scholarly journals Retinoids increase human apolipoprotein A-11 expression through activation of the retinoid X receptor but not the retinoic acid receptor.

1996 ◽  
Vol 16 (7) ◽  
pp. 3350-3360 ◽  
Author(s):  
N Vu-Dac ◽  
K Schoonjans ◽  
V Kosykh ◽  
J Dallongeville ◽  
R A Heyman ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Primary Cultures ◽  
Retinoid X Receptor ◽  
Site Directed Mutagenesis ◽  
Transcriptional Level ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Reporter Construct ◽  
Response Element ◽  
Peroxisome Proliferator Activated Receptor

Considering the link between plasma high-density lipoprotein (HDL) cholesterol levels and a protective effect against coronary artery disease as well as the suggested beneficial effects of retinoids on the production of the major HDL apolipoprotein (apo), apo A-I, the goal of this study was to analyze the influence of retinoids on the expression of apo A-II, the other major HDL protein. Retinoic acid (RA) derivatives have a direct effect on hepatic apo A-II production, since all-trans (at) RA induces apo A-II mRNA levels and apo A-II secretion in primary cultures of human hepatocytes. In the HepG2 human hepatoblastoma cell line, both at-RA and 9-cis RA as well as the retinoid X receptor (RXR)-specific agonist LGD 1069, but not the RA receptor (RAR) agonist ethyl-p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-l-pro penyl]-benzoic acid (TTNPB), induce apo A-II mRNA levels. Transient-transfection experiments with a reporter construct driven by the human apo A-II gene promoter indicated that 9-cis RA and at-RA, as well as the RXR agonists LGD 1069 and LG 100268, induced apo A-II gene expression at the transcriptional level. Only minimal effects of the RAR agonist TTNPB were observed on the apo A-II promoter reporter construct. Unilateral deletions and site-directed mutagenesis identified the J site of the apo A-II promoter mediating the responsiveness to RA. This element contains two imperfect half-sites spaced by 1 oligonucleotide. Cotransfection assays in combination with the use of RXR or RAR agonists showed that RXR but not RAR transactivates the apo A-II promoter through this element. By contrast, RAR inhibits the inductive effects of RXR on the apo A-II J site in a dose-dependent fashion. Gel retardation assays demonstrated that RXR homodimers bind, although with a lower affinity than RAR-RXR heterodimers, to the AH-RXR response element. In conclusion, retinoids induce hepatic apo A-II production at the transcriptional level via the interaction of RXR with an element in the J site containing two imperfect half-sites spaced by 1 oligonucleotide, thereby demonstrating an important role of RXR in controlling human lipoprotein metabolism. Since the J site also confers responsiveness of the apo A-II gene to fibrates and fatty acids via the activation of peroxisome proliferator-activated receptor-RXR heterodimers, this site can be considered a plurimetabolic response element.

scholarly journals Attenuation of Colon Inflammation through Activators of the Retinoid X Receptor (Rxr)/Peroxisome Proliferator–Activated Receptor γ (Pparγ) Heterodimer

2001 ◽  
Vol 193 (7) ◽  
pp. 827-838 ◽  
Author(s):  
Pierre Desreumaux ◽  
Laurent Dubuquoy ◽  
Sophie Nutten ◽  
Michel Peuchmaur ◽  
Walter Englaro ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Synergistic Effects ◽  
Survival Rates ◽  
Nuclear Factor Κb ◽  
Retinoid X Receptor ◽  
Trinitrobenzene Sulfonic Acid ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Colon Inflammation

The peroxisome proliferator–activated receptor γ (PPARγ) is highly expressed in the colon mucosa and its activation has been reported to protect against colitis. We studied the involvement of PPARγ and its heterodimeric partner, the retinoid X receptor (RXR) in intestinal inflammatory responses. PPARγ1/− and RXRα1/− mice both displayed a significantly enhanced susceptibility to 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis compared with their wild-type littermates. A role for the RXR/PPARγ heterodimer in the protection against colon inflammation was explored by the use of selective RXR and PPARγ agonists. TNBS-induced colitis was significantly reduced by the administration of both PPARγ and RXR agonists. This beneficial effect was reflected by increased survival rates, an improvement of macroscopic and histologic scores, a decrease in tumor necrosis factor α and interleukin 1β mRNA levels, a diminished myeloperoxidase concentration, and reduction of nuclear factor κB DNA binding activity, c-Jun NH2-terminal kinase, and p38 activities in the colon. When coadministered, a significant synergistic effect of PPARγ and RXR ligands was observed. In combination, these data demonstrate that activation of the RXR/PPARγ heterodimer protects against colon inflammation and suggest that combination therapy with both RXR and PPARγ ligands might hold promise in the clinic due to their synergistic effects.

