scholarly journals Regulation of Immune Responses and Autoimmune Encephalomyelitis by PPARs

PPAR Research ◽  
2010 ◽  
Vol 2010 ◽  
pp. 1-11 ◽  
Author(s):  
Yuhong Yang ◽  
Amy E. Lovett-Racke ◽  
Michael K. Racke
Keyword(s):  
Gene Expression ◽  
Lipid Metabolism ◽  
Immune Responses ◽  
Nuclear Receptor ◽  
Target Genes ◽  
Steroid Hormone ◽  
Autoimmune Encephalomyelitis ◽  
Inflammatory Gene Expression ◽  
Nuclear Receptor Superfamily ◽  
Ppar Agonists

PPARs are members of the steroid hormone nuclear receptor superfamily and play an important role in regulating inflammation as well as lipid metabolism. The PPAR subfamily has been defined as PPARα, PPARβ/δ, and PPARγ, each with different ligands, target genes, and biological roles. PPARs regulate the expression of target inflammatory genes through mechanisms involving both transactivation and transrepression. The anti-inflammatory properties of PPAR agonists have led to the investigation of PPAR functions in regulating autoimmune encephalomyelitis. This paper will summarize some of the general mechanisms by which PPARs regulate inflammatory gene expression and focus on the recent advances of PPAR regulation of autoimmune encephalomyelitis.

scholarly journals PPAR Alpha Regulation of the Immune Response and Autoimmune Encephalomyelitis

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-6 ◽  
Author(s):  
Yuhong Yang ◽  
Anne R. Gocke ◽  
Amy Lovett-Racke ◽  
Paul D. Drew ◽  
Michael K. Racke
Keyword(s):  
Multiple Sclerosis ◽  
Immune Response ◽  
T Cells ◽  
Transcription Factors ◽  
Lipid Metabolism ◽  
Steroid Hormone ◽  
Autoimmune Encephalomyelitis ◽  
Ppar Alpha ◽  
Nuclear Receptor Superfamily ◽  
Experimental Autoimmune

PPARs are members of the steroid hormone nuclear receptor superfamily and play an important role in the regulation of lipid metabolism, energy balance, artherosclerosis and glucose control. Recent studies suggest that they play an important role in regulating inflammation. This review will focus on PPAR-αregulation of the immune response. We describe how PPAR-αregulates differentiation of T cells by transactivation and/or interaction with other transcription factors. Moreover, PPAR-αagonists have been shown to ameliorate experimental autoimmune encephalomyelitis (EAE) in mice, suggesting that they could provide a therapy for human autoimmune diseases such as multiple sclerosis.

Abstract 43: Activation of the Nuclear Receptor Coactivator PGC-1α Mediates an Atheroprotective Effect

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Cathal McCarthy ◽  
Declan Mooney ◽  
Monica de Gaetano ◽  
William James ◽  
Desmond J Fitzgerald ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Target Genes ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Nuclear Receptor Coactivator ◽  
Hub Gene ◽  
Cd36 Expression ◽  
Ppar Agonists ◽  
Human Atherosclerosis

Supplementing dietary chow with conjugated linoleic acid (CLA) induces marked regression of pre-established murine atherosclerosis, in contrast to other PPAR agonists. The finding suggests that there are unidentified endogenous pathways that suppress the progression or promote the regression of atherosclerosis. Identifying these pathways in the mouse and their homologues in humans may help elucidate the mechanisms of the disease and targets for future therapies. Here, we provide evidence that CLA inhibits foam cell formation via regulation of the nuclear receptor co-activator, PGC-1α in a manner that differs from PPAR activation. Gene expression analysis was performed in the aorta of ApoE -/- mice following induction of atherosclerosis and dietary supplementation with/without CLA. CLA induced dramatic regression of the cholesterol-induced atherosclerosis. PGC-1α was identified as a ‘hub’ gene within a cluster of genes induced by CLA in the aorta of the ApoE -/- during regression. PGC-1α protein was also found in murine and human atherosclerotic plaque, where it was localised to macrophage/foam cells. In a mouse macrophage cell line exposed to oxLDL, CLA induced PGC-1α and several genes in the network in an isomer specific fashion, including RORαand ABCA1. CLA also induced the PGC-1α target genes Cyp7b1 and UCP-1, and PPAR. CLA inhibited foam cell formation in the same cells exposed to oxLDL and suppressed the expression of the scavenger receptors, SRA-1 and CD36. Expression of the PGC-1α in macrophages had similar effects. Thus, over-expression of PGC-1α limited the accumulation of oxLDL and subsequent foam cell formation, while deletion of the gene promoted foam cell formation in bone marrow derived macrophages upon exposure to oxLDL. Moreover, deletion of PGC-1α prevented the inhibition of macrophages/foam cell formation by CLA. The nuclear receptor co-activator PGC-1α is a hub gene in a network of genes activated in the aorta during CLA-induced regression of atherosclerosis and mediates CLA’s inhibition of foam cell formation. PGC-1α is also is also expressed in human plaques where its expression is inversely associated with disease progression, raising the possibility that this pathway if activated could regulate human atherosclerosis.

