Transcriptional regulation of the human acetoacetyl-CoA synthetase gene by PPARγ

2010 ◽  
Vol 427 (2) ◽  
pp. 255-264 ◽  
Author(s):  
Francesca Aguiló ◽  
Nuria Camarero ◽  
Joana Relat ◽  
Pedro F. Marrero ◽  
Diego Haro
Keyword(s):  
Gene Expression ◽  
Fatty Acids ◽  
Target Gene ◽  
Adipocyte Differentiation ◽  
Ketone Bodies ◽  
Physiological Role ◽  
Direct Interaction ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Human Promoter

In the cytosol of lipogenic tissue, ketone bodies are activated by AACS (acetoacetyl-CoA synthetase) and incorporated into cholesterol and fatty acids. AACS gene expression is particularly abundant in white adipose tissue, as it is induced during adipocyte differentiation. In order to elucidate the mechanism controlling the gene expression of human AACS and to clarify its physiological role, we isolated the human promoter, characterized the elements required to initiate transcription and analysed the expression of the gene in response to PPARγ (peroxisome-proliferator-activated receptor γ), an inducer of adipogenesis. We show that the human AACS promoter is a PPARγ target gene and that this nuclear receptor is recruited to the AACS promoter by direct interaction with Sp1 (stimulating protein-1).

scholarly journals Activated Liver X Receptors Stimulate Adipocyte Differentiation through Induction of Peroxisome Proliferator-Activated Receptor γ Expression

2004 ◽  
Vol 24 (8) ◽  
pp. 3430-3444 ◽  
Author(s):  
Jong Bae Seo ◽  
Hyang Mi Moon ◽  
Woo Sik Kim ◽  
Yun Sok Lee ◽  
Hyun Woo Jeong ◽  
...  
Keyword(s):  
Gene Expression ◽  
Target Gene ◽  
Adipocyte Differentiation ◽  
Specific Gene ◽  
Peroxisome Proliferator ◽  
Liver X Receptors ◽  
Gene Promoters ◽  
Peroxisome Proliferator Activated Receptor ◽  
Specific Gene Expression ◽  
X Receptors

ABSTRACT Liver X receptors (LXRs) are nuclear hormone receptors that regulate cholesterol and fatty acid metabolism in liver tissue and in macrophages. Although LXR activation enhances lipogenesis, it is not well understood whether LXRs are involved in adipocyte differentiation. Here, we show that LXR activation stimulated the execution of adipogenesis, as determined by lipid droplet accumulation and adipocyte-specific gene expression in vivo and in vitro. In adipocytes, LXR activation with T0901317 primarily enhanced the expression of lipogenic genes such as the ADD1/SREBP1c and FAS genes and substantially increased the expression of the adipocyte-specific genes encoding PPARγ (peroxisome proliferator-activated receptor γ) and aP2. Administration of the LXR agonist T0901317 to lean mice promoted the expression of most lipogenic and adipogenic genes in fat and liver tissues. It is of interest that the PPARγ gene is a novel target gene of LXR, since the PPARγ promoter contains the conserved binding site of LXR and was transactivated by the expression of LXRα. Moreover, activated LXRα exhibited an increase of DNA binding to its target gene promoters, such as ADD1/SREBP1c and PPARγ, which appeared to be closely associated with hyperacetylation of histone H3 in the promoter regions of those genes. Furthermore, the suppression of LXRα by small interfering RNA attenuated adipocyte differentiation. Taken together, these results suggest that LXR plays a role in the execution of adipocyte differentiation by regulation of lipogenesis and adipocyte-specific gene expression.

scholarly journals Alternative Mechanisms by Which Mediator Subunit MED1/TRAP220 Regulates Peroxisome Proliferator-Activated Receptor γ-Stimulated Adipogenesis and Target Gene Expression

2007 ◽  
Vol 28 (3) ◽  
pp. 1081-1091 ◽  
Author(s):  
Kai Ge ◽  
Young-Wook Cho ◽  
Hong Guo ◽  
Teresa B. Hong ◽  
Mohamed Guermah ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Polymerase Ii ◽  
Nuclear Receptor ◽  
Transcriptional Activity ◽  
Target Gene ◽  
Molecular Mechanisms ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cultured Fibroblasts ◽  
Target Gene Expression

