scholarly journals The Preservation of PPARγ Genome Duplicates in Some Teleost Lineages: Insights into Lipid Metabolism and Xenobiotic Exploitation

Genes ◽  
2022 ◽  
Vol 13 (1) ◽  
pp. 107
Author(s):  
Inês Páscoa ◽  
Elza Fonseca ◽  
Renato Ferraz ◽  
André M. Machado ◽  
Francisca Conrado ◽  
...  
Keyword(s):  
Whole Genome Duplication ◽  
Genome Duplication ◽  
Transcriptional Response ◽  
Peroxisome Proliferator ◽  
Aquatic Species ◽  
Sardina Pilchardus ◽  
Peroxisome Proliferator Activated Receptor ◽  
Astyanax Mexicanus ◽  
Natural Ligands ◽  
Functional Profiles

Three peroxisome proliferator-activated receptor paralogues (PPARα, -β and -γ) are currently recognized in vertebrate genomes. PPARγ is known to modulate nutrition, adipogenesis and immunity in vertebrates. Natural ligands of PPARγ have been proposed; however, the receptor also binds synthetic ligands such as endocrine disruptors. Two paralogues of PPARα and PPARβ have been documented in teleost species, a consequence of the 3R WGD. Recently, two PPARγ paralogue genes were also identified in Astyanax mexicanus. We aimed to determine whether the presence of two PPARγ paralogues is prevalent in other teleost genomes, through genomic and phylogenetic analysis. Our results showed that besides Characiformes, two PPARγ paralogous genes were also identified in other teleost taxa, coinciding with the teleost-specific, whole-genome duplication and with the retention of both genes prior to the separation of the Clupeocephala. To functionally characterize these genes, we used the European sardine (Sardina pilchardus) as a model. PPARγA and PPARγB display a different tissue distribution, despite the similarity of their functional profiles: they are unresponsive to tested fatty acids and other human PPARγ ligands yet yield a transcriptional response in the presence of tributyltin (TBT). This observation puts forward the relevance of comparative analysis to decipher alternative binding architectures and broadens the disruptive potential of man-made chemicals for aquatic species.

scholarly journals The Transcriptional Response to a Peroxisome Proliferator-activated Receptor α Agonist Includes Increased Expression of Proteome Maintenance Genes

2004 ◽  
Vol 279 (50) ◽  
pp. 52390-52398 ◽  
Author(s):  
Steven P. Anderson ◽  
Paul Howroyd ◽  
Jie Liu ◽  
Xun Qian ◽  
Rainer Bahnemann ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stress Responses ◽  
Transcriptional Response ◽  
Lipid Homeostasis ◽  
Peroxisome Proliferator ◽  
Wild Type ◽  
Peroxisome Proliferator Activated Receptor ◽  
Proteasomal Genes ◽  
Oxidative Stress Responses

The nuclear receptor peroxisome proliferator-activated receptor α (PPARα), in addition to regulating lipid homeostasis, controls the level of tissue damage after chemical or physical stress. To determine the role of PPARα in oxidative stress responses, we examined damage after exposure to chemicals that increase oxidative stress in wild-type or PPARα-null mice. Primary hepatocytes from wild-type but not PPARα-null mice pretreated with the PPAR pan-agonist WY-14,643 (WY) were protected from damage to cadmium and paraquat. The livers from intact wild-type but not PPARα-null mice were more resistant to damage after carbon tetrachloride treatment. To determine the molecular basis of the protection by PPARα, we identified by transcript profiling genes whose expression was altered by a 7-day exposure to WY in wild-type and PPARα-null mice. Of the 815 genes regulated by WY in wild-type mice (p≤ 0.001; ≥1.5-fold or ≤-1.5-fold), only two genes were regulated similarly by WY in PPARα-null mice. WY increased expression of stress modifier genes that maintain the health of the proteome, including those that prevent protein aggregation (heat stress-inducible chaperones) and eliminate damaged proteins (proteasome components). Although the induction of proteasomal genes significantly overlapped with those regulated by 1,2-dithiole-3-thione, an activator of oxidant-inducible Nrf2, WY increased expression of proteasomal genes independently of Nrf2. Thus, PPARα controls the vast majority of gene expression changes after exposure to WY in the mouse liver and protects the liver from oxidant-induced damage, possibly through regulation of a distinct set of proteome maintenance genes.