scholarly journals 2,4-Dinitrotoluene (DNT) Perturbs Yolk Absorption, Liver Development and Lipid Metabolism/Oxygen Transport Gene Expression in Zebrafish Embryos and Larvae

2019 ◽  
Vol 20 (15) ◽  
pp. 3632
Author(s):  
Jianglin Xiong ◽  
Hang Sha ◽  
Hualin Zhou ◽  
Lijuan Peng ◽  
Lingying Wu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lipid Metabolism ◽  
Oxygen Transport ◽  
Target Genes ◽  
Environmental Pollutant ◽  
International Agency ◽  
Liver Development ◽  
Expression Of Genes ◽  
Yolk Absorption ◽  
Carcinogenic Compound

2,4-dinitrotoluene (2,4-DNT) is a common environmental pollutant, and was classified as a group 2B human carcinogenic compound by the International Agency for Research on Cancer. This study determined the toxic effects of 2,4-DNT exposure on zebrafish at the embryo-larvae stage, in terms of organ morphogenesis and the expression pattern of selected target genes related to lipid metabolism and oxygen transportation. The results showed that the 120-h post-fertilization LC50 of 2,4-DNT was 9.59 mg/L with a 95% confidence interval of 8.89–10.44 mg/L. The larvae treated with 2,4-DNT showed toxic symptoms including smaller body, less skin pigment production, yolk malabsorption, and disordered liver development. Further studies on the expression of genes related to lipid transport and metabolism, and respiration indicated that they were significantly affected by 2,4-DNT. It is concluded that 2,4-DNT exposure perturbed liver development and yolk absorption in early-life zebrafish, and disturbed the lipid metabolism /oxygen transport gene expression.

scholarly journals Endocrine Disrupting Chemicals, Phthalic Acid and Nonylphenol, Activate Pregnane X Receptor-Mediated Transcription

2000 ◽  
Vol 14 (3) ◽  
pp. 421-428 ◽  
Author(s):  
Hisashi Masuyama ◽  
Yuji Hiramatsu ◽  
Mamoru Kunitomi ◽  
Takafumi Kudo ◽  
Paul N. MacDonald
Keyword(s):  
Gene Expression ◽  
Bisphenol A ◽  
Nuclear Receptor ◽  
Phthalic Acid ◽  
Steroid Hormone ◽  
Endocrine Disrupting Chemicals ◽  
Pregnane X Receptor ◽  
Specific Gene ◽  
Hormone Metabolism ◽  
Endocrine Disrupting

