Activation of glucokinase gene expression by hepatic nuclear factor 4α in primary hepatocytes

Roth, Ulrike; Jungermann, Kurt; Kietzmann, Thomas

doi:10.1042/bj20020340

Cited by 44 publications

(39 citation statements)

References 55 publications

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“…2B, treatment with resveratrol reduced GK activity in a dose-dependent fashion in the presence of different glucose concentrations. In contrast, insulin induced GK enzyme activity ϳ2-fold, consistent with previous studies (13). As shown in Fig.…”

Section: Suppression Of Glucokinase Expression By Resveratrol-tosupporting

confidence: 80%

“…Digoxigenin-labeled antisense RNA hybridization probes were generated by in vitro transcription from pBS-GK-1 using T3 RNA polymerase or from pBS-␤-actin using T7 RNA polymerase and RNA labeling mixture containing 3.5 mM 11-digoxigenin-UTP, 6.5 mM UTP, 10 mM GTP, 10 mM CTP, and 10 mM ATP. Hybidizations and detections by chemiluminescence were carried out essentially as previously described (13). Blots were quantified with a videodensitometer (Biotech Fischer, Reiskirchen, Germany).…”

Section: Methodsmentioning

confidence: 99%

“…RNA Preparation and Northern Analysis-Isolation of total RNA and Northern analysis were performed as described (13,55). Digoxigenin-labeled antisense RNA hybridization probes were generated by in vitro transcription from pBS-GK-1 using T3 RNA polymerase or from pBS-␤-actin using T7 RNA polymerase and RNA labeling mixture containing 3.5 mM 11-digoxigenin-UTP, 6.5 mM UTP, 10 mM GTP, 10 mM CTP, and 10 mM ATP.…”

Section: Methodsmentioning

confidence: 99%

“…Plasmid Constructs-Luciferase (Luc) reporter gene plasmids containing the wild type rat GK promoter and the GK promoter mutated in the HNF binding site (13) or an array of five Gal4 binding sites upstream of the minimal E1b promoter upstream of the firefly luciferase cDNA (pG 5 E1B-Luc) (47) were described previously. The constructs pGL3rGK-mFBEa, pGL3rGK-mFBEb, and pGL3rGK-dmFBEab contain mutations of putative FoxO-binding element a or b (FBEa or FBEb) or both, respectively.…”

Section: Methodsmentioning

confidence: 99%

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FOXO1 and HNF-4 are involved in regulation of hepatic glucokinase gene expression by Resveratrol

Kietzmann¹,

Ganjam²,

Dimova³

2010

Z Gastroenterol

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Resveratrol, a polyphenol derived from grapes, exerts important effects on glucose and lipid metabolism, yet detailed mechanisms mediating these effects remain unknown. The liver plays a central role in energy homeostasis, and glucokinase (GK) is a key enzyme involved in glucose utilization. Resveratrol activates SIRT1 (sirtuin 1), which promotes deacetylation of the forkhead transcription factor FoxO1. Previously, we reported that FoxO1 can suppress and that HNF-4 can stimulate GK expression in the liver. Here, we examined the role of FoxO1 and HNF-4 in mediating resveratrol effects on liver GK expression. Resveratrol suppressed hepatic GK expression in vivo and in isolated hepatocytes, and knocking down FoxO1 with shRNAs disrupted this effect. Reporter gene, gel shift, supershift assay, and chromatin immunoprecipitation studies show that FoxO1 binds to the GK promoter and that the interplay between FoxO1 and HNF-4 within the GK promoter is essential for mediating the effects of resveratrol. Resveratrol promotes deacetylation of FoxO1 and enhances its recruitment to the FoxO-binding element. Conversely, resveratrol suppresses recruitment of HNF-4 to its binding site, and knockdown of FoxO1 blocks this effect of resveratrol. Coprecipitation and chromatin immunoprecipitation studies show that resveratrol enhances interaction between FoxO1 and HNF-4, reduces binding of HNF-4 to its own site, and promotes its recruitment to the FoxO site in a FoxO1-dependent manner. These results provide the first evidence that resveratrol represses GK expression via FoxO1 and that the interaction between FoxO1 and HNF-4 contributes to these effects of resveratrol.The liver is a key organ in energy homeostasis, and glucokinase (GK) 3 plays a major role in promoting hepatic glucose utilization and maintenance of blood glucose homeostasis.Compared with other hexokinases, GK has a smaller molecular mass (100 versus 52 kDa, respectively) and a lower affinity for glucose, with an S 0.5 for glucose in the range of about 7-8 mmol/liter. Although GK binds to a regulatory protein (GKRP) and exists as a monomer, it displays sigmoidal kinetics with a Hill coefficient of about 1.5-1.7, indicating cooperativity with its substrate, glucose (1-3). These characteristics allow GK to react with glucose across the range of physiological glucose concentrations reached in vivo. Although GK is expressed predominantly in hepatocytes and pancreatic ␤-cells, it also is expressed in some neuroendocrine cells of the gastrointestinal tract and the brain, where it also may contribute to glucose sensing (4).In the liver, GK is expressed predominantly in the less aerobic perivenous zone (5), and its expression is stimulated by insulin (6). Previous studies indicate that several transcription factors, including USF-1 and -2 (upstream stimulatory factor-1 and -2) (7, 8), HIF-1 (hypoxia-inducible factor-1) (9), PPAR␥ (peroxisome proliferator-activated receptor-␥) (10), sterol regulatory element binding protein-1c (11,12), and hepatocyte nuclear factor-4␣ (HNF-4␣) (...