Transcriptional regulation of temperature-induced remodeling of muscle bioenergetics in goldfish

2012 ◽  
Vol 303 (2) ◽  
pp. R150-R158 ◽  
Author(s):  
Katharina Bremer ◽  
Christopher T. Monk ◽  
Brendon J. Gurd ◽  
Christopher D. Moyes
Keyword(s):  
Dna Binding ◽  
Mitochondrial Biogenesis ◽  
Binding Proteins ◽  
Nuclear Protein ◽  
Transcriptional Response ◽  
Dna Binding Proteins ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Protein Patterns ◽  
Peroxisome Proliferator Activated Receptor

Central to mammalian mitochondrial biogenesis is the transcriptional master regulator peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1α (PGC-1α), and a network of DNA-binding proteins it coactivates. We explored the role of this pathway in muscle mitochondrial biogenesis in response to thermal acclimation in goldfish ( Carassius auratus ). We investigated the transcriptional response of PGC-1α, PGC-1β, and their antagonist the nuclear receptor interacting protein 1 ( RIP140), as well as the mRNA and protein patterns of DNA-binding proteins that bind PGC-1, including nuclear respiratory factors (NRF) 1 and 2, retinoid X receptor α (RXRα), estrogen-related receptor α (ERRα), thyroid receptor α-1 (TRα-1), PPARα, and PPARβ/δ, and the host cell factor 1 (HCF1), which links PGC-1 and NRF-2. Cold-acclimated (4°C) fish had higher COX activities (4.5-fold) and COX4-1 mRNA levels (3.5-fold per total RNA; 6.5-fold per gram tissue) than warm-acclimated (32°C) fish. The transcription factor patterns were profoundly influenced by changes in RNA per gram tissue (2-fold higher in cold fish) and nuclear protein content (2-fold higher in warm fish). In cold-acclimated fish, mRNA per gram tissue was elevated for PGC-1β, RIP140, NRF-1, HCF1, NRF-2α, NRF-2β-2, ERRα, PPAR β/δ, and RXRα, but other transcriptional regulators either did not change ( PGC-1α, PPARα) or even decreased ( TRα-1). Nuclear protein levels in cold-acclimated fish were higher only for NRF-1; other proteins were either unaffected (NRF-2α, ERRα) or decreased (NRF-2β1/2, TRα, RXRα). Collectively, these data support the role for NRF-1 in regulating cold-induced mitochondrial biogenesis in goldfish, with effects mediated by PGC-1β, rather than PGC-1α.

scholarly journals Cooperative Cobinding of Synthetic and Natural Ligands to the Nuclear Receptor PPARγ

2018 ◽  
Author(s):  
Jinsai Shang ◽  
Richard Brust ◽  
Sarah A. Mosure ◽  
Jared Bass ◽  
Paola Munoz-Tello ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Peroxisome Proliferator ◽  
Binding Modes ◽  
Endogenous Ligand ◽  
Peroxisome Proliferator Activated Receptor ◽  
X Ray Crystallography ◽  
Natural Ligands ◽  
Synthetic Ligand ◽  
Dynamics Simulations ◽  
And Function

Crystal structures of peroxisome proliferator-activated receptor gamma (PPARγ) have revealed overlapping binding modes for synthetic and natural/endogenous ligands, indicating competition for the orthosteric pocket. Here we show that cobinding of a synthetic ligand to the orthosteric pocket can push natural and endogenous PPARγ ligands (fatty acids) out of the orthosteric pocket towards an alternate ligand-binding site near the functionally important omega (Ω) loop. X-ray crystallography, NMR spectroscopy, all-atom molecular dynamics simulations, and mutagenesis coupled to quantitative functional assays reveal that synthetic ligand and fatty acid cobinding can form a “ligand link” to the Ω loop and synergistically affect the structure and function of PPARγ. These findings contribute to a growing body of evidence indicating ligand binding to nuclear receptors can be more complex than the classical one-for-one orthosteric exchange of a natural or endogenous ligand with a synthetic ligand.

scholarly journals Perinatal deiodinase 2 expression in hepatocytes defines epigenetic susceptibility to liver steatosis and obesity

2015 ◽  
Vol 112 (45) ◽  
pp. 14018-14023 ◽  
Author(s):  
Tatiana L. Fonseca ◽  
Gustavo W. Fernandes ◽  
Elizabeth A. McAninch ◽  
Barbara M. L. C. Bocco ◽  
Sherine M. Abdalla ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Liver Steatosis ◽  
Transcriptional Response ◽  
Cholesterol Transport ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Genome Methylation ◽  
Analytical Platforms

