PPARγ regulates the function of human dendritic cells primarily by altering lipid metabolism

Blood ◽  
2007 ◽  
Vol 110 (9) ◽  
pp. 3271-3280 ◽  
Author(s):  
Istvan Szatmari ◽  
Daniel Töröcsik ◽  
Maura Agostini ◽  
Tibor Nagy ◽  
Mark Gurnell ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Lipid Metabolism ◽  
Receptor Activation ◽  
Dominant Negative ◽  
Transcriptional Level ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Positive Effects ◽  
Dominant Negative Mutation ◽  
Human Dendritic Cells

Abstract Activation of the lipid-regulated nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) modifies the immunophenotype of monocyte-derived dendritic cells (DCs). However it has not been analyzed in a systematic manner how lipid metabolism and immune regulation are connected at the transcriptional level via this receptor. Here we present the genome-wide expression analyses of PPARγ-instructed human DCs. Receptor activation was achieved by exogenous, synthetic as well as endogenous, natural means. More than 1000 transcripts are regulated during DC development by activation of PPARγ; half of the changes are positive effects. These changes appear to enhance and modulate the robust gene expression alterations associated with monocyte to DC transition. Strikingly, only genes related to lipid metabolism are overrepresented among early induced genes. As a net consequence, lipid accumulation appears to be diminished in these cells. In contrast, genes related to immune response are regulated after 24 hours, implying the existence of indirect mechanisms of modulation. Receptor dependence was established by using DCs of patients harboring a dominant-negative mutation of PPARγ. Our data show that PPARγ acts as a mostly positive transcriptional regulator in human developing DCs, acting primarily through controlling genes involved in lipid metabolism and via this, indirectly modifying the immune phenotype.

scholarly journals Peroxisome Proliferator-Activated Receptor γ Recruits the Positive Transcription Elongation Factor b Complex to Activate Transcription and Promote Adipogenesis

2006 ◽  
Vol 20 (7) ◽  
pp. 1494-1505 ◽  
Author(s):  
Irena Iankova ◽  
Rasmus K. Petersen ◽  
Jean-Sébastien Annicotte ◽  
Carine Chavey ◽  
Jacob B. Hansen ◽  
...  
Keyword(s):  
Transcription Elongation ◽  
Elongation Factor ◽  
Dominant Negative ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Factor B ◽  
Cyclin T1 ◽  
Positive Effects ◽  
Positive Transcription Elongation Factor ◽  
Transcription Elongation Factor

Abstract Positive transcription elongation factor b (P-TEFb) phosphorylates the C-terminal domain of RNA polymerase II, facilitating transcriptional elongation. In addition to its participation in general transcription, P-TEFb is recruited to specific promoters by some transcription factors such as c-Myc or MyoD. The P-TEFb complex is composed of a cyclin-dependent kinase (cdk9) subunit and a regulatory partner (cyclin T1, cyclin T2, or cyclin K). Because cdk9 has been shown to participate in differentiation processes, such as muscle cell differentiation, we studied a possible role of cdk9 in adipogenesis. In this study we show that the expression of the cdk9 p55 isoform is highly regulated during 3T3-L1 adipocyte differentiation at RNA and protein levels. Furthermore, cdk9, as well as cyclin T1 and cyclin T2, shows differences in nuclear localization at distinct stages of adipogenesis. Overexpression of cdk9 increases the adipogenic potential of 3T3-L1 cells, whereas inhibition of cdk9 by specific cdk inhibitors, and dominant-negative cdk9 mutant impairs adipogenesis. We show that the positive effects of cdk9 on the differentiation of 3T3-L1 cells are mediated by a direct interaction with and phosphorylation of peroxisome proliferator-activated receptor γ (PPARγ), which is the master regulator of this process, on the promoter of PPARγ target genes. PPARγ-cdk9 interaction results in increased transcriptional activity of PPARγ and therefore increased adipogenesis.

scholarly journals Peroxisome Proliferator-activated Receptor γ-regulated ABCG2 Expression Confers Cytoprotection to Human Dendritic Cells

2006 ◽  
Vol 281 (33) ◽  
pp. 23812-23823 ◽  
Author(s):  
Istvan Szatmari ◽  
György Vámosi ◽  
Peter Brazda ◽  
Balint L. Balint ◽  
Szilvia Benko ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Human Dendritic Cells

scholarly journals Failure to vasodilate in response to salt loading blunts renal blood flow and causes salt-sensitive hypertension

