Hepatic Nuclear Factor 3- and Hormone-Regulated Expression of the Phosphoenolpyruvate Carboxykinase and Insulin-Like Growth Factor-Binding Protein 1 Genes

O’Brien, Richard M.; Noisin, E L; Suwanichkul, Adisak; Yamasaki, Tomoyuki; Lucas, Peter C.; Wang, Jen-Chywan; Powell, David R.; Granner, Daryl K.

doi:10.1128/mcb.15.3.1747

Cited by 218 publications

(187 citation statements)

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“…FOXO1 has been shown to activate expression of Pck1 and G6pc through directly binding to IREs mapped in the promoters of these target genes [14,15]. However, FOXQ1 may act as a transcriptional repressor [18,22].…”

Section: Resultsmentioning

confidence: 99%

“…Phosphorylated FOXO1 induced by increased insulin levels is excluded from the nucleus, thereby decreasing its transcriptional activity [5,12,13]. In contrast, the decreased blood insulin levels during fasting promote FOXO1 nuclear localisation, where it collaborates with peroxisome proliferator-activated receptor, γ, co-activator 1 α (PGC-1α) to increase the expression of the key gluconeogenic genes, Pck1 and G6pc, via direct binding to insulin response elements (IREs) in their promoters [2,11,14,15]. Hepatic FOXO1 deficiency in mice impairs fasting-induced gluconeogenesis, subsequently leading to lowered blood glucose level [8].…”

Section: Introductionmentioning

confidence: 99%

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The hepatic FOXQ1 transcription factor regulates glucose metabolism in mice

et al. 2016

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Aim/hypothesis Hepatic forkhead box q1 (FOXQ1) expression levels are regulated by nutritional and pathophysiological status. In this study we investigated the role of FOXQ1 in the regulation of hepatic gluconeogenesis. Methods We used multiple mouse and cell models to study the role of FOXQ1 in regulating expression of gluconeogenic genes, and cellular and hepatic glucose production. Results Expression of hepatic FOXQ1 was regulated by fasting in normal mice and was dysregulated in diabetic mice. Overexpression of FOXQ1 in primary hepatocytes inhibited expression of gluconeogenic genes and decreased cellular glucose output. Hepatic FOXQ1 rescue in db/db and high-fat diet-induced obese mice markedly decreased blood glucose level and improved glucose intolerance. In contrast, wildtype C57 mice with hepatic FOXQ1 deficiency displayed increased blood glucose levels and impaired glucose tolerance. Interestingly, studies into molecular mechanisms indicated that FOXQ1 interacts with FOXO1, thereby blocking FOXO1 activity on hepatic gluconeogenesis, preventing it from directly binding to insulin response elements mapped in the promoter region of gluconeogenic genes. Conclusions/interpretation FOXQ1 is a novel factor involved in regulating hepatic gluconeogenesis, and the decreased FOXQ1 expression in liver may contribute to the development of type 2 diabetes.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The hepatic FOXQ1 transcription factor regulates glucose metabolism in mice

et al. 2016

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“…The L-CPT I and actin RNAs are indicated by arrows. The tissue source of the RNA is indicated at the top of the Figure. carboxykinase (PEPCK) or insulin-like growth factor binding protein (ILGFβ) genes which are inhibited by insulin [37,38]. The transcriptional effects of long chain fatty acids and peroxisomal proliferators have been postulated to be mediated through peroxisomal proliferator-activated receptors (PPAR) [39,40].…”

Section: Figure 7 Tissue Specific Expression Of L-cpt I Mrnamentioning

confidence: 99%

Cloning and characterization of the promoter for the liver isoform of the rat carnitine palmitoyltransferase I (L-CPT I) gene

Park

Steffen

Song

et al. 1998

Biochemical Journal

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Carnitine palmitoyltransferase I (CPT I) catalyses the transfer of long chain fatty acids to carnitine for translocation across the mitochondrial inner membrane. The cDNAs of two isoforms of CPT I, termed the hepatic and muscle isoforms, have been cloned. Expression of the hepatic CPT I gene (L-CPT I) is subject to developmental, hormonal and tissue specific regulation. We have cloned the promoter of the L-CPT I gene from a rat genomic library. In the L-CPT I gene, there are two exons 5ʹ to the exon containing the ATG that initiates translation. Exon 1 and the 5ʹ end of exon 2 contain sequences that were not previously described in the rat L-CPT I cDNA. There is an alternatively spliced form of the L-CPT I mRNA in which exon 2 is skipped. The proximal promoter of the L-CPT I gene is extremely GC rich and does not contain a TATA box. There are several putative Sp1 binding sites near the transcriptional start site. A 190 base pair fragment of the promoter can efficiently drive transcription of luciferase and CAT (chloramphenicol acetyltransferase) reporter genes transiently transfected into HepG2 cells. Sequences in both the first intron and the promoter contribute to basal expression. Our results provide the foundation for further studies into the regulation of L-CPTI gene expression.

