Transcriptional regulation by HNF-4 of the steroid 15α-hydroxylase P450 (Cyp2a-4) gene in mouse liver

Yokomori, Norihiko; Nishio, Koji; Aida, Kaoru; Negishi, Masahiko

doi:10.1016/s0960-0760(97)00048-4

Cited by 30 publications

(23 citation statements)

References 21 publications

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“…It is essential for normal liver development (Lemaigre and Zaret, 2004) and regulates multiple liver functions, including lipid homeostasis, lipoprotein production, and bile acid biosynthesis (Hayhurst et al, 2001;Hanniman et al, 2006;Inoue et al, 2006;Miura et al, 2006). Many sex-specific hepatic genes require HNF4␣ for full expression, as evidenced by the functional binding sites for HNF4␣ found in the promoters of several sex-specific P450 genes, including mouse Cyp2a4, mouse Cyp3a16, and rat CYP2C12 (Yokomori et al, 1997;Sasaki et al, 1999;Nakayama et al, 2001). In humans, a single nucleotide polymorphism at a putative HNF4␣ binding site in the CYP2B6 gene has been linked to polymorphic gene expression (Lamba et al, 2003), and in primary human hepatocytes, HNF4␣ is required for the expression of CYP3A4, CYP3A5, and CYP2A6 (Jover et al, 2001).…”

Section: Impact Of Liver-specific Hnf4␣-deletion On Sex-specific Genementioning

confidence: 99%

“…STAT5b and HNF4␣ exhibit mutual signaling cross-talk ; STAT5b is able to enhance HNF4␣ activation of select male-specific liver P450 genes, including Cyp2d9 and CYP8B1 (Wiwi and Waxman, 2005). STAT5b and HNF4␣ binding sites are found in the promoter regions of several sex-specific Cyp genes, including Cyp2d9 and Cyp2a4 (Yokomori et al, 1997;Wiwi et al, 2004). Moreover, HNF6 (ONECUT1), a female-predominant transcription factor (Lahuna et al, 1997) that positively regulates the femalespecific genes CYP2C12 and A1BG (Delesque-Touchard et al, 2000;Gardmo and Mode, 2006), shows increased 5Ј-regulatory region binding of STAT5b and HNF4␣ in liver cells stimulated with GH (Lahuna et al, 2000).…”

Section: Downloaded Frommentioning

confidence: 99%

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Sex Differences in the Expression of Hepatic Drug Metabolizing Enzymes

Waxman

Holloway²

2009

Mol Pharmacol

619

584

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Sex differences in pharmacokinetics and pharmacodynamics characterize many drugs and contribute to individual differences in drug efficacy and toxicity. Sex-based differences in drug metabolism are the primary cause of sex-dependent pharmacokinetics and reflect underlying sex differences in the expression of hepatic enzymes active in the metabolism of drugs, steroids, fatty acids and environmental chemicals, including cytochromes P450 (P450s), sulfotransferases, glutathione transferases, and UDP-glucuronosyltransferases. Studies in the rat and mouse liver models have identified more than 1000 genes whose expression is sex-dependent; together, these genes impart substantial sexual dimorphism to liver metabolic function and pathophysiology. Sex differences in drug metabolism and pharmacokinetics also occur in humans and are due in part to the female-predominant expression of CYP3A4, the most important P450 catalyst of drug metabolism in human liver. The sexually dimorphic expression of P450s and other liver-expressed genes is regulated by the temporal pattern of plasma growth hormone (GH) release by the pituitary gland, which shows significant sex differences. These differences are most pronounced in rats and mice, where plasma GH profiles are highly pulsatile (intermittent) in male animals versus more frequent (nearly continuous) in female animals. This review discusses key features of the cell signaling and molecular regulatory mechanisms by which these sex-dependent plasma GH patterns impart sex specificity to the liver. Moreover, the essential role proposed for the GH-activated transcription factor signal transducer and activator of transcription (STAT) 5b, and for hepatic nuclear factor (HNF) 4␣, as mediators of the sexdependent effects of GH on the liver, is evaluated. Together, these studies of the cellular, molecular, and gene regulatory mechanisms that underlie sex-based differences in liver gene expression have provided novel insights into the physiological regulation of both xenobiotic and endobiotic metabolism.

