Glucose administration induces the premature expression of liver glucokinase gene in newborn rats

Bossard, Pascale; Parsa, Ramine; Decaux, Jean‐François; Iynedjian, Patrick B.; Girard, Jean

doi:10.1111/j.1432-1033.1993.tb18106.x

Cited by 21 publications

(27 citation statements)

References 45 publications

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“…To answer this question, two types of experiments were performed. First, as previously reported, the oral administration of glucose to 10-day-old suckling rats provoked a rapid accumulation (within 6 h) of glucokinase mRNA by increasing the rate of gene transcription [38]. After 18 h, both glucokinase mRNA and gene transcription had returned to very low values [38].…”

Section: Exposure Of Suckling Rat Liver To High Plasma Insulin Level mentioning

confidence: 54%

Initial expression of glucokinase gene in cultured hepatocytes from suckling rats is linked to the synthesis of an insulin‐dependent protein

Bossard¹,

Decaux²,

Juanes³

et al. 1994

European Journal of Biochemistry

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The initial accumulation of glucokinase mRNA in response to insulin in cultured hepatocytes from 10-day-old suckling rats was characterized by a delay of 18-24 h with a maximal level reached after 48 h. This delay is not observed in cultured adult rat hepatocytes. When hepatocytes from 10-day-old suckling rats were cultured for 48 h in the presence of insulin (to obtain a maximal accumulation of glucokinase mRNA) and then deprived of insulin for 18 h, glucokinase mRNA returned to very low levels. Reexposure of these cultured hepatocytes to insulin allowed a rapid accumulation of glucokinase mRNA, with a maximal level reached after 8 h, as in adult rat hepatocytes. The aim of the present study was to investigate the factors responsible for the delay in insulin action during first exposure to insulin. The difference in the kinetics of glucolunase mRNA accumulation after the first and secondary exposure to insulin was due to differences in the rate of transcriptional activity of the glucokinase gene, as shown by a run-on assay on isolated nuclei. The half-life of glucokinase mRNA was similar after the first and second exposure to insulin. The delay in the initial accumulation of glucokinase mRNA in response to the first exposure to insulin was not due to elevated levels of CAMP (a potent inhibitor of glucokinase gene expression) or to a defect in insulin signalling (insulin inhibited without delay phosphoenolpyruvate carboxykinase gene expression). In contrast, it was markedly dependent upon whether glucokinase has been already expressed in vivo. Hepatocytes from rats that had already expressed glucokinase in vivo (suckling rats force-fed with glucose or rats weaned to a high-carbohydrate diet) showed no delay in their response to insulin in culture, whereas hepatocytes from rats that have never expressed glucokinase in vivo (suckling rats or rats weaned to a high-fat diet) showed a delay of 24 h. Two different inhibitors of protein synthesis (cycloheximide and puromycin) prevented the initial accumulation of glucokinase mRNA in response to the first exposure to insulin but not to the secondary accumulation of glucokinase mRNA in response to reexposure to insulin. This suggests that the synthesis of one or several insulin-dependent proteins is necessary for the first activation of glucokinase gene transcription in response to the first exposure to insulin.Glucokinase, a key enzyme of the glycolytic pathway, catalyses the ATP-dependent phosphorylation of glucose into glucose 6-phosphate. It is the predominant isoform of hexokinase expressed in the liver and the only one present in parenchymal cells [l-31. It has a higher K, for glucose (=lo mh4 versus =20-130 pM) and a higher specificity for glucose [4] than other hexokinases and it is not inhibited by its reaction product glucose 6-phosphate. These properties allow for rapid adjustements in the rate of liver glucose phosphorylation in response to changes in plasma glucose concentration [5].In adult rat liver, glucokinase activity is subject to longterm changes depe...

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Section: Exposure Of Suckling Rat Liver To High Plasma Insulin Level mentioning

confidence: 54%

Initial expression of glucokinase gene in cultured hepatocytes from suckling rats is linked to the synthesis of an insulin‐dependent protein

Bossard¹,

Decaux²,

Juanes³

et al. 1994

European Journal of Biochemistry

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“…The Gck promoter structure [13,28,38], shown in Fig. 2a by nest PCR from nt −518 to nt +83 and sequenced directly.…”

Section: Resultsmentioning

confidence: 99%

“…Here, we have presented data to support the notion that differential DNA methylation results in the agedependent reduction of Gck expression. The Gck promoter structure [13,28,38] is shown in Fig. 2a.…”

