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ABSTRACT: Glucose-6-phosphatase (G6Pase) is a key enzyme that is responsible for the production of glucose in the liver during fasting
or in type 2 diabetes mellitus (T2DM). During fasting or in T2DM, peroxisome proliferator-activated receptor α (PPARα) is
activated, which may contribute to increased hepatic glucose output. However, the mechanism by which PPARα up-regulates hepatic
G6Pase gene expression in these states is not well understood. We evaluated the mechanism by which PPARα up-regulates hepatic
G6Pase gene expression in fasting and T2DM states. In PPARα-null mice, both hepatic G6Pase and phosphoenolpyruvate carboxykinase
levels were not increased in the fasting state. Moreover, treatment of primary cultured hepatocytes with Wy14,643 or fenofibrate
increased the G6Pase mRNA level. In addition, we have localized and characterized a PPAR-responsive element in the promoter
region of the G6Pase gene. Chromatin immunoprecipitation (ChIP) assay revealed that PPARα binding to the putative PPAR-responsive
element of the G6Pase promoter was increased in fasted wild-type mice and db/db mice. These results indicate that PPARα is responsible for glucose production through the up-regulation of hepatic G6Pase
gene expression during fasting or T2DM animal models.
Journal of Biological Chemistry 01/2011; 286(2):1157-1164. · 4.77 Impact Factor
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ABSTRACT: Glucose-6-phosphatase (G6Pase) is a key liver enzyme in glucose synthesis activated by hyperglycemic conditions caused by
fasting or type 2 diabetes mellitus (T2DM). These conditions activate the peroxisome proliferator activated receptor alpha
(PPARα), which is thought to contribute to increased hepatic glucose output via unknown mechanisms involving G6Pase. We found
that hepatic G6Pase and phosphoenolpyruvate carboxykinase (PEPCK) levels did not increase in fasting PPARα null mice, suggesting
that PPARα is required for G6Pase expression. Consistent with this model, treatment of primary-cultured hepatocytes with the
PPAR agonist Wy14,643 increased G6Pase mRNA levels. In addition, we identified and characterized a PPARα responsive element
(PPRE) in the promoter region of the G6Pase gene. Chromatin immunoprecipitation (ChIP) assays demonstrated that the levels
of PPARα/RXRα bound to the PPRE of the G6Pase promoter were higher in fasting wild type mice and db/db mice than in wild type
fed control mice. These results indicate that PPARα stimulates glucose production by upregulating hepatic G6Pase gene expression
caused by fasting or type 2 diabetes in mice.
Journal of Biological Chemistry 11/2010; · 4.77 Impact Factor
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ABSTRACT: Glucose-6-phosphatase (G6Pase) is a key enzyme that is responsible for the production of glucose in the liver during fasting or in type 2 diabetes mellitus (T2DM). During fasting or in T2DM, peroxisome proliferator-activated receptor α (PPARα) is activated, which may contribute to increased hepatic glucose output. However, the mechanism by which PPARα up-regulates hepatic G6Pase gene expression in these states is not well understood. We evaluated the mechanism by which PPARα up-regulates hepatic G6Pase gene expression in fasting and T2DM states. In PPARα-null mice, both hepatic G6Pase and phosphoenolpyruvate carboxykinase levels were not increased in the fasting state. Moreover, treatment of primary cultured hepatocytes with Wy14,643 or fenofibrate increased the G6Pase mRNA level. In addition, we have localized and characterized a PPAR-responsive element in the promoter region of the G6Pase gene. Chromatin immunoprecipitation (ChIP) assay revealed that PPARα binding to the putative PPAR-responsive element of the G6Pase promoter was increased in fasted wild-type mice and db/db mice. These results indicate that PPARα is responsible for glucose production through the up-regulation of hepatic G6Pase gene expression during fasting or T2DM animal models.
Journal of Biological Chemistry 11/2010; 286(2):1157-64. · 4.77 Impact Factor
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ABSTRACT: The mechanism of how PPARgamma decrease gluconeogenic gene expressions in liver is still unclear. Since PPARgamma is a transcriptional activator, it requires a mediator to decrease the transcription of gluconeogenic genes. Recently, SHP has been shown to mediate the bile acid-dependent down regulation of gluconeogenic gene expression in liver. This led us to explore the possibility that SHP may mediate the antigluconeogenic effect of PPARgamma. In the present study, we have identified and characterized the presence of functional PPRE in human SHP promoter. We show the binding of PPARgamma/RXRalpha heterodimer to the PPRE and increased SHP expression by rosiglitazone in primary rat hepatocytes. Taken together with the previous reports about the function of SHP on gluconeogenesis, our results indicate that SHP can mediate the acute antigluconeogenic effect of PPARgamma.
