The Repression of Hormone-activated PEPCK Gene Expression by Glucose Is Insulin-independent but Requires Glucose Metabolism

Scott, Donald K.; O’Doherty, Robert M.; Stafford, John M.; Newgard, Christopher B.; Granner, Daryl K.

doi:10.1074/jbc.273.37.24145

Cited by 102 publications

(92 citation statements)

References 57 publications

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“…Insulin and glucose, by inhibiting basal and hormone-induced transcription (3,6,25), set the lower end of expression of the PEPCK gene. The synergistic effect of Dex/RA sets the upper end and expands the repertoire of responses available from this MCD.…”

Section: Discussionmentioning

confidence: 99%

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The Synergistic Effect of Dexamethasone and All-trans-retinoic Acid on Hepatic Phosphoenolpyruvate Carboxykinase Gene Expression Involves the Coactivator p300

Wang

Herzog²,

Waltner-Law³

et al. 2004

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

“…The expression of hepatic PEPCK is primarily accomplished at the transcriptional level (3). Glucagon (acting through cAMP), glucocorticoids, all-trans-retinoic acid (RA), and thyroid hormone activate PEPCK gene expression, whereas insulin and glucose are inhibitory (3)(4)(5)(6).…”

mentioning

confidence: 99%

The Synergistic Effect of Dexamethasone and All-trans-retinoic Acid on Hepatic Phosphoenolpyruvate Carboxykinase Gene Expression Involves the Coactivator p300

Wang

Herzog²,

Waltner-Law³

et al. 2004

Journal of Biological Chemistry

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“…AdHNF3-infected mice possessed minimal damage to the biliary epithelial cells as indicated by normal serum ALP levels and AdHNF3␣-infected mice exhibited delayed elevation of serum liver AST and ALT levels ( Table 1). To prevent the variation in insulin levels, which is known to influence expression of glucose homeostasis genes, 30,31 WT and Ad-infected mice were starved for 16 hours prior to harvesting the liver (Table 1; S). Compared with their fed cohorts starved AdHNF3-infected mice exhibited a diminished magnitude of increase in serum aminotransferase levels ( Table 1).…”

Section: Mouse Tail Vein Injection Of Recombinant Adenovirusmentioning

confidence: 99%

Adenovirus-mediated increase in HNF-3β or HNF-3α shows differences in levels of liver glycogen and gene expression

et al. 2002

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We previously generated a transgenic mouse line (T-77) in which increased hepatic expression of the hepatocyte nuclear factor-3␤ (HNF-3␤) protein was used to assess its role in hepatocyte-specific gene transcription. The T-77 transgenic mice displayed elevated serum bile acid and bilirubin levels and a complete absence of hepatic glycogen storage. These postnatal liver defects were associated with diminished expression of hepatocyte genes involved in gluconeogenesis and bile acid transport as well as reduced levels of hepatocyte transcription factors. In this study, we show that mouse tail vein injections of adenovirus expressing the rat HNF-3␤ (AdHNF3␤) cDNA efficiently increased its levels throughout the liver lobule and recapitulated the T-77 transgenic liver phenotype within several days postinfection. Likewise, the AdHNF3␤-infected liver phenotype was associated with reduced hepatic expression of genes involved in glucose homeostasis, bile acid transport, and bilirubin conjugation, which were not found with control adenovirus infections. These studies show that adenovirus-mediated gene transfer is an effective method for rapid hepatic increases in transcription factor levels to determine in vivo target genes. In contrast, AdHNF3␣-infected liver displayed only a transient reduction in hepatic glycogen levels and was associated with less severe decreases in hepatic expression of gluconeogenic and bilirubin metabolism genes. Consistent with these findings, only T-77 transgenic and AdHNF3␤-infected liver exhibited diminished hepatic expression of the HNF-6 transcription factor, suggesting that reduced HNF-6 levels contribute to diminished HNF-3␤-specific transcriptional activity. T he liver performs essential functions in the body by transcriptionally regulating expression of hepatocyte-specific genes encoding plasma proteins and enzymes involved in glucose metabolism, gluconeogenesis and glycogen storage, and cholesterol and bile acid homeostasis. 1,2 Functional analysis of numerous hepatocyte-specific regulatory regions reveals that they are composed of multiple cis-acting DNA sequences that bind different families of hepatocyte nuclear factors (HNF) genes. 3,4 Although none of these transcription factors is entirely liver specific, the requirement for combinatorial protein interactions among them to achieve high transcriptional levels plays an important role in maintaining hepatocyte-specific gene expression. Isolation of the cDNA clones encoding these HNF proteins facilitated the identification of their DNA binding and transcriptional activation domains. On the basis of homology within the DNA binding domains, the transcription factors were grouped into related protein families. These include the Pou-Homeodomain HNF-1, the winged helix containing Forkhead Box (Fox) HNF-3, the steroid hormone receptor HNF-4, the basic leucine zipper CCAAT/enhancer binding protein (C/EBP), and the One-Cut Homeodomain HNF-6 families. 3,4 The Fox transcription factors 5 are an extensive protein family that shares homology in th...

