyperglyceroluria, and “pseudohypertriglyceridemia.” In vivo glycerol metabolism has not been assessed in GKD. A 62‐year‐old man with suspected GKD and his extended family underwent whole exome sequencing and fasting blood work with two modes of lipid measurements: (1) standard lipase‐based methodology and (2) nuclear magnetic resonance (NMR). Two overnight fasted men with GKD and a heterozygote female carrier then underwent 13C3‐glycerol infusion. Affected family members had a novel two‐nucleotide deletion in exon 5 of the GK gene (c.373_374del). Compared to their family members (n = 14), men with GKD (n = 5) had significantly lower total cholesterol levels (3.72 ± 0.70 vs. 4.77 ± 0.85 mmol/L, p = 0.024). Compared to NMR, lipase‐based assays overreported triglycerides (5.28 ± 1.38 vs. 0.81 ± 0.32, mmol/L, p < 0.001) and underreported low‐density lipoprotein cholesterol values (0.93 ± 0.23 vs. 2.18 ± 0.42 mmol/L, p = 0.001) in GKD. Men with GKD could not convert glycerol into glucose or triglycerides, which was preserved in the heterozygote carrier. Glycolytic metabolism of glycerol to lactate persisted in GKD, but it was reduced by a magnitude and, possibly, due to homologous glycerol kinases encoded by other genes. In summary, we report a novel GK pathogenic variant; affected men cannot convert circulating glycerol to glucose or triglycerides and have lower cholesterol levels. These results offer a human model for potentially targeting glycerol kinase to treat conditions associated with hyperglycemia and hyperlipidemia and warrant further investigation.

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Glycerol kinase deficiency in adults: Description of 4 novel cases, systematic review and development of a clinical diagnostic score

Cited by 5 publications

References 31 publications

Exploring the dynamic three-dimensional chromatin architecture and transcriptional landscape in goose liver tissues underlying metabolic adaptations induced by a high-fat diet

Exploring the dynamic three-dimensional chromatin architecture and transcriptional landscape in goose liver tissues underlying metabolic adaptations induced by a high-fat diet

New Mammalian Glycerol-3-Phosphate Phosphatase: Role in β-Cell, Liver and Adipocyte Metabolism

In vivo glycerol metabolism in patients with glycerol kinase deficiency

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