scholarly journals Sterol Regulation of 3-Hydroxy-3-Methylglutaryl-coenzyme A Synthase Gene through a Direct Interaction Between Sterol Regulatory Element Binding Protein and the Trimeric CCAAT-binding Factor/Nuclear Factor Y

1998 ◽  
Vol 273 (3) ◽  
pp. 1349-1356 ◽  
Author(s):  
Kimberly A. Dooley ◽  
Shawn Millinder ◽  
Timothy F. Osborne
Keyword(s):  
Coenzyme A ◽  
Binding Protein ◽  
Regulatory Element ◽  
Direct Interaction ◽  
Nuclear Factor ◽  
Nuclear Factor Y ◽  
Binding Factor ◽  
Element Binding Protein ◽  
Sterol Regulatory Element

Sterol-regulatory-element-binding protein 2 and nuclear factor Y control human farnesyl diphosphate synthase expression and affect cell proliferation in hepatoblastoma cells

2010 ◽  
Vol 429 (2) ◽  
pp. 347-357 ◽  
Author(s):  
Kenji Ishimoto ◽  
Keisuke Tachibana ◽  
Ikuko Hanano ◽  
Daisuke Yamasaki ◽  
Hiroki Nakamura ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Zoledronic Acid ◽  
Binding Protein ◽  
Regulatory Element ◽  
Farnesyl Diphosphate ◽  
Farnesyl Diphosphate Synthase ◽  
Nuclear Factor ◽  
Nuclear Factor Y ◽  
Element Binding Protein ◽  
Sterol Regulatory Element

FDPS (farnesyl diphosphate synthase) catalyses the formation of farnesyl diphosphate, a key intermediate in the synthesis of cholesterol and isoprenylated cellular metabolites. FDPS is also the molecular target of nitrogen-containing bisphosphonates, which are used as bone-antiresorptive drugs in various disorders. In the present study, we characterized the sterol-response element and NF-Y (nuclear factor Y)-binding site in the human FDPS promoter. Using a luciferase assay, electrophoretic mobility-shift assay and chromatin immunoprecipitation assay, we demonstrated that these elements are responsible for the transcription of the FDPS gene, and that its transcriptional activation is mediated by SREBP-2 (sterol-regulatory-element-binding protein 2) and NF-Y. We also investigated whether sterol-mediated FDPS expression is involved in the cell proliferation induced by zoledronic acid, an FDPS inhibitor. We show that the SREBP-2- and NF-Y-mediated regulation of FDPS gene transcription modulates cell proliferation. These results suggest that SREBP-2 and NF-Y are required to trigger cell proliferation through the induction of FDPS expression and that the pharmacological action of zoledronic acid is involved in this pathway.

scholarly journals Sterol Regulatory Element Binding Protein 1a Regulates Hepatic Fatty Acid Partitioning by Activating Acetyl Coenzyme A Carboxylase 2

2009 ◽  
Vol 29 (17) ◽  
pp. 4864-4872 ◽  
Author(s):  
Seung-Soon Im ◽  
Linda E. Hammond ◽  
Leyla Yousef ◽  
Cherryl Nugas-Selby ◽  
Dong-Ju Shin ◽  
...  
Keyword(s):  
Insertional Mutagenesis ◽  
Coenzyme A ◽  
Binding Protein ◽  
Regulatory Element ◽  
Fatty Acyl ◽  
Acetyl Coenzyme A ◽  
Acetyl Coenzyme ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Microarray Expression

ABSTRACT We generated a line of mice in which sterol regulatory element binding protein 1a (SREBP-1a) was specifically inactivated by insertional mutagenesis. Homozygous mutant mice were completely viable despite expressing SREBP-1a mRNA below 5% of normal, and there were minimal effects on expression of either SREBP-1c or -2. Microarray expression studies in liver, where SREBP-1a mRNA is 1/10 the level of the highly similar SREBP-1c, demonstrated that only a few genes were affected. The only downregulated genes directly linked to lipid metabolism were Srebf1 (which encodes SREBP-1) and Acacb (which encodes acetyl coenzyme A [acetyl-CoA] carboxylase 2 [ACC2], a critical regulator of fatty acyl-CoA partitioning between cytosol and mitochondria). ACC2 regulation is particularly important during food restriction. Similar to Acacb knockout mice, SREBP-1a-deficient mice have lower hepatic triglycerides and higher serum ketones during fasting than wild-type mice. SREBP-1a and -1c have identical DNA binding and dimerization domains; thus, the failure of the more abundant SREBP-1c to substitute for activating hepatic ACC2 must relate to more efficient recruitment of transcriptional coactivators to the more potent SREBP-1a activation domain. Our chromatin immunoprecipitation results support this hypothesis.

scholarly journals Inhibition of cannabinoid CB1 receptor upregulates Slc2a4 expression via nuclear factor-κB and sterol regulatory element-binding protein-1 in adipocytes

