scholarly journals A Combination of Transcriptomics and Metabolomics Uncovers Enhanced Bile Acid Biosynthesis in HepG2 Cells Expressing CCAAT/Enhancer-Binding Protein β (C/EBPβ), Hepatocyte Nuclear Factor 4α (HNF4α), and Constitutive Androstane Receptor (CAR)

2013 ◽  
Vol 12 (6) ◽  
pp. 2732-2741 ◽  
Author(s):  
Marina Blazquez ◽  
Aitor Carretero ◽  
James K. Ellis ◽  
Toby J. Athersuch ◽  
Rachel Cavill ◽  
...  
Keyword(s):  
Bile Acid ◽  
Hepg2 Cells ◽  
Binding Protein ◽  
Constitutive Androstane Receptor ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Acid Biosynthesis ◽  
Bile Acid Biosynthesis ◽  
Enhancer Binding Protein ◽  
Hepatocyte Nuclear Factor 4Α

scholarly journals Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4α

2005 ◽  
Vol 47 (1) ◽  
pp. 215-227 ◽  
Author(s):  
Yusuke Inoue ◽  
Ai-Ming Yu ◽  
Sun Hee Yim ◽  
Xiaochao Ma ◽  
Kristopher W. Krausz ◽  
...  
Keyword(s):  
Bile Acid ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Acid Biosynthesis ◽  
Bile Acid Biosynthesis ◽  
Hepatocyte Nuclear Factor 4Α

scholarly journals The Xenobiotic-Sensing Nuclear Receptors Pregnane X Receptor, Constitutive Androstane Receptor, and Orphan Nuclear Receptor Hepatocyte Nuclear Factor 4α in the Regulation of Human Steroid-/Bile Acid-Sulfotransferase

2007 ◽  
Vol 21 (9) ◽  
pp. 2099-2111 ◽  
Author(s):  
Ibtissam Echchgadda ◽  
Chung S. Song ◽  
Taesung Oh ◽  
Mohamed Ahmed ◽  
Isidro John De La Cruz ◽  
...  
Keyword(s):  
Bile Acid ◽  
Nuclear Receptors ◽  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Nuclear Factor ◽  
Orphan Nuclear Receptor ◽  
Hepatocyte Nuclear Factor ◽  
Site Mutation ◽  
Composite Element ◽  
Hepatocyte Nuclear Factor 4Α

Abstract The nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are the primary transcription factors coordinating induced expression of the enzymes and proteins directing oxidative, conjugative, and transport phases of endobiotic and xenobiotic metabolism, whereas hepatocyte nuclear factor 4α (HNF4α), a regulator of hepatic lipid homeostasis, can modify the PXR/CAR response. Steroid- and bile acid-sulfotransferase (SULT2A1) promotes phase II metabolism through its sulfonating action on certain endobiotics, including steroids and bile acids, and on diverse xenobiotics, including therapeutic drugs. This study describes characterization of a PXR- and CAR-inducible composite element in the human SULT2A1 promoter and its synergistic interaction with HNF4α. Inverted and direct repeats of AG(G/T)TCA (IR2 and DR4), both binding to PXR and CAR, define the composite element. Differential recognition of the composite element by PXR and CAR is evident because single-site mutation at either IR2 or DR4 in the natural gene abolished the PXR response, whereas mutations at both repeats were necessary to abrogate completely the CAR response. The composite element conferred xenobiotic response to a heterologous promoter, and the cognate ligands induced PXR and CAR recruitment to the chromatin-associated response region. An HNF4α element adjacent to the −30 position enhanced basal promoter activity. Although functioning as a synergizer, the HNF4α element was not essential for the PXR/CAR response. An emerging role of SULT2A1 in lipid and caloric homeostasis suggests that illumination on the regulatory interactions driving human SULT2A1 expression may reveal new avenues to control certain metabolic disorders.

scholarly journals A Distal Region Involving Hepatocyte Nuclear Factor 4α and CAAT/Enhancer Binding Protein Markedly Potentiates the Protein Kinase A Stimulation of the Glucose-6-Phosphatase Promoter