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“…This observation may have broader significance because within this region (between -460 and -456) is found the same T(G/A)TTll motif that has been identified as the core IRS in the phosphoenolpyruvate carboxykinase (PEPCK), insulin-like growth factor binding protein-I (IGFBP-I), and (probably) tyrosine aminotransferase (TAT) genes (6-9). Hepatic nuclear factor-3 (HNF-3) binds to the IRS in all three genes but does not appear to be the protein through which insulin manifests its inhibitory action on gene transcription (7). Rather, HNF-3 acts as an accessory factor required for the full induction of the transcription of all three genes by glucocorticoids (7,9 …”

mentioning

confidence: 99%

“…Hepatic nuclear factor-3 (HNF-3) binds to the IRS in all three genes but does not appear to be the protein through which insulin manifests its inhibitory action on gene transcription (7). Rather, HNF-3 acts as an accessory factor required for the full induction of the transcription of all three genes by glucocorticoids (7,9 …”

mentioning

confidence: 99%

Why there is an IRS.

O'Brien¹,

Granner²

1995

J. Clin. Invest.

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Insulin regulates the expression of at least 100 genes (1). This major action of the hormone is important for normal metabolism but gains added significance in view of the fact that insulin resistance is the cornerstone of genetic diseases such as noninsulin-dependent diabetes mellitus and obesity. The possibility that faulty regulation of gene expression by insulin could result in disease is now given credence by the observations reported by Li et al. (2) in this issue of The Journal.Hypertriglyceridemia (HTG) is a risk factor for coronary heart disease. Plasma triglycerides are carried mainly in VLDL and chylomicrons, both of which contain apo CIII as a major protein constituent; several studies have suggested that the overexpression of apo CIII causes some forms of HTG (3). Perhaps most convincing is the observation that overexpression of human apo CIII in transgenic mice results in HTG (4).Chen et al. (5) showed that transcription of the hepatic apo CIII gene is increased in diabetic mice and that insulin treatment reduces apo CIII gene transcription to basal levels. In addition, a reporter gene containing the apo CIII promoter sequence from -854 to + 22 is inhibited by insulin (5), thus the DNA sequence responsible for the insulin effect must be in that segment. Recently, Dammerman et al. (3) identified five polymorphisms in this region of the apo CIII promoter. Li et al. (2) now show that single base pair changes at either of two of the five variant sites (at -482 and -455) abolish the repression of apo CIII gene transcription by insulin, an observation that reveals why these mutations lead to apo CIII overexpression. The functional significance of the nucleotide changes in the other three variant sites is unclear but is not related to regulation of apo CIII gene expression by insulin. Moreover, the increased susceptibility to HTG associated with the mutation at -482 is dependent on the presence of a particular polymorphism in the apo CIII 3' UTR, suggesting that other factors are important in vivo.The region containing the variant sites at -482 and -455 is sufficient to confer an inhibitory effect of insulin on reporter gene expression when ligated to a minimal apo CIII promoter (Leff, T., personal communication) and therefore represents an insulin response sequence (IRS) (1). This observation may have broader significance because within this region (between -460 and -456) is found the same T(G/A)TTll motif that has been identified as the core IRS in the phosphoenolpyruvate carboxykinase (PEPCK), insulin-like growth factor binding protein-I (IGFBP-I), and (probably) tyrosine aminotransferase (TAT) genes (6-9). Hepatic nuclear factor-3 (HNF-3) binds to the IRS in all three genes but does not appear to be the protein through which insulin manifests its inhibitory action on gene transcription (7). Rather, HNF-3 acts as an accessory factor required for the full induction of the transcription of all three genes by glucocorticoids (7,9

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Hepatic Nuclear Factor 3- and Hormone-Regulated Expression of the Phosphoenolpyruvate Carboxykinase and Insulin-Like Growth Factor-Binding Protein 1 Genes

Cited by 218 publications

References 73 publications

The hepatic FOXQ1 transcription factor regulates glucose metabolism in mice

The hepatic FOXQ1 transcription factor regulates glucose metabolism in mice

Cloning and characterization of the promoter for the liver isoform of the rat carnitine palmitoyltransferase I (L-CPT I) gene

Why there is an IRS.

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