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Section: Suppression Of Glucokinase Expression By Resveratrol-tosupporting

confidence: 80%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

FOXO1 and HNF-4 are involved in regulation of hepatic glucokinase gene expression by Resveratrol

Kietzmann¹,

Ganjam²,

Dimova³

2010

Z Gastroenterol

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“…HNF-4 is known to interact with the ␤-subunit of HIF-1 and both, the ␣-and ␤-subunits of HIF-1 are able to bind the transcriptional activator p300 (34, 35, 52). We recently identified an HNF-4-responsive element located downstream to the GK-HRE, implicating a similar mechanism of transcriptional regulation as with the EPO gene (30).…”

Section: Insulin Stimulates Rat Gk Promoter Activity In Hepatocytes Vmentioning

confidence: 99%

The Transcription Factors HIF-1 and HNF-4 and the Coactivator p300 Are Involved in Insulin-regulated Glucokinase Gene Expression via the Phosphatidylinositol 3-Kinase/Protein Kinase B Pathway

Roth

Curth

Unterman

et al. 2004

Journal of Biological Chemistry

Self Cite

104

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Glucokinase plays a key role in the regulation of glucose utilization in liver and its expression is strongly enhanced by insulin and modulated by venous pO 2 . In primary rat hepatocytes, pO 2 modulated insulindependent glucokinase (GK) gene expression was abolished by wortmannin an inhibitor of phosphatidylinositol 3-kinase (PI3K). Transfection of vectors encoding the p110 catalytic subunit of PI3K or constitutively active proteinkinase B (PKB) stimulated GK mRNA and protein expression. The transfection of GK promoter constructs together with expression vectors for p110 or constitutively active PKB revealed that the GK promoter region ؊87/؊80 mediates the response to PI3K/PKB. Transfection experiments and gel shift assays show that this element is able to bind hypoxia-inducible factor-1 (HIF-1) in a hypoxia-and PKB-dependent manner. The ability of HIF-1␣ to activate the GK promoter was enhanced by hepatocyte nuclear factor-4␣ (HNF-4␣), acting via the sequence ؊52/؊39, and by the coactivator p300. Stimulation of the GK promoter by insulin was dependent on the intact ؊87/؊80 region and maximal stimulation was achieved when HIF-1␣, HNF-4, and p300 were cotransfected with the ؊1430 GK promoter Luc construct in primary hepatocytes. Maximal stimulation of GK promoter activity by insulin was inhibited when a p300 vector was used containing a mutation within a PKB phosphorylation site. Thus, a regulatory transcriptional complex consisting of HIF-1, HNF-4, and p300 appears to be involved in insulin-dependent GK gene activation.

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Molecular Physiology of Mammalian Glucokinase

Iynedjian

2008

Cell. Mol. Life Sci.

310

294

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Abstract. The glucokinase (GCK) gene was one of the first candidate genes to be identified as a human "diabetes gene". Subsequently, important advances were made in understanding the impact of GCK in the regulation of glucose metabolism. Structure elucidation by crystallography provided insight into the kinetic properties of GCK. Protein interaction partners of GCK were discovered. Gene expression studies revealed new facets of the tissue distribution of GCK, including in the brain, and its regulation by insulin in the liver. Metabolic control analysis coupled to gene overexpression and knockout experiments highlighted the unique impact of GCK as a regulator of glucose metabolism. Human GCK mutants were studied biochemically to understand disease mechanisms. Drug development programs identified small molecule activators of GCK as potential antidiabetics. These advances are summarized here, with the aim of offering an integrated view of the role of GCK in the molecular physiology and medicine of glucose homeostasis.

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Activation of glucokinase gene expression by hepatic nuclear factor 4α in primary hepatocytes

Cited by 44 publications

References 55 publications

FOXO1 and HNF-4 are involved in regulation of hepatic glucokinase gene expression by Resveratrol

FOXO1 and HNF-4 are involved in regulation of hepatic glucokinase gene expression by Resveratrol

The Transcription Factors HIF-1 and HNF-4 and the Coactivator p300 Are Involved in Insulin-regulated Glucokinase Gene Expression via the Phosphatidylinositol 3-Kinase/Protein Kinase B Pathway

Molecular Physiology of Mammalian Glucokinase

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