2005 ◽  
Vol 19 (1) ◽  
pp. 163-174 ◽  
Author(s):  
Amandine Gautier-Stein ◽  
Gilles Mithieux ◽  
Fabienne Rajas
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Binding Sites ◽  
Binding Protein ◽  
Distal Region ◽  
Proximal Region ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Enhancer Binding Protein ◽  
Kinase A

Abstract Glucose-6-phosphatase (Glc6Pase) is the last enzyme of gluconeogenesis and is only expressed in the liver, kidney, and small intestine. In these tissues, the mRNA and its activity are increased when cAMP levels increased (e.g. in fasting or diabetes). We first report that a proximal region (within −200 bp relative to the transcription start site) and a distal region (−694/−500 bp) are both required for a potent cAMP and a protein kinase A (PKA) responsiveness of the Glc6Pase promoter. Using different molecular approaches, we demonstrate that hepatocyte nuclear factor (HNF4α), CAAT/ enhancer-binding protein-α (C/EBPα), C/EBPβ, and cAMP response element-binding protein (CREB) are involved in the potentiated PKA responsiveness: in the distal region, via one HNF4α- and one C/EBP-binding sites, and in the proximal region, via two HNF4α and two CREB-binding sites. We also show that HNF4α, C/EBPα, and C/EBPβ are constitutively bound to the endogenous Glc6Pase gene, whereas CREB and CREB-binding protein (CBP) will be bound to the gene upon stimulation by cAMP. These data strongly suggest that the cAMP responsiveness of the Glc6Pase promoter requires a tight cooperation between a proximal and a distal region, which depends on the presence of several HNF4α-, C/EBP-, and CREB-binding sites, therefore involving an intricate association of hepatic and ubiquitous transcription factors.

scholarly journals CCAAT enhancer binding protein β and hepatocyte nuclear factor 3β are necessary and sufficient to mediate dexamethasone-induced up-regulation of alpha2HS-glycoprotein/fetuin-A gene expression

2006 ◽  
Vol 36 (2) ◽  
pp. 261-277 ◽  
Author(s):  
Michael Wöltje ◽  
Beate Tschöke ◽  
Verena von Bülow ◽  
Ralf Westenfeld ◽  
Bernd Denecke ◽  
...  
Keyword(s):  
Serum Protein ◽  
Binding Protein ◽  
Protein A ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Tissue Remodelling ◽  
Mobility Shift ◽  
Fetuin A ◽  
Enhancer Binding Protein ◽  
Ccaat Enhancer Binding Protein

Alpha2HS-glycoprotein/fetuin-A (Ahsg) is a serum protein preventing soft tissue calcification. In trauma and inflammation, Ahsg is down-regulated and therefore considered a negative acute phase protein. Enhancement of Ahsg expression as a protective serum protein is desirable in several diseases including tissue remodelling after trauma and infection, kidney and heart failure, and cancer. Using reporter gene assays in hepatoma cells combined with electrophoretic mobility shift assays we determined that dexamethasone up-regulates hepatic Ahsg. A steroid response unit at position −146/−119 within the mouse Ahsg promoter mediates the glucocorticoid-induced increase of Ahsg mRNA. It binds the hepatocyte nuclear factor 3β and CCAAT enhancer binding protein β (C/EBP-β). The up-regulation is mediated indirectly via glucocorticoid hormone-induced transcriptional up-regulation in C/EBP-β protein. A high degree of sequence identity in mouse, rat and human Ahsg promoters suggests that the promoter is similarly up-regulated by dexamethasone in all three species. Therefore, our findings suggest that glucocorticoids may be used to enhance the level of Ahsg protein circulating in serum.

scholarly journals Thyroid hormones act indirectly to increase sex hormone-binding globulin production by liver via hepatocyte nuclear factor-4α

2009 ◽  
Vol 43 (1) ◽  
pp. 19-27 ◽  
Author(s):  
David M Selva ◽  
Geoffrey L Hammond
Keyword(s):  
Thyroid Hormones ◽  
Hepg2 Cells ◽  
Sex Hormone ◽  
Sex Hormone Binding Globulin ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Hormone Binding ◽  
Metabolic State ◽  
Hepatocyte Nuclear Factor 4Α