2020 ◽  
Author(s):  
Jing Wu ◽  
Larry N Agbor ◽  
Shi Fang ◽  
Masashi Mukohda ◽  
Anand R Nair ◽  
...  
Keyword(s):  
Blood Flow ◽  
Smooth Muscle ◽  
Renal Blood Flow ◽  
Vascular Dysfunction ◽  
Dominant Negative ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Salt Loading ◽  
Dominant Negative Mutation ◽  
Induced Hypertension

Abstract Aims Salt-sensitive (SS) hypertension is accompanied by impaired vasodilation in the systemic and renal circulation. However, the causal relationship between vascular dysfunction and salt-induced hypertension remains controversial. We sought to determine whether primary vascular dysfunction, characterized by a failure to vasodilate during salt loading, plays a causal role in the pathogenesis of SS hypertension. Methods and results Mice selectively expressing a peroxisome proliferator-activated receptor γ dominant-negative mutation in vascular smooth muscle (S-P467L) exhibited progressive SS hypertension during a 4 week high salt diet (HSD). This was associated with severely impaired vasodilation in systemic and renal vessels. Salt-induced impairment of vasodilation occurred as early as 3 days after HSD, which preceded the onset of SS hypertension. Notably, the overt salt-induced hypertension in S-P467L mice was not driven by higher cardiac output, implying elevations in peripheral vascular resistance. In keeping with this, HSD-fed S-P467L mice exhibited decreased smooth muscle responsiveness to nitric oxide (NO) in systemic vessels. HSD-fed S-P467L mice also exhibited elevated albuminuria and a blunted increase in urinary NO metabolites which was associated with blunted renal blood flow and increased sodium retention mediated by a lack of HSD-induced suppression of NKCC2. Blocking NKCC2 function prevented the salt-induced increase in blood pressure in S-P467L mice. Conclusion We conclude that failure to vasodilate in response to salt loading causes SS hypertension by restricting renal perfusion and reducing renal NO through a mechanism involving NKCC2 in a mouse model of vascular peroxisome proliferator-activated receptor γ impairment.

scholarly journals Peroxisome proliferator-activated receptor-γ protects against vascular aging

2012 ◽  
Vol 302 (10) ◽  
pp. R1184-R1190 ◽  
Author(s):  
Mary L. Modrick ◽  
Dale A. Kinzenbaw ◽  
Yi Chu ◽  
Curt D. Sigmund ◽  
Frank M. Faraci
Keyword(s):  
Endothelial Dysfunction ◽  
Vascular Disease ◽  
Protective Role ◽  
Dominant Negative ◽  
Peroxisome Proliferator ◽  
Vascular Aging ◽  
Wild Type ◽  
No Donor ◽  
Peroxisome Proliferator Activated Receptor ◽  
Dominant Negative Mutation

Vascular disease occurs commonly during aging. Carotid artery and cerebrovascular disease are major causes of stroke and contributors to dementia. Recent evidence suggests that peroxisome proliferator-activated receptor-γ (PPARγ) may play a protective role in the vasculature, but the potential importance of PPARγ in vascular aging is unknown. To examine the hypothesis that PPARγ normally protects against vascular aging, we studied heterozygous knockin mice expressing a human dominant-negative mutation in PPARγ (P465L, designated L/+). Endothelial dysfunction, a major contributor to vascular disease, was studied using carotid arteries from adult (8 ± 1 mo) and old (24 ± 1 mo) L/+ mice and wild-type littermates. In arteries from wild-type mice, responses to the endothelium-dependent agonist ACh were similar in adult and old wild-type mice but were reduced by ∼50% in old L/+ mice ( n = 7–10, P < 0.05). Impaired responses in arteries from old L/+ mice were restored to normal by a scavenger of superoxide. Relaxation of arteries to nitroprusside (an NO donor) was similar in all groups. Contraction of arteries to U46619 was not affected by age or genotype, while maximal responses to endothelin-1 were reduced with age in both wild-type and L/+ mice. Vascular expression (mRNA) of the catalytic component of NADPH oxidase (Nox2) was not altered in wild-type mice but was increased significantly in old L/+ mice. These findings provide the first evidence that interference with PPARγ function accelerates vascular aging, suggesting a novel role for PPARγ in protecting against age-induced oxidative stress and endothelial dysfunction.

scholarly journals Peroxisome Proliferator-Activated Receptor Activation is Associated with Altered Plasma One-Carbon Metabolites and B-Vitamin Status in Rats

Nutrients ◽  
2016 ◽  
Vol 8 (1) ◽  
pp. 26 ◽  
Author(s):  
Vegard Lysne ◽  
Elin Strand ◽  
Gard Svingen ◽  
Bodil Bjørndal ◽  
Eva Pedersen ◽  
...  
Keyword(s):  
Receptor Activation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Vitamin Status ◽  
B Vitamin
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