2012 ◽  
Vol 49 (2) ◽  
pp. 97-106 ◽  
Author(s):  
D T Furuya ◽  
A C Poletto ◽  
H S Freitas ◽  
U F Machado
Keyword(s):  
Glucose Transporter ◽  
Binding Protein ◽  
Regulatory Element ◽  
Endocannabinoid System ◽  
Cb1 Receptor ◽  
Binding Activity ◽  
Nuclear Factor ◽  
Mobility Shift ◽  
Element Binding Protein ◽  
Sterol Regulatory Element

Evidences have suggested that the endocannabinoid system is overactive in obesity, resulting in enhanced endocannabinoid levels in both circulation and visceral adipose tissue. The blockade of cannabinoid receptor type 1 (CB1) has been proposed for the treatment of obesity. Besides loss of body weight, CB1 antagonism improves insulin sensitivity, in which the glucose transporter type 4 (GLUT4) plays a key role. The aim of this study was to investigate the modulation of GLUT4-encoded gene (Slc2a4 gene) expression by CB1 receptor. For this, 3T3-L1 adipocytes were incubated in the presence of a highly selective CB1 receptor agonist (1 μM arachidonyl-2′-chloroethylamide) and/or a CB1 receptor antagonist/inverse agonist (0.1, 0.5, or 1 μM AM251, 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide). After acute (2 and 4 h) and chronic (24 h) treatments, cells were harvested to evaluate: i) Slc2a4, Cnr1 (CB1 receptor-encoded gene), and Srebf1 type a (SREBP-1a type-encoded gene) mRNAs (real-time PCR); ii) GLUT4 protein (western blotting); and iii) binding activity of nuclear factor (NF)-κB and sterol regulatory element-binding protein (SREBP)-1 specifically in the promoter of Slc2a4 gene (electrophoretic mobility shift assay). Results revealed that both acute and chronic CB1 receptor antagonism greatly increased (∼2.5-fold) Slc2a4 mRNA and protein content. Additionally, CB1-induced upregulation of Slc2a4 was accompanied by decreased binding activity of NF-κB at 2 and 24 h, and by increased binding activity of the SREBP-1 at 24 h. In conclusion, these findings reveal that the blockade of CB1 receptor markedly increases Slc2a4/GLUT4 expression in adipocytes, a feature that involves NF-κB and SREBP-1 transcriptional regulation.

scholarly journals Functional Interaction of Hepatic Nuclear Factor-4 and Peroxisome Proliferator-Activated Receptor-γ Coactivator 1α in CYP7A1 Regulation Is Inhibited by a Key Lipogenic Activator, Sterol Regulatory Element-Binding Protein-1c

2007 ◽  
Vol 21 (11) ◽  
pp. 2698-2712 ◽  
Author(s):  
Bhaskar Ponugoti ◽  
Sungsoon Fang ◽  
Jongsook Kim Kemper
Keyword(s):  
Binding Protein ◽  
Regulatory Element ◽  
Dominant Negative Mutant ◽  
Peroxisome Proliferator ◽  
Nuclear Factor ◽  
Functional Interaction ◽  
Peroxisome Proliferator Activated Receptor ◽  
Histone Deacetylase 2 ◽  
Element Binding Protein ◽  
Sterol Regulatory Element

Abstract Insulin inhibits transcription of cholesterol 7α-hydroxylase (Cyp7a1), a key gene in bile acid synthesis, and the hepatic nuclear factor-4 (HNF-4) site in the promoter was identified as a negative insulin response sequence. Using a fasting/feeding protocol in mice and insulin treatment in HepG2 cells, we explored the inhibition mechanisms. Expression of sterol regulatory element-binding protein-1c (SREBP-1c), an insulin-induced lipogenic factor, inversely correlated with Cyp7a1 expression in mouse liver. Interaction of HNF-4 with its coactivator, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), was observed in livers of fasted mice and was reduced after feeding. Conversely, HNF-4 interaction with SREBP-1c was increased after feeding. In vitro studies suggested that SREBP-1c competed with PGC-1α for direct interaction with the AF2 domain of HNF-4. Reporter assays showed that SREBP-1c, but not of a SREBP-1c mutant lacking the HNF-4 interacting domain, inhibited HNF-4/PGC-1α transactivation of Cyp7a1. SREBP-1c also inhibited PGC-1α-coactivation of estrogen receptor, constitutive androstane receptor, pregnane X receptor, and farnesoid X receptor, implying inhibition of HNF-4 by SREBP-1c could extend to other nuclear receptors. In chromatin immunoprecipitation studies, HNF-4 binding to the promoter was not altered, but PGC-1α was dissociated, SREBP-1c and histone deacetylase-2 (HDAC2) were recruited, and acetylation of histone H3 was decreased upon feeding. Adenovirus-mediated expression of a SREBP-1c dominant-negative mutant, which blocks the interaction of SREBP-1c and HNF-4, partially but significantly reversed the inhibition of Cyp7a1 after feeding. Our data show that SREBP-1c functions as a non-DNA-binding inhibitor and mediates, in part, suppression of Cyp7a1 by blocking functional interaction of HNF-4 and PGC-1α. This mechanism may be relevant to known repression of many other HNF-4 target genes upon feeding.

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