scholarly journals The Nuclear Receptors Peroxisome Proliferator-activated Receptor α and Rev-erbα Mediate the Species-specific Regulation of Apolipoprotein A-I Expression by Fibrates

1998 ◽  
Vol 273 (40) ◽  
pp. 25713-25720 ◽  
Author(s):  
Ngoc Vu-Dac ◽  
Sandrine Chopin-Delannoy ◽  
Philippe Gervois ◽  
Edith Bonnelye ◽  
Geneviève Martin ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Apolipoprotein A ◽  
Specific Regulation ◽  
Species Specific

scholarly journals Post-Translational Modifications of Nuclear Receptors and Human Disease

2012 ◽  
Vol 10 (1) ◽  
pp. nrs.10001 ◽  
Author(s):  
Muralidharan Anbalagan ◽  
Brandy Huderson ◽  
Leigh Murphy ◽  
Brian G. Rowan
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Clinical Outcome ◽  
Nuclear Receptors ◽  
Inflammatory Diseases ◽  
Peroxisome Proliferator ◽  
Additional Measure ◽  
Peroxisome Proliferator Activated Receptor ◽  
Post Translational Modifications ◽  
Pparγ Phosphorylation

Nuclear receptors (NR) impact a myriad of physiological processes including homeostasis, reproduction, development, and metabolism. NRs are regulated by post-translational modifications (PTM) that markedly impact receptor function. Recent studies have identified NR PTMs that are involved in the onset and progression of human diseases, including cancer. The majority of evidence linking NR PTMs with disease has been demonstrated for phosphorylation, acetylation and sumoylation of androgen receptor (AR), estrogen receptor α (ERα), glucocorticoid receptor (GR) and peroxisome proliferator activated receptor γ (PPARΓ). Phosphorylation of AR has been associated with hormone refractory prostate cancer and decreased disease-specific survival. AR acetylation and sumoylation increased growth of prostate cancer tumor models. AR phosphorylation reduced the toxicity of the expanded polyglutamine AR in Kennedy's Disease as a consequence of reduced ligand binding. A comprehensive evaluation of ERα phosphorylation in breast cancer revealed several sites associated with better clinical outcome to tamoxifen therapy, whereas other phosphorylation sites were associated with poorer clinical outcome. ERα acetylation and sumoylation may also have predictive value for breast cancer. GR phosphorylation and acetylation impact GR responsiveness to glucocorticoids that are used as anti-inflammatory drugs. PPARγ phosphorylation can regulate the balance between growth and differentiation in adipose tissue that is linked to obesity and insulin resistance. Sumoylation of PPARγ is linked to repression of inflammatory genes important in patients with inflammatory diseases. NR PTMs provide an additional measure of NR function that can be used as both biomarkers of disease progression, and predictive markers for patient response to NR-directed treatments.

Cytosol-nucleus traffic and colocalization with FXR of conjugated bile acids in rat hepatocytes

2008 ◽  
Vol 295 (1) ◽  
pp. G54-G62 ◽  
Author(s):  
Maria J. Monte ◽  
Ruben Rosales ◽  
Rocio I. R. Macias ◽  
Valeria Iannota ◽  
Almudena Martinez-Fernandez ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Bile Acids ◽  
Nuclear Receptors ◽  
Rat Hepatocytes ◽  
Nuclear Volume ◽  
Farnesoid X Receptor ◽  
Nuclear Accumulation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Rat Liver Cells