Abstract Recently, Pregnane X receptor (PXR), a new member of the nuclear receptor superfamily, was shown to mediate the effects of several steroid hormones, such as progesterone, glucocorticoid, pregnenolone, and xenobiotics on cytochrome P450 3A genes (CYP3A) through the specific DNA sequence for CYP3A, suggesting that PXR may play a role in steroid hormone metabolism. In this paper, we demonstrated that phthalic acid and nonylphenol, endocrine-disrupting chemicals (EDCs), stimulated PXR-mediated transcription at concentrations comparable to those at which they activate estrogen receptor-mediated transcription using a transient reporter gene expression assay in COS-7 cells. However, bisphenol A, another EDC, had no effect on PXR-mediated transcription, although this chemical significantly enhanced ER-mediated transcription. In the yeast two-hybrid protein interaction assay, PXR interacted with two nuclear receptor coactivator proteins, steroid hormone receptor coactivator-1 and receptor interacting protein 140, in the presence of phthalic acid or nonylphenol. Thus, EDC-occupied PXR may regulate its specific gene expression through the receptor-coactivator interaction. In contrast, these EDCs had no effect on the interaction between PXR and suppressor for gal 1, a component of proteasome. Finally, the expression of CYP3A1 mRNA in the liver of rats exposed to phthalic acid or nonylphenol markedly increased compared with that in rats treated with estradiol, bisphenol A, or ethanol as assessed by competitive RT-PCR. These data suggest that EDCs may affect endocrine functions by altering steroid hormone metabolism through PXR.

scholarly journals Linoleic acid, α-linolenic acid and enterolactone affect lipid oxidation and expression of lipid metabolism and antioxidant-related genes in hepatic tissue of dairy cows

2017 ◽  
Vol 117 (9) ◽  
pp. 1199-1211 ◽  
Author(s):  
Émilie Fortin ◽  
Richard Blouin ◽  
Jérôme Lapointe ◽  
Hélène V. Petit ◽  
Marie-France Palin
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Lipid Metabolism ◽  
Linoleic Acid ◽  
Oxidative Damage ◽  
Dairy Cows ◽  
Linolenic Acid ◽  
Target Genes ◽  
Culture Media ◽  
Oxidative Damages

AbstractAlthough beneficial effects have been attributed to PUFA supplementation in high-yielding dairy cows, diets rich in PUFA may also increase oxidative stress in tissues such as the liver. To fully exploit the health benefits of PUFA, we believe that the addition of natural antioxidants could help in preventing oxidative damage. Using an in vitro precision-cut liver slices (PCLS) tissue culture system, we investigated the effects of different linoleic acid (LA, n-6):α-linolenic acid (ALA, n-3) ratios (LA:ALA ratio of 4, LA:ALA ratio of 15 and LA:ALA ratio of 25) in the presence or absence of the antioxidant enterolactone (ENL) on (1) the mRNA abundance of genes with key roles in hepatic lipid metabolism, oxidative stress response and inflammatory processes, (2) oxidative damages to lipids and proteins and (3) superoxide dismutase activity in early-lactating dairy cows. The addition of LA and ALA to PCLS culture media increased oxidative damage to lipids as suggested by higher concentrations of thiobarbituric acid reactive substances and increased the expression of nuclear factor erythroid 2-related factor 2 target genes. The addition of ENL was effective in preventing lipid peroxidation caused by LA and ALA. Transcript abundance of sterol regulatory element-binding transcription factor 1 and its lipogenic target genes acetyl-CoA carboxylase α, fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD) was decreased with LA and ALA, whereas ENL decreased FASN and SCD gene expression. Our results show that addition of LA and ALA to PCLS culture media lowers hepatic lipogenic gene expression and increases oxidative damages to lipids. On the other hand, addition of ENL prevents oxidative damages provoked by these PUFA.

scholarly journals The Orphan Nuclear Receptor, RORα, Regulates Gene Expression That Controls Lipid Metabolism

2008 ◽  
Vol 283 (26) ◽  
pp. 18411-18421 ◽  
Author(s):  
Patrick Lau ◽  
Rebecca L. Fitzsimmons ◽  
Suryaprakash Raichur ◽  
Shu-Ching M. Wang ◽  
Adriane Lechtken ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lipid Metabolism ◽  
Nuclear Receptor ◽  
Orphan Nuclear Receptor

scholarly journals Bile acids inhibit duodenal secretin expression via orphan nuclear receptor small heterodimer partner (SHP)