Thermogenically competent nonadrenergic recruitment in brown preadipocytes by a PPARγ agonist

2008 ◽  
Vol 295 (2) ◽  
pp. E287-E296 ◽  
Author(s):  
Natasa Petrovic ◽  
Irina G. Shabalina ◽  
James A. Timmons ◽  
Barbara Cannon ◽  
Jan Nedergaard
Keyword(s):  
Primary Cultures ◽  
Brown Adipocyte ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Sympathetic Stimulation ◽  
Promoting Effect ◽  
Brown Adipocytes ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Agonist ◽  
Brown Adipose

Most physiologically induced examples of recruitment of brown adipose tissue (BAT) occur as a consequence of chronic sympathetic stimulation (norepinephrine release within the tissue). However, in some physiological contexts (e.g., prenatal and prehibernation recruitment), this pathway is functionally contraindicated. Thus a nonsympathetically mediated mechanism of BAT recruitment must exist. Here we have tested whether a PPARγ activation pathway could competently recruit BAT, independently of sympathetic stimulation. We continuously treated primary cultures of mouse brown (pre)adipocytes with the potent peroxisome proliferator-activated receptor-γ (PPARγ) agonist rosiglitazone. In rosiglitazone-treated cultures, morphological signs of adipose differentiation and expression levels of the general adipogenic marker aP2 were manifested much earlier than in control cultures. Importantly, in the presence of the PPARγ agonist the brown adipocyte phenotype was significantly enhanced: UCP1 was expressed even in the absence of norepinephrine, and PPARα expression and norepinephrine-induced PGC-1α mRNA levels were significantly increased. However, the augmented levels of PPARα could not explain the brown-fat promoting effect of rosiglitazone, as this effect was still evident in PPARα-null cells. In continuously rosiglitazone-treated brown adipocytes, mitochondriogenesis, an essential part of BAT recruitment, was significantly enhanced. Most importantly, these mitochondria were capable of thermogenesis, as rosiglitazone-treated brown adipocytes responded to the addition of norepinephrine with a large increase in oxygen consumption. This thermogenic response was not observable in rosiglitazone-treated brown adipocytes originating from UCP1-ablated mice; hence, it was UCP1 dependent. Thus the PPARγ pathway represents an alternative, potent, and fully competent mechanism for BAT recruitment, which may be the cellular explanation for the enigmatic recruitment in prehibernation and prenatal states.

Fibrates down-regulate IL-1–stimulated C-reactive protein gene expression in hepatocytes by reducing nuclear p50-NFκB–C/EBP-β complex formation

Blood ◽  
2003 ◽  
Vol 101 (2) ◽  
pp. 545-551 ◽  
Author(s):  
Robert Kleemann ◽  
Philippe P. Gervois ◽  
Lars Verschuren ◽  
Bart Staels ◽  
Hans M. G. Princen ◽  
...  
Keyword(s):  
Acute Phase ◽  
Promoter Activity ◽  
Interleukin 1 ◽  
Site Directed Mutagenesis ◽  
Nuclear Accumulation ◽  
Transcriptional Level ◽  
Peroxisome Proliferator ◽  
C Reactive Protein ◽  
Peroxisome Proliferator Activated Receptor ◽  
Reactive Protein

C-reactive protein (CRP) is a major acute-phase protein in humans. Elevated plasma CRP levels are a risk factor for cardiovascular disease. CRP is predominantly expressed in hepatocytes and is induced by interleukin-1 (IL-1) and IL-6 under inflammatory situations, such as the acute phase. Fibrates are hypolipidemic drugs that act through the nuclear receptor peroxisome proliferator-activated receptor-α (PPAR-α). Fibrates have been shown to reduce elevated CRP levels in humans, but the molecular mechanism is unknown. In this study, we demonstrate that different PPAR-α activators suppress IL-1–induced, but not IL-6–induced, expression of CRP in primary human hepatocytes and HuH7 hepatoma cells. Induction of CRP expression by IL-1 occurs at the transcriptional level. Site-directed mutagenesis experiments show that IL-1 induces CRP expression through 2 overlapping response elements, the binding sites for CCAAT-box/enhancer–binding protein-β (C/EBP-β) and p50-nuclear factor-κB (p50-NFκB). Cotransfection of C/EBP-β and p50-NFκB enhances CRP promoter activity, and coimmunoprecipitation experiments indicate that the increase in CRP promoter activity by IL-1 is related to the generation and nuclear accumulation of C/EBP-β–p50-NFκB complexes. Interestingly, PPAR-α activators reduce the formation of nuclear C/EBP-β–p50-NFκB complexes, and thereby CRP promoter activity, by 2 mechanisms. First, PPAR-α increases IκB-α expression and thus prevents p50-NFκB translocation to the nucleus. Second, fibrates decrease hepatic C/EBP-β and p50-NFκB protein levels in mice in a PPAR-α–dependent way. Our findings identify C/EBP-β and p50-NFκB as novel targets for PPAR-α and provide a molecular explanation for the reduction of plasma CRP levels by fibrates.