ABSTRACT Mediator is a general coactivator complex connecting transcription activators and RNA polymerase II. Recent work has shown that the nuclear receptor-interacting MED1/TRAP220 subunit of Mediator is required for peroxisome proliferator-activated receptor γ (PPARγ)-stimulated adipogenesis of mouse embryonic fibroblasts (MEFs). However, the molecular mechanisms remain undefined. Here, we show an intracellular PPARγ-Mediator interaction that requires the two LXXLL nuclear receptor recognition motifs on MED1/TRAP220 and, furthermore, we show that the intact LXXLL motifs are essential for optimal PPARγ function in a reconstituted cell-free transcription system. Surprisingly, a conserved N-terminal region of MED1/TRAP220 that lacks the LXXLL motifs but gets incorporated into Mediator fully supports PPARγ-stimulated adipogenesis. Moreover, in undifferentiated MEFs, MED1/TRAP220 is dispensable both for PPARγ-mediated target gene activation and for recruitment of Mediator to a PPAR response element on the aP2 target gene promoter. However, PPARγ shows significantly reduced transcriptional activity in cells deficient for a subunit (MED24/TRAP100) important for the integrity of the Mediator complex, indicating a general Mediator requirement for PPARγ function. These results indicate that there is a conditional requirement for MED1/TRAP220 and that a direct interaction between PPARγ and Mediator through MED1/TRAP220 is not essential either for PPARγ-stimulated adipogenesis or for PPARγ target gene expression in cultured fibroblasts. As Mediator is apparently essential for PPARγ transcriptional activity, our data indicate the presence of alternative mechanisms for Mediator recruitment, possibly through intermediate cofactors or other cofactors that are functionally redundant with MED1/TRAP220.

scholarly journals The Role of ATF-2 Family Transcription Factors in Adipocyte Differentiation: Antiobesity Effects of p38 Inhibitors

2009 ◽  
Vol 30 (3) ◽  
pp. 613-625 ◽  
Author(s):  
Toshio Maekawa ◽  
Wanzhu Jin ◽  
Shunsuke Ishii
Keyword(s):  
Transcription Factors ◽  
Adipocyte Differentiation ◽  
Physiological Role ◽  
Bone Morphogenetic Protein 2 ◽  
Peroxisome Proliferator ◽  
Necrosis Factor Alpha ◽  
Peroxisome Proliferator Activated Receptor ◽  
P38 Inhibitor ◽  
Morphogenetic Protein

ABSTRACT ATF-2 is a member of the ATF/CREB family of transcription factors and is activated by stress-activated protein kinases, such as p38. To analyze the physiological role of ATF-2 family transcription factors, we have generated mice with mutations in Atf-2 and Cre-bpa, an Atf-2-related gene. The trans-heterozygotes of both mutants were lean and had reduced white adipose tissue (WAT). ATF-2 and CRE-BPa were required for bone morphogenetic protein 2 (BMP-2)-and p38-dependent induction of peroxisome proliferator-activated receptor γ2 (PPARγ2), a key transcription factor mediating adipocyte differentiation. Since stored fat supplies have been recognized as a possible target for antiobesity treatments, we tested whether inhibition of the p38-ATF-2 pathway suppresses adipocyte differentiation and leads to reduced WAT by treating mice with a p38 inhibitor for long periods of time. High-fat diet (HFD)-induced obesity was significantly reduced in mice fed the p38 inhibitor. Furthermore, the p38 inhibitor alleviated HFD-induced insulin resistance. In p38 inhibitor-treated mice, macrophage infiltration into WAT was reduced and the tumor necrosis factor alpha (TNF-α) levels were lower than control mice. Thus, p38 inhibitors may provide a novel antiobesity treatment.

scholarly journals Developmental and Tissue-Specific Involvement of Peroxisome Proliferator-Activated Receptor-α in the Control of Mouse Uncoupling Protein-3 Gene Expression

Endocrinology ◽  
2006 ◽  
Vol 147 (10) ◽  
pp. 4695-4704 ◽  
Author(s):  
Neus Pedraza ◽  
Meritxell Rosell ◽  
Joan Villarroya ◽  
Roser Iglesias ◽  
Frank J. Gonzalez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Mrna Expression ◽  
Uncoupling Protein ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ucp3 Gene ◽  
Uncoupling Protein 3

Uncoupling protein-3 (UCP3) is a member of the mitochondrial carrier family expressed preferentially in skeletal muscle and heart. It appears to be involved in metabolic handling of fatty acids in a way that minimizes excessive production of reactive oxygen species. Fatty acids are powerful regulators of UCP3 gene transcription. We have found that the role of peroxisome proliferator-activated receptor-α (PPARα) on the control of UCP3 gene expression depends on the tissue and developmental stage. In adults, UCP3 mRNA expression is unaltered in skeletal muscle from PPARα-null mice both in basal conditions and under the stimulus of starvation. In contrast, UCP3 mRNA is down-regulated in adult heart both in fed and fasted PPARα-null mice. This occurs despite the increased levels of free fatty acids caused by fasting in PPARα-null mice. In neonates, PPARα-null mice show impaired UCP3 mRNA expression in skeletal muscle in response to milk intake, and this is not a result of reduced free fatty acid levels. The murine UCP3 promoter is activated by fatty acids through either PPARα or PPARδ but not by PPARγ or retinoid X receptor alone. PPARδ-dependent activation could be a potential compensatory mechanism to ensure appropriate expression of UCP3 gene in adult skeletal muscle in the absence of PPARα. However, among transcripts from other PPARα and PPARδ target genes, only those acutely induced by milk intake in wild-type neonates were altered in muscle or heart from PPARα-null neonates. Thus, PPARα-dependent regulation is required for appropriate gene regulation of UCP3 as part of the subset of fatty-acid-responsive genes in neonatal muscle and heart.