2009 ◽  
Vol 297 (1) ◽  
pp. G90-G97 ◽  
Author(s):  
Ian P. Y. Lam ◽  
Leo T. O. Lee ◽  
Hueng-Sik Choi ◽  
Gianfranco Alpini ◽  
Billy K. C. Chow
Keyword(s):  
Gene Expression ◽  
Bile Acids ◽  
Nuclear Receptor ◽  
Target Genes ◽  
In Vivo Studies ◽  
Control Group ◽  
Orphan Nuclear Receptor ◽  
Small Heterodimer Partner

Small heterodimer partner (SHP) is an orphan nuclear receptor in which gene expression can be upregulated by bile acids. It regulates its target genes by repressing the transcriptional activities of other nuclear receptors including NeuroD, which has been shown to regulate secretin gene expression. Here, we evaluated the regulation on duodenal secretin gene expression by SHP and selected bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA). In vitro treatment of CDCA or fexaramine elevated the SHP transcript level and occupancy on secretin promoter. The increase in the SHP level, induced by bile acid treatment or overexpression, reduced secretin gene expression, whereas this gene inhibitory effect was reversed by silencing of endogenous SHP. In in vivo studies, double-immunofluorescence staining demonstrated the coexpression of secretin and SHP in mouse duodenum. Feeding mice with 1% CA-enriched rodent chow resulted in upregulation of SHP and a concomitant decrease in secretin transcript and protein levels in duodenum compared with the control group fed with normal chow. A diet enriched with 5% cholestyramine led to a decrease in SHP level and a corresponding increase in secretin expression. Overall, this study showed that bile acids via SHP inhibit duodenal secretin gene expression. Because secretin is a key hormone that stimulates bile flow in cholangiocytes, this pathway thus provides a novel means to modulate secretin-stimulated choleresis in response to intraduodenal bile acids.

scholarly journals A direct and widespread role for the nuclear receptor EcR in mediating the response to ecdysone in Drosophila

2019 ◽  
Author(s):  
Christopher M. Uyehara ◽  
Daniel J. McKay
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Dna Binding ◽  
Nuclear Receptor ◽  
Binding Sites ◽  
Target Genes ◽  
Transcriptional Responses ◽  
Developmental Transitions ◽  
The Impact

ABSTRACTThe ecdysone pathway was amongst the first experimental systems employed to study the impact of steroid hormones on the genome. In Drosophila and other insects, ecdysone coordinates developmental transitions, including wholesale transformation of the larva into the adult during metamorphosis. Like other hormones, ecdysone controls gene expression through a nuclear receptor, which functions as a ligand-dependent transcription factor. Although it is clear that ecdysone elicits distinct transcriptional responses within its different target tissues, the role of its receptor, EcR, in regulating target gene expression is incompletely understood. In particular, EcR initiates a cascade of transcription factor expression in response to ecdysone, making it unclear which ecdysone-responsive genes are direct EcR targets. Here, we use the larval-to-prepupal transition of developing wings to examine the role of EcR in gene regulation. Genome-wide DNA binding profiles reveal that EcR exhibits widespread binding across the genome, including at many canonical ecdysone-response genes. However, the majority of its binding sites reside at genes with wing-specific functions. We also find that EcR binding is temporally dynamic, with thousands of binding sites changing over time. RNA-seq reveals that EcR acts as both a temporal gate to block precocious entry to the next developmental stage as well as a temporal trigger to promote the subsequent program. Finally, transgenic reporter analysis indicates that EcR regulates not only temporal changes in target enhancer activity but also spatial patterns. Together, these studies define EcR as a multipurpose, direct regulator of gene expression, greatly expanding its role in coordinating developmental transitions.SIGNIFICANCENuclear receptors (NRs) are sequence-specific DNA binding proteins that act as intracellular receptors for small molecules such as hormones. Prior work has shown that NRs function as ligand-dependent switches that initiate a cascade of gene expression changes. The extent to which NRs function as direct regulators of downstream genes in these hierarchies remains incompletely understood. Here, we study the role of the NR EcR in metamorphosis of the Drosophila wing. We find that EcR directly regulates many genes at the top of the hierarchy as well as at downstream genes. Further, we find that EcR binds distinct sets of target genes at different developmental times. This work helps inform how hormones elicit tissue- and temporal-specific responses in target tissues.

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