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Section: Impact Of Liver-specific Hnf4␣-deletion On Sex-specific Genementioning

confidence: 99%

Section: Downloaded Frommentioning

confidence: 99%

Sex Differences in the Expression of Hepatic Drug Metabolizing Enzymes

Waxman

Holloway²

2009

Mol Pharmacol

619

584

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“…HNF4α is also a key regulator of many hepatic CYP genes, as demonstrated by in vitro promoter analyses [7][8][9][10], by expression of HNF4α antisense transcripts [11] and by characterization of mice with a liver-specific deficiency of HNF4α [2,6]. In particular, HNF4α was shown to determine the expression of a unique subset of mouse liver genes which differs markedly between the sexes.…”

Section: Introductionmentioning

confidence: 99%

Signalling cross-talk between hepatocyte nuclear factor 4α and growth-hormone-activated STAT5b

Park

Wiwi

Waxman

2006

Biochemical Journal

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In the present study, we have characterized signalling cross-talk between STAT5b (signal transducer and activator of transcription 5b) and HNF4α (hepatocyte nuclear factor 4α), two major regulators of sex-dependent gene expression in the liver. In a HepG2 liver cell model, HNF4α strongly inhibited β-casein and ntcp (Na + /taurocholate cotransporting polypeptide) promoter activity stimulated by GH (growth hormone)-activated STAT5b, but had no effect on interferon-γ -stimulated STAT1 transcriptional activity. By contrast, STAT5b synergistically enhanced the transcriptional activity of HNF4α towards the ApoCIII (apolipoprotein CIII) promoter. The inhibitory effect of HNF4α on STAT5b transcription was associated with the inhibition of GH-stimulated STAT5b tyrosine phosphorylation and nuclear translocation. The short-chain fatty acid, butyrate, reversed STAT5b transcriptional inhibition by HNF4α, but did not reverse the inhibition of STAT5b tyrosine phosphorylation. HNF4α inhibition of STAT5b tyrosine phosphorylation was not reversed by pervanadate or by dominant-negative phosphotyrosine phosphatase 1B, suggesting that it does not result from an increase in STAT5b dephosphorylation. Rather, HNF4α blocked GHstimulated tyrosine phosphorylation of JAK2 (Janus kinase 2), a STAT5b tyrosine kinase. Thus STAT5b and HNF4α exhibit bidirectional cross-talk that may augment HNF4α-dependent gene transcription while inhibiting STAT5b transcriptional activity via the inhibitory effects of HNF4α on JAK2 phosphorylation, which leads to inhibition of STAT5b signalling initiated by the GH receptor at the cell surface.

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“…However, transcriptional regulation of human CYP2A6 mRNA and protein are not well understood, even though the regulation of murine Cyp2a orthologs has been well studied. It has been reported that the hepatocyte nuclear factor-4 (HNF-4) activates hepatic expression of the mouse Cyp2a4 and Cyp2a5 genes (Yokomori et al, 1997;Ulvila et al, 2004). Similarly, human hepatocytes with reduced HNF-4␣ expression have decreased CYP2A6 mRNA levels, suggesting an important role of this transcription factor in CYP2A6 expression .…”

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confidence: 99%

Transcriptional Regulation of the Human CYP2A6 Gene

Pitarque¹,

Rodríguez‐Antona²,

Oscarson³

et al. 2005

J Pharmacol Exp Ther

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Nicotine C-oxidation is primarily catalyzed by CYP2A6 in humans. This enzymatic activity exhibits a large interindividual variability, which to a great extent is caused by genetic polymorphisms in the CYP2A6 gene. There are large interindividual differences in CYP2A6 mRNA and protein levels, but little is known about the transcriptional regulation of CYP2A6, which can, e.g., explain such differences. Using transient transfections of 5Ј-deleted CYP2A6 promoter constructs in human hepatoma B16A2 cells, we show that maximal promoter activity was harbored in the sequence spanning from Ϫ112 to Ϫ61. Putative response elements for the transcription factors hepatocyte nuclear factor-4 (HNF-4)␣, CCAAT-box/enhancer binding protein (C/EBP)␣, C/EBP␤, and octamer transcription factor-1 (Oct-1) were identified in this region, and electrophoretic mobility shift assays showed that these transcription factors bind to the predicted elements. To determine the relevance of these sites, expression vectors for these transcription factors were cotransfected with CYP2A6 promoter constructs in HepG2 cells. HNF-4␣, C/EBP␣, and Oct-1 exerted an activating effect, whereas overexpression of C/EBP␤ reduced CYP2A6 promoter activity. To confirm the importance of these sites in vivo, mutated CYP2A6 reporter constructs were injected into mouse liver. Mutation of either HNF-4 or C/EBP-Oct-1 motifs significantly decreased promoter activity, 52 and 26% of wildtype, respectively, whereas when both motifs were mutated the activity in mice decreased to 14% of wild type. In conclusion, the data indicate that the constitutive hepatic expression of CYP2A6 is governed by an interplay between the transcription factors HNF-4␣, C/EBP␣, C/EBP␤, and Oct-1. These results will be important for the identification of new polymorphisms affecting CYP2A6 gene expression.

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Transcriptional regulation by HNF-4 of the steroid 15α-hydroxylase P450 (Cyp2a-4) gene in mouse liver

Cited by 30 publications

References 21 publications

Sex Differences in the Expression of Hepatic Drug Metabolizing Enzymes

Sex Differences in the Expression of Hepatic Drug Metabolizing Enzymes

Signalling cross-talk between hepatocyte nuclear factor 4α and growth-hormone-activated STAT5b

Transcriptional Regulation of the Human CYP2A6 Gene

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