Section: Discussionmentioning

confidence: 99%

Hypermethylation of hepatic Gck promoter in ageing rats contributes to diabetogenic potential

et al. 2008

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Aims/hypothesis Hepatic glucokinase (GCK) is a key enzyme in glucose utilisation. Downregulation of its activity is associated with insulin resistance and type 2 diabetes mellitus. However, it is unknown whether hepatic Gck expression is influenced by age and is involved in ageing-mediated diabetes, and whether the degree of methylation of the hepatic Gck promoter is correlated with the transcription of Gck. To address the question, we evaluated hepatic Gck transcription and promoter methylation in young (14 weeks), adult (40 weeks) and aged (80 weeks) rats. Methods Hepatic glycogen, Gck expression and the kinase activity of GCK were measured in three age groups. The CpG methylation status was determined by both bisulphite direct sequencing and clone sequencing of the PCR amplificates of Gck promoter. The causal relationship between Gck methylation and mRNA expression was confirmed by treating rat primary hepatocytes with 5-aza-2′-deoxycytidine (5-Aza-CdR). Results We have shown an age-associated decline in hepatic glycogen, Gck expression levels and the kinase activity of hepatic GCK. The eleven CpG sites studied displayed age-related progressive methylation changes in hepatic Gck promoter, which were confirmed by two methods: direct and clone sequencing. After 5-Aza-CdR treatment of rat primary hepatocytes, there was a fourfold increase in Gck expression. Conclusions/interpretation Our results demonstrate that an age-related increase in methylation is negatively associated with hepatic Gck expression, suggesting that DNA methylation could be involved in increasing age-dependent susceptibility to hepatic insulin resistance and diabetes. Thus, the epigenetic modification of the hepatic Gck promoter may represent an important marker for diabetogenic potential during the ageing process.

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“…This fragment is located at the beginning of the first intron of the gene. The probe was labelled by random priming and the blot was washed as described [9] before autoradiography.…”

Section: Dnase Hypersensitives Sitesmentioning

confidence: 99%

“…Indeed mutasensitive sites (Hss), which are indicative of nucleosome disruption. This technique has shown that, both in rats and in mice, the hepatic promoter of the glucokinase gene encompasses about 7 kb of 5′ flanking sequence [9,10,11]. The factors that determine the liver-specific transcription of the hepatic glucokinase mRNA have not been identified.…”

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confidence: 99%

Liver glucokinase gene expression is controlled by the onecut transcription factor hepatocyte nuclear factor-6

et al. 2002

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Aims/hypothesis. Glucokinase plays a key role in glucose homeostasis and the expression of its gene is differentially regulated in pancreatic beta cells and in the liver through distinct promoters. The factors that determine the tissue-specific expression of the glucokinase gene are not known. Putative binding sites for hepatocyte nuclear factor (HNF)-6, the prototype of the ONECUT family of transcription factors, are present in the hepatic promoter of the glucokinase gene and in diabetic hnf6 knockout mice. We hypothesized that HNF-6 controls the activity of the hepatic glucokinase promoter. Methods. We tested the binding of recombinant HNF-6 to DNA sequences from the mouse hepatic glucokinase promoter in vitro and the effect of HNF-6 on promoter activity in transfected cells. We investigated in vivo the role of HNF-6 in mice by examining the effect of inactivating the hnf6 gene on glucokinase gene-specific deoxyribonuclease I hypersensitive sites in liver chromatin and on liver glucokinase mRNA concentration.Results. HNF-6 bound to the hepatic promoter of the glucokinase gene and stimulated its activity. Inactivation of the hnf6 gene did not modify the pattern of deoxyribonuclease I hypersensitive sites but was associated with a decrease of liver glucokinase mRNA to half the control value. Conclusions/interpretation. Although HNF-6 is not required to open chromatin of the hepatic promoter of the glucokinase gene, it stimulates transcription of the glucokinase gene in the liver. This could partly explain the diabetes observed in hnf6 knockout mice.

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Glucose administration induces the premature expression of liver glucokinase gene in newborn rats

Cited by 21 publications

References 45 publications

Initial expression of glucokinase gene in cultured hepatocytes from suckling rats is linked to the synthesis of an insulin‐dependent protein

Initial expression of glucokinase gene in cultured hepatocytes from suckling rats is linked to the synthesis of an insulin‐dependent protein

Hypermethylation of hepatic Gck promoter in ageing rats contributes to diabetogenic potential

Liver glucokinase gene expression is controlled by the onecut transcription factor hepatocyte nuclear factor-6

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