Fibrates Suppress Fibrinogen Gene Expression in Rodents Via Activation of the Peroxisome Proliferator-Activated Receptor-

Blood ◽  
1999 ◽  
Vol 93 (9) ◽  
pp. 2991-2998 ◽  
Author(s):  
Maaike Kockx ◽  
Philippe P. Gervois ◽  
Philippe Poulain ◽  
Bruno Derudas ◽  
Jeffrey M. Peters ◽  
...  
Keyword(s):  
Gene Expression ◽  
Plasma Fibrinogen ◽  
Male Rats ◽  
Transcriptional Level ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Affinity Ligand ◽  
A Chain ◽  
Dose Dependent

Plasma fibrinogen levels have been identified as an important risk factor for cardiovascular diseases. Among the few compounds known to lower circulating fibrinogen levels in humans are certain fibrates. We have studied the regulation of fibrinogen gene expression by fibrates in rodents. Treatment of adult male rats with fenofibrate (0.5% [wt/wt] in the diet) for 7 days decreased hepatic A-, Bβ-, and γ-chain mRNA levels to 52% ± 7%, 46% ± 8%, and 81% ± 19% of control values, respectively. In parallel, plasma fibrinogen concentrations were decreased to 63% ± 7% of controls. The suppression of fibrinogen expression was dose-dependent and was already evident after 1 day at the highest dose of fenofibrate tested (0.5% [wt/wt]). Nuclear run-on experiments showed that the decrease in fibrinogen expression after fenofibrate occurred at the transcriptional level, as exemplified for the gene for the A-chain. Other fibrates tested showed similar effects on fibrinogen expression and transcription. The effect of fibrates is specific for peroxisome proliferator-activated receptor- (PPAR) because a high-affinity ligand for PPARγ, the thiazolidinedione BRL 49653, lowered triglyceride levels, but was unable to suppress fibrinogen expression. Direct evidence for the involvement of PPAR in the suppression of fibrinogen by fibrates was obtained using PPAR-null (−/−) mice. Compared with (+/+) mice, plasma fibrinogen levels in (−/−) mice were significantly higher (3.20 ± 0.48 v 2.67 ± 0.42 g/L). Also, hepatic fibrinogen A-chain mRNA levels were 25% ± 11% higher in the (−/−) mice. On treatment with 0.2% (wt/wt) fenofibrate, a significant decrease in plasma fibrinogen to 77% ± 10% of control levels and in hepatic fibrinogen A-chain mRNA levels to 65% ± 12% of control levels was seen in (+/+) mice, but not in (−/−) mice. These studies show that PPAR regulates basal levels of plasma fibrinogen and establish that fibrate-suppressed expression of fibrinogen in rodents is mediated through PPAR.

Transactivation of the human retinoid X receptor by organotins: use of site-directed mutagenesis to identify critical amino acid residues for organotin-induced transactivation

Metallomics ◽  
2015 ◽  
Vol 7 (7) ◽  
pp. 1180-1188 ◽  
Author(s):  
Youhei Hiromori ◽  
Akira Aoki ◽  
Jun-ichi Nishikawa ◽  
Hisamitsu Nagase ◽  
Tsuyoshi Nakanishi
Keyword(s):  
Amino Acid ◽  
Retinoid X Receptor ◽  
Site Directed Mutagenesis ◽  
Directed Mutagenesis ◽  
Peroxisome Proliferator ◽  
Amino Acid Residues ◽  
Endocrine Activity ◽  
Peroxisome Proliferator Activated Receptor ◽  
Critical Amino Acid ◽  
Ability To Act

Organotins, such as tributyltin (TBT) and triphenyltin (TPT), may disrupt endocrine activity in mammals arising from their ability to act as ligands for the retinoid X receptor (RXR) and the peroxisome proliferator-activated receptor γ (PPARγ).

scholarly journals Peroxisomal-proliferator-activated receptor alpha activates transcription of the rat hepatic malonyl-CoA decarboxylase gene: a key regulation of malonyl-CoA level

2004 ◽  
Vol 378 (3) ◽  
pp. 983-990 ◽  
Author(s):  
Gha Young LEE ◽  
Nam Hee KIM ◽  
Zheng-Shan ZHAO ◽  
Bong Soo CHA ◽  
Y. Sam KIM
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Retinoid X Receptor ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Mobility Shift ◽  
Peroxisome Proliferator Activated Receptor ◽  
Malonyl Coa ◽  
Promoter Deletion Analysis