scholarly journals Transcription Suppression of Peroxisome Proliferator-Activated Receptor γ2 Gene Expression by Tumor Necrosis Factor α via an Inhibition of CCAAT/ Enhancer-binding Protein δ during the Early Stage of Adipocyte Differentiation

Endocrinology ◽  
2004 ◽  
Vol 145 (11) ◽  
pp. 4948-4956 ◽  
Author(s):  
Masataka Kudo ◽  
Akira Sugawara ◽  
Akira Uruno ◽  
Kazuhisa Takeuchi ◽  
Sadayoshi Ito
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Gene Transcription ◽  
Adipocyte Differentiation ◽  
Early Stage ◽  
Binding Protein ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels ◽  
Enhancer Binding Protein

Abstract TNFα is known to inhibit adipocyte differentiation and induce insulin resistance. Moreover, TNFα is known to down-regulate peroxisome proliferator-activated receptor (PPAR)γ2, an adipocyte-specific nuclear receptor of insulin-sensitizer thiazolidinediones. To clarify molecular mechanisms of TNFα- mediated PPARγ2 down-regulation, we here examined the effect of TNFα on transcription regulation of PPARγ2 gene expression during the early stage of adipocyte differentiation. 3T3-L1 preadipocytes (2 d after 100% confluent) were incubated in a differentiation mixture (dexamethasone, insulin, 3-isobutyl-1-methlxanthine), with or without 50 ng/ml TNFα, for 24 h. TNFα significantly decreased PPARγ2 expression both at mRNA and protein levels (to ∼40%), as well as aP2 mRNA expression. The mouse PPARγ2 gene promoter region (2.2-kb) was isolated and was used for luciferase reporter assays by transient transfection. TNFα significantly suppressed PPARγ2 gene transcription (to ∼50%), and deletion analyses demonstrated that the suppression was mediated via CCAAT/enhancer-binding protein (C/EBP) binding elements at the −320/−340 region of the promoter. Moreover, TNFα significantly decreased expression of C/EBPδ mRNA and protein levels (to ∼40%). EMSA, using 3T3-L1 cells nuclear extracts with the −320/−340 region as a probe, demonstrated the binding of C/EBPδ to the element, which was significantly decreased by TNFα treatment. Overexpression of CEBP/δ prevented the TNFα-mediated suppression of PPARγ2 transactivation. Taken together, TNFα suppresses PPARγ2 gene transcription by the inhibition of C/EBPδ expression and its DNA binding during the early stage of adipocyte differentiation, which may contribute to the inhibition of adipocyte differentiation, as well as the induction of insulin resistance.

scholarly journals CITED2 Restrains Proinflammatory Macrophage Activation and Response

2017 ◽  
Vol 38 (5) ◽  
Author(s):  
Gun-Dong Kim ◽  
Riku Das ◽  
Xiaoquan Rao ◽  
Jixin Zhong ◽  
Jeffrey A. Deiuliis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Target Gene ◽  
Hypoxia Inducible Factor ◽  
Myeloid Cell ◽  
Negative Regulator ◽  
Peroxisome Proliferator ◽  
Gene Promoters ◽  
Loss Of Function ◽  
Peroxisome Proliferator Activated Receptor ◽  
Anti Inflammatory

ABSTRACT Macrophages are strategically distributed in mammalian tissues and play an essential role in priming the immune response. However, macrophages need to constantly strike a balance between activation and inhibition states to avoid a futile inflammatory reaction. Here, we identify the CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 2 (CITED2) as a potent repressor of macrophage proinflammatory activation. Gain- and loss-of-function studies revealed that CITED2 is required for optimal peroxisome proliferator-activated receptor gamma (PPARγ) activation and attendant select anti-inflammatory gene expression in macrophages. More importantly, deficiency of CITED2 resulted in significant attenuation of rosiglitazone-induced PPARγ activity, PPARγ recruitment to target gene promoters, and anti-inflammatory target gene expression in macrophages. Interestingly, deficiency of Cited2 strikingly heightened proinflammatory gene expression through stabilization of hypoxia-inducible factor 1 alpha (HIF1α) protein in macrophages. Further, overexpression of Egln3 or inhibition of HIF1α in Cited2 -deficient macrophages completely reversed elevated proinflammatory cytokine/chemokine gene expression. Importantly, mice bearing a myeloid cell-specific deletion of Cited2 were highly susceptible to endotoxin-induced sepsis symptomatology and mortality. Collectively, our observations identify CITED2 as a novel negative regulator of macrophage proinflammatory activation that protects the host from inflammatory insults.

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