Thyroid hormones increase hepatic sex hormone-binding globulin (SHBG) production, which is also regulated by hepatocyte nuclear factor-4α (HNF-4α) in response to changes in the metabolic state of the liver. Since the human SHBG promoter lacks a typical thyroid hormone response element, and because thyroid hormones influence metabolic state, we set out to determine whether thyroid hormones mediate SHBG expression indirectly via changes in HNF-4α levels in HepG2 human hepatoblastoma cells, and in the livers of transgenic mice that express a 4.3 kb human SHBG transgene under the control of its own 0.8 kb promoter sequence. Thyroid hormones (triiodothyronine (T3) and thyroxine (T4)) increase SHBG accumulation in HepG2 cell culture medium over 5 days, and increase cellular SHBG mRNA levels. In addition, T4 treatment of HepG2 cells for 5 days increased HNF-4α mRNA and HNF-4α levels in concert with decreased cellular palmitate levels. Plasma SHBG levels were also increased in mice expressing a human SHBG transgene after 5 days treatment with T3 along with increased hepatic HNF-4α levels. In HepG2 cells, the human SHBG promoter failed to respond acutely (within 24 h) to T4 treatment, but a 4-day pre-treatment with T4 resulted in a robust response that was prevented by co-treatment with HNF-4α siRNA, or by blocking the β-oxidation of palmitate through co-treatment with the carnitine palmitoyltransferase I inhibitor, etomoxir. These data lead us to conclude that thyroid hormones increase SHBG production indirectly by increasing HNF-4α gene expression, and by reducing cellular palmitate levels that further contribute to increased HNF-4α levels in hepatocytes.

Temporal expression of the human alcohol dehydrogenase gene family during liver development correlates with differential promoter activation by hepatocyte nuclear factor 1, CCAAT/enhancer-binding protein alpha, liver activator protein, and D-element-binding protein

1992 ◽  
Vol 12 (7) ◽  
pp. 3023-3031
Author(s):  
C van Ooij ◽  
R C Snyder ◽  
B W Paeper ◽  
G Duester
Keyword(s):  
Gene Family ◽  
Fetal Liver ◽  
Binding Protein ◽  
Liver Development ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Enhancer Binding Protein ◽  
Element Binding Protein ◽  
Adh Gene ◽  
Nuclear Factor 1

The human class I alcohol dehydrogenase (ADH) gene family consists of ADH1, ADH2, and ADH3, which are sequentially activated in early fetal, late fetal, and postnatal liver, respectively. Analysis of ADH promoters revealed differential activation by several factors previously shown to control liver transcription. In cotransfection assays, the ADH1 promoter, but not the ADH2 or ADH3 promoter, was shown to respond to hepatocyte nuclear factor 1 (HNF-1), which has previously been shown to regulate transcription in early liver development. The ADH2 promoter, but not the ADH1 or ADH3 promoter, was shown to respond to CCAAT/enhancer-binding protein alpha (C/EBP alpha), a transcription factor particularly active during late fetal liver and early postnatal liver development. The ADH1, ADH2, and ADH3 promoters all responded to the liver transcription factors liver activator protein (LAP) and D-element-binding protein (DBP), which are most active in postnatal liver. For all three promoters, the activation by LAP or DBP was higher than that seen by HNF-1 or C/EBP alpha, and a significant synergism between C/EBP alpha and LAP was noticed for the ADH2 and ADH3 promoters when both factors were simultaneously cotransfected. A hierarchy of ADH promoter responsiveness to C/EBP alpha and LAP homo- and heterodimers is suggested. In all three ADH genes, LAP bound to the same four sites previously reported for C/EBP alpha (i.e., -160, -120, -40, and -20 bp), but DBP bound strongly only to the site located at -40 bp relative to the transcriptional start. Mutational analysis of ADH2 indicated that the -40 bp element accounts for most of the promoter regulation by the bZIP factors analyzed. These studies suggest that HNF-1 and C/EBP alpha help establish ADH gene family transcription in fetal liver and that LAP and DBP help maintain high-level ADH gene family transcription in postnatal liver.

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