MCD (malonyl-CoA decarboxylase), which catalyses decarboxylation of malonyl-CoA, is known to play an important role in the regulation of malonyl-CoA concentration. Recently, it has been observed that the expression of MCD is significantly decreased in the hearts of the PPARα (peroxisome-proliferator-activated receptor α) (−/−) mice, where the rate of fatty-acid oxidation is decreased by the increased malonyl-CoA level [Campbell, Kozak, Wagner, Altarejos, Dyck, Belke, Severson, Kelly and Lopaschuk (2002) J. Biol. Chem. 277, 4098–4103]. This suggests that MCD may be transcriptionally regulated by PPARα. To investigate whether PPARα is truly responsible for transcriptional regulation of the rat MCD gene, transient reporter assay was performed in CV-1 cells. The promoter activity was increased by 17-fold in CV-1 cells co-transfected with PPARα/retinoid X receptor α expression plasmid. In sequence analysis of the promoter region, three putative PPREs (PPAR response elements) were identified, and promoter deletion analysis showed that PPRE2 and PPRE3 were functional. Electrophoretic mobility-shift assays revealed that PPARα/retinoid X receptor α heterodimer indeed bound to the two PPREs, and the binding specificity of PPARα on PPRE was also confirmed by experiments with mutated oligonucleotides. These results indicate that the elements behaved as a responsive site to PPARα activation. MCD mRNA levels in WY14643-treated rat hepatoma cells as well as in the liver of fenofibrate-fed Otsuka Long-Evans Tokushima fatty rats were also found to be increased, suggesting that PPARα can activate the rat hepatic MCD transcription by binding to the PPREs in the promoter. We propose that MCD performs an important role in understanding the regulatory mechanism between activated PPARα and fatty-acid oxidation by altering the malonyl-CoA concentration.

Fibrates Suppress Fibrinogen Gene Expression in Rodents Via Activation of the Peroxisome Proliferator-Activated Receptor-

Blood ◽  
1999 ◽  
Vol 93 (9) ◽  
pp. 2991-2998 ◽  
Author(s):  
Maaike Kockx ◽  
Philippe P. Gervois ◽  
Philippe Poulain ◽  
Bruno Derudas ◽  
Jeffrey M. Peters ◽  
...  
Keyword(s):  
Gene Expression ◽  
Plasma Fibrinogen ◽  
Male Rats ◽  
Transcriptional Level ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Affinity Ligand ◽  
A Chain ◽  
Dose Dependent

Abstract Plasma fibrinogen levels have been identified as an important risk factor for cardiovascular diseases. Among the few compounds known to lower circulating fibrinogen levels in humans are certain fibrates. We have studied the regulation of fibrinogen gene expression by fibrates in rodents. Treatment of adult male rats with fenofibrate (0.5% [wt/wt] in the diet) for 7 days decreased hepatic A-, Bβ-, and γ-chain mRNA levels to 52% ± 7%, 46% ± 8%, and 81% ± 19% of control values, respectively. In parallel, plasma fibrinogen concentrations were decreased to 63% ± 7% of controls. The suppression of fibrinogen expression was dose-dependent and was already evident after 1 day at the highest dose of fenofibrate tested (0.5% [wt/wt]). Nuclear run-on experiments showed that the decrease in fibrinogen expression after fenofibrate occurred at the transcriptional level, as exemplified for the gene for the A-chain. Other fibrates tested showed similar effects on fibrinogen expression and transcription. The effect of fibrates is specific for peroxisome proliferator-activated receptor- (PPAR) because a high-affinity ligand for PPARγ, the thiazolidinedione BRL 49653, lowered triglyceride levels, but was unable to suppress fibrinogen expression. Direct evidence for the involvement of PPAR in the suppression of fibrinogen by fibrates was obtained using PPAR-null (−/−) mice. Compared with (+/+) mice, plasma fibrinogen levels in (−/−) mice were significantly higher (3.20 ± 0.48 v 2.67 ± 0.42 g/L). Also, hepatic fibrinogen A-chain mRNA levels were 25% ± 11% higher in the (−/−) mice. On treatment with 0.2% (wt/wt) fenofibrate, a significant decrease in plasma fibrinogen to 77% ± 10% of control levels and in hepatic fibrinogen A-chain mRNA levels to 65% ± 12% of control levels was seen in (+/+) mice, but not in (−/−) mice. These studies show that PPAR regulates basal levels of plasma fibrinogen and establish that fibrate-suppressed expression of fibrinogen in rodents is mediated through PPAR.

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