Biochemical and Biophysical Research Communications 09/2007; 360(2):301-6. · 2.48 Impact Factor
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ABSTRACT: The gene expression of glucose transporter type 4 isoform (GLUT4) is known to be controlled by metabolic, nutritional, or hormonal status. Understanding the molecular mechanisms governing GLUT4 gene expression is critical, because glucose disposal in the body depends on the activities of GLUT4 in the muscle and adipocytes. The GLUT4 activities are regulated by a variety of mechanisms. One of them is transcriptional regulation. GLUT4 gene expression is regulated by a variety of transcriptional factors in muscle and adipose tissue. These data are accumulating regarding the transcriptional factors regulating GLUT4 gene expression. These include MyoD, MEF2A, GEF, TNF-alpha, TR-1alpha, KLF15, SREBP-1c, C/EBP-alpha, O/E-1, free fatty acids, PAPRgamma, LXRalpha, NF-1, etc. These factors are involved in the positive or negative regulation of GLUT4 gene expression. In addition, there is a complex interplay between these factors in transactivating GLUT4 promoter activity. Understanding the mechanisms controlling GLUT4 gene transcription in these tissues will greatly promote the potential therapeutic drug development for obesity and T2DM.
International Union of Biochemistry and Molecular Biology Life 04/2007; 59(3):134-45. · 3.51 Impact Factor
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ABSTRACT: Expression of the GLUT4 (glucose transporter type 4 isoform) gene in adipocytes is subject to hormonal or metabolic control. In the present study, we have characterized an adipose tissue transcription factor that is influenced by fasting/refeeding regimens and insulin. Northern blotting showed that refeeding increased GLUT4 mRNA levels for 24 h in adipose tissue. Consistent with an increased GLUT4 gene expression, the mRNA levels of SREBP (sterol-regulatory-element-binding protein)-1c in adipose tissue were also increased by refeeding. In streptozotocin-induced diabetic rats, insulin treatment increased the mRNA levels of GLUT4 in adipose tissue. Serial deletion, luciferase reporter assays and electrophoretic mobility-shift assay studies indicated that the putative sterol response element is located in the region between bases -109 and -100 of the human GLUT4 promoter. Transduction of the SREBP-1c dominant negative form to differentiated 3T3-L1 adipocytes caused a reduction in the mRNA levels of GLUT4, suggesting that SREBP-1c mediates the transcription of GLUT4. In vivo chromatin immunoprecipitation revealed that refeeding increased the binding of SREBP-1 to the putative sterol-response element in the GLUT4. Furthermore, treating streptozotocin-induced diabetic rats with insulin restored SREBP-1 binding. In addition, we have identified an Sp1 binding site adjacent to the functional sterol-response element in the GLUT4 promoter. The Sp1 site appears to play an additive role in SREBP-1c mediated GLUT4 gene upregulation. These results suggest that upregulation of GLUT4 gene transcription might be directly mediated by SREBP-1c in adipose tissue.
Biochemical Journal 11/2006; 399(1):131-9. · 4.90 Impact Factor
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[show abstract]
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ABSTRACT: The mechanism of how PPARγ decrease gluconeogenic gene expressions in liver is still unclear. Since PPARγ is a transcriptional activator, it requires a mediator to decrease the transcription of gluconeogenic genes. Recently, SHP has been shown to mediate the bile acid-dependent down regulation of gluconeogenic gene expression in liver. This led us to explore the possibility that SHP may mediate the antigluconeogenic effect of PPARγ. In the present study, we have identified and characterized the presence of functional PPRE in human SHP promoter. We show the binding of PPARγ/RXRα heterodimer to the PPRE and increased SHP expression by rosiglitazone in primary rat hepatocytes. Taken together with the previous reports about the function of SHP on gluconeogenesis, our results indicate that SHP can mediate the acute antigluconeogenic effect of PPARγ.
Biochemical and Biophysical Research Communications.