Bile acids (BAs) are natural ligands of nuclear receptors, in particular farnesoid X receptor (FXR). Whether, in addition to protein-mediated cytosolic-nuclear BA translocation, other mechanisms are involved in the access of BAs to nuclear FXR was investigated. When rat hepatocytes were incubated with radiolabeled taurocholic acid, taurodeoxycholic acid, taurochenodeoxycholic acid, and tauroursodeoxycholic acid, their nuclear accumulation was proportional to their intracellular levels. With the use of flow cytometry analysis, the accumulation by nuclei isolated from rat liver cells was found to differ for several fluorescent compounds of similar molecular weight and different charge, including fluorescein-tagged BAs [cholylglycyl amidofluorescein (CGamF), ursodeoxycholylglycyl amidofluorescein, or chenodeoxycholylglycyl amidofluorescein]. When we varied nuclear volume by incubation with different sucrose concentrations, a similar relationship between nuclear volume and content of FITC and 4-kDa FITC-dextran was found. In contrast, this relationship was markedly lower for CGamF. Confocal microscopy studies revealed that fluorescein-tagged BAs, but also FITC or 10-kDa FITC-dextran were found in the nuclear envelope and concentrated in regions where DNA was less densely packed. In contrast to the cytosolic subcellular localization of peroxisome proliferator-activated receptor-α, FXR and nucleolin (a marker of transcriptional active chromatin) were also localized by immunoreactivity in these intranuclear regions. In conclusion, although intranuclear levels of small organic molecules including conjugated BAs depend on their concentrations in the extranuclear space, the existence of certain molecular selectivity (not strictly dependent on molecular weight or charge) suggests that, in addition to simple diffusional exchange, other mechanisms may be also involved in determining their overall nuclear content in regions where these compounds coincide and may interact with nuclear receptors such as FXR.

Nuclear receptors and hepatic lipidogenic enzyme response to a dyslipidemic sucrose-rich diet and its reversal by fish oil n-3 polyunsaturated fatty acids

2010 ◽  
Vol 298 (3) ◽  
pp. E429-E439 ◽  
Author(s):  
Gustavo J. Hein ◽  
Ana M. Bernasconi ◽  
Mauro A. Montanaro ◽  
Magali Pellon-Maison ◽  
Gabriela Finarelli ◽  
...  
Keyword(s):  
Oleic Acid ◽  
Lipid Metabolism ◽  
Fish Oil ◽  
Nuclear Receptors ◽  
Peroxisome Proliferator ◽  
Cod Liver Oil ◽  
Hepatic Enzymes ◽  
Peroxisome Proliferator Activated Receptor ◽  
Liver X Receptor Α ◽  
Glucose 6 Phosphate Dehydrogenase

A sucrose-rich diet (SRD), compared with a starch diet, induces time-dependent metabolic disorders and insulin resistance with hypertriglyceridemia, similar to type 2 diabetes. In this study, we examined the effect of SRD, after 8 mo, on nuclear receptors peroxisome proliferator-activated receptor-α (PPARα), and liver X receptor-α (LXRα), stearoyl-CoA desaturase-1 (SCD-1), and Δ6 and Δ5 desaturases mRNA and activity, hepatic enzymes involved in lipid metabolism, and fatty acid (FA) composition as well as the reversal produced by cod liver oil. SRD induced triglyceride increase in plasma and liver, increasing the anabolic FA synthase, malic enzyme, and glucose-6-phosphate dehydrogenase, but not the prooxidative enzymes FA oxidase and carnitine palmitoyltransferase I, and correspondingly decreased PPARα and increased LXRα expressions. Results suggest a contribution of both nuclear receptors' interaction on these enzymatic activities. SRD depressed SCD-1 without altering oleic acid proportion and increased Δ6 and Δ5 desaturases and the proportion of n-6 arachidonic acid. Therefore, the data do not support that SRD hypertriglyceridemia is produced by increased SCD-1-dependent oleic acid biosynthesis. The administration of 7% cod liver oil for 2 mo depressed LXRα, enhancing PPARα in control and SRD-fed rats, reversing the activity of the hepatic enzymes involved in lipid metabolism and therefore the hyperlipidemia produced by the SRD. Fish oil increased n-3 PUFA and depressed n-6 PUFA of liver lipids without altering the 18:1/18:0 ratio, suggesting that its effects were produced mainly by competition of dietary n-6 and n-3 FA and not through desaturase activity modification.

scholarly journals Alteration of a Single Amino Acid in Peroxisome Proliferator-Activated Receptor-α (PPARα) Generates a PPARδ Phenotype