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“…Both PEPCK and G-6-Pase expression are regulated at the level of transcription, inhibited by insulin, and stimulated by glucagon and glucocorticoids (16,28,29,32). PEPCK and G-6-Pase promoters share a distinctive structural motif [T(G/ A)TTT(T/G)(G/T)], termed insulin response element (IRE), which is also found in the promoters of other genes that are downregulated by insulin, including insulin-like growth factor-binding protein-1 (IGFBP-1) (12,13,22).…”

mentioning

confidence: 99%

Inhibition of Foxo1 function is associated with improved fasting glycemia in diabetic mice

Altomonte

Richter²,

Harbaran³

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

186

184

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Excessive hepatic glucose production is a contributing factor to fasting hyperglycemia in diabetes. Insulin suppresses hepatic glucose production by inhibiting the expression of two gluconeogenic enzymes, phospho enolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G-6-Pase). The forkhead transcription factor Foxo1 has been implicated as a mediator of insulin action in regulating hepatic gluconeogenesis, and a Foxo1 mutant (Foxo1-Δ256), devoid of its carboxyl domain, has been shown to interfere with Foxo1 function and inhibit gluconeogenic gene expression in cultured cells. To study the effect of Foxo1-Δ256 on glucose metabolism in animals, the Foxo1-Δ256 cDNA was delivered to the livers of mice by adenovirus-mediated gene transfer. Hepatic Foxo1-Δ256 production resulted in inhibition of gluconeogenic activity, as evidenced by reduced PEPCK and G-6-Pase expression in the liver. Mice treated with the Foxo1-Δ256 vector exhibited significantly reduced blood glucose levels. In contrast, blood glucose levels in control vector-treated animals remained unchanged, which coincided with the lack of alterations in the expression levels of PEPCK and G-6-Pase. When tested in diabetic db/db mice, hepatic production of Foxo1-Δ256 was shown to reduce fasting hyperglycemia. Furthermore, we showed that hepatic Foxo1 expression was deregulated as a result of insulin resistance in diabetic mice and that Foxo1-Δ256 interfered with Foxo1 function via competitive binding to target promoters. These results demonstrated that functional inhibition of Foxo1, caused by hepatic expression of its mutant, is associated with reduced hepatic gluconeogenic activity and improved fasting glycemia in diabetic mice.

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The Repression of Hormone-activated PEPCK Gene Expression by Glucose Is Insulin-independent but Requires Glucose Metabolism

Cited by 102 publications

References 57 publications

The Synergistic Effect of Dexamethasone and All-trans-retinoic Acid on Hepatic Phosphoenolpyruvate Carboxykinase Gene Expression Involves the Coactivator p300

The Synergistic Effect of Dexamethasone and All-trans-retinoic Acid on Hepatic Phosphoenolpyruvate Carboxykinase Gene Expression Involves the Coactivator p300

Adenovirus-mediated increase in HNF-3β or HNF-3α shows differences in levels of liver glycogen and gene expression

Inhibition of Foxo1 function is associated with improved fasting glycemia in diabetic mice

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