2000 ◽  
Vol 14 (5) ◽  
pp. 733-740 ◽  
Author(s):  
Ichiro Takada ◽  
Ruth T. Yu ◽  
H. Eric Xu ◽  
Millard H. Lambert ◽  
Valerie G. Montana ◽  
...  
Keyword(s):  
Amino Acid ◽  
Nuclear Receptors ◽  
Site Directed Mutagenesis ◽  
Single Amino Acid ◽  
Peroxisome Proliferator ◽  
Transcriptional Responses ◽  
Peroxisome Proliferator Activated Receptor ◽  
Single Amino Acid Change ◽  
Close Relationship ◽  
Peroxisome Proliferator Activated Receptors

Abstract Three pharmacologically important nuclear receptors, the peroxisome proliferator-activated receptors (PPARs α,γ , and δ), mediate key transcriptional responses involved in lipid homeostasis. The PPARα and γ subtypes are well conserved from Xenopus to man, but the β/δ subtypes display substantial species variations in both structure and ligand activation profiles. Characterization of the avian cognates revealed a close relationship between chick (c) α and γ subtypes to their mammalian counterparts, whereas the third chicken subtype was intermediate to Xenopus (x) β and mammalian δ, establishing that β and δ are orthologs. Like xPPARβ, cPPARβ responded efficiently to hypolipidemic compounds that fail to activate the human counterpart. This provided the opportunity to address the pharmacological problem as to how drug selectivity is achieved and the more global evolutionary question as to the minimal changes needed to generate a new class of receptor. X-ray crystallography and chimeric analyses combined with site-directed mutagenesis of avian and mammalian cognates revealed that a Met to Val change at residue 417 was sufficient to switch the human and chick phenotype. These results establish that the genetic drive to evolve a novel and functionally selectable receptor can be modulated by a single amino acid change and suggest how nuclear receptors can accommodate natural variation in species physiology.

scholarly journals Peroxisome Proliferator-Activated Receptor γ Coactivator 1α and Small Heterodimer Partner Differentially Regulate Nuclear Receptor-Dependent Hepatitis B Virus Biosynthesis

2009 ◽  
Vol 83 (23) ◽  
pp. 12535-12544 ◽  
Author(s):  
Caitlin R. Ondracek ◽  
Christel N. Rushing ◽  
Vanessa C. Reese ◽  
Claudia E. Oropeza ◽  
Alan McLachlan
Keyword(s):  
Transcription Factors ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Cell Line ◽  
Nuclear Receptors ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Small Heterodimer Partner ◽  
B Virus ◽  
Transcription And Replication

ABSTRACT Hepatitis B virus (HBV) biosynthesis involves the transcription of the 3.5-kb viral pregenomic RNA, followed by its reverse transcription into viral DNA. Consequently, the modulation of viral transcription influences the level of virus production. Nuclear receptors are the only transcription factors known to support viral pregenomic RNA transcription and replication. The coactivator peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) and corepressor small heterodimer partner (SHP) have central roles in regulating energy homeostasis in the liver by modulating the transcriptional activities of nuclear receptors. Therefore, the effect of PGC1α and SHP on HBV transcription and replication mediated by nuclear receptors was examined in the context of individual nuclear receptors in nonhepatoma cells and in hepatoma cells. This analysis indicated that viral replication mediated by hepatocyte nuclear factor 4α, retinoid X receptor α (RXRα) plus peroxisome proliferator-activated receptor α (PPARα), and estrogen-related receptor (ERR) displayed differential sensitivity to PGC1α activation and SHP inhibition. The effects of PGC1α and SHP on viral biosynthesis in the human hepatoma cell line Huh7 were similar to those observed in the nonhepatoma cells expressing ERRα and ERRγ. This suggests that these nuclear receptors, potentially in combination with RXRα plus PPARα, may have a major role in governing HBV transcription and replication in this cell line. Additionally, this functional approach may help to distinguish the transcription factors in various liver cells governing viral biosynthesis under a variety of physiologically relevant conditions.

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