Thyroid hormone binds to nuclear receptors and regulates gene transcription. Here we report that in mice, at around the first day of life, there is a transient surge in hepatocyte type 2 deiodinase (D2) that activates the prohormone thyroxine to the active hormone triiodothyronine, modifying the expression of ∼165 genes involved in broad aspects of hepatocyte function, including lipid metabolism. Hepatocyte-specific D2 inactivation (ALB-D2KO) is followed by a delay in neonatal expression of key lipid-related genes and a persistent reduction in peroxisome proliferator-activated receptor-γ expression. Notably, the absence of a neonatal D2 peak significantly modifies the baseline and long-term hepatic transcriptional response to a high-fat diet (HFD). Overall, changes in the expression of approximately 400 genes represent the HFD response in control animals toward the synthesis of fatty acids and triglycerides, whereas in ALB-D2KO animals, the response is limited to a very different set of only approximately 200 genes associated with reverse cholesterol transport and lipase activity. A whole genome methylation profile coupled to multiple analytical platforms indicate that 10–20% of these differences can be related to the presence of differentially methylated local regions mapped to sites of active/suppressed chromatin, thus qualifying as epigenetic modifications occurring as a result of neonatal D2 inactivation. The resulting phenotype of the adult ALB-D2KO mouse is dramatic, with greatly reduced susceptibility to diet-induced steatosis, hypertriglyceridemia, and obesity.

scholarly journals Cooperative cobinding of synthetic and natural ligands to the nuclear receptor PPARγ

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Jinsai Shang ◽  
Richard Brust ◽  
Sarah A Mosure ◽  
Jared Bass ◽  
Paola Munoz-Tello ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Peroxisome Proliferator ◽  
Binding Modes ◽  
Peroxisome Proliferator Activated Receptor ◽  
X Ray Crystallography ◽  
Cellular Assays ◽  
Natural Ligands ◽  
Synthetic Ligand ◽  
Dynamics Simulations ◽  
And Function

Crystal structures of peroxisome proliferator-activated receptor gamma (PPARγ) have revealed overlapping binding modes for synthetic and natural/endogenous ligands, indicating competition for the orthosteric pocket. Here we show that cobinding of a synthetic ligand to the orthosteric pocket can push natural and endogenous PPARγ ligands (fatty acids) out of the orthosteric pocket towards an alternate ligand-binding site near the functionally important omega (Ω)-loop. X-ray crystallography, NMR spectroscopy, all-atom molecular dynamics simulations, and mutagenesis coupled to quantitative biochemical functional and cellular assays reveal that synthetic ligand and fatty acid cobinding can form a ‘ligand link’ to the Ω-loop and synergistically affect the structure and function of PPARγ. These findings contribute to a growing body of evidence indicating ligand binding to nuclear receptors can be more complex than the classical one-for-one orthosteric exchange of a natural or endogenous ligand with a synthetic ligand.

scholarly journals α,β-Unsaturated Ketone Is a Core Moiety of Natural Ligands for Covalent Binding to Peroxisome Proliferator-activated Receptor γ

2005 ◽  
Vol 280 (14) ◽  
pp. 14145-14153 ◽  
Author(s):  
Takuma Shiraki ◽  
Narutoshi Kamiya ◽  
Sayaka Shiki ◽  
Takashi S. Kodama ◽  
Akira Kakizuka ◽  
...  
Keyword(s):  
Covalent Binding ◽  
Peroxisome Proliferator ◽  
Unsaturated Ketone ◽  
Peroxisome Proliferator Activated Receptor ◽  
Natural Ligands

scholarly journals Effects of exercise in a cold environment on transcriptional control of PGC-1α

2018 ◽  
Vol 314 (6) ◽  
pp. R850-R857 ◽  
Author(s):  
Robert J. Shute ◽  
Matthew W. Heesch ◽  
Roksana B. Zak ◽  
Jodi L. Kreiling ◽  
Dustin R. Slivka
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcriptional Control ◽  
Room Temperature ◽  
Vastus Lateralis ◽  
Transcriptional Response ◽  
Camp Response Element Binding ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nuclear Respiratory Factor

Peroxisome proliferator-activated receptor-α coactivator-1α (PGC-1α) mRNA is increased with both exercise and exposure to cold temperature. However, transcriptional control has yet to be examined during exercise in the cold. Additionally, the need for environmental cold exposure after exercise may not be a practical recovery modality. The purpose of this study was to determine mitochondrial-related gene expression and transcriptional control of PGC-1α following exercise in a cold compared with room temperature environment. Eleven recreationally trained males completed two 1-h cycling bouts in a cold (7°C) or room temperature (20°C) environment, followed by 3 h of supine recovery in standard room conditions. Muscle biopsies were taken from the vastus lateralis preexercise, postexercise, and after a 3-h recovery. Gene expression and transcription factor binding to the PGC-1α promoter were analyzed. PGC-1α mRNA increased from preexercise to 3 h of recovery, but there was no difference between trials. Estrogen-related receptor-α (ERRα), myocyte enhancer factor-2 (MEF2A), and nuclear respiratory factor-1 (NRF-1) mRNA were lower in cold than at room temperature. Forkhead box class-O (FOXO1) and cAMP response element-binding protein (CREB) binding to the PGC-1α promoter were increased postexercise and at 3 h of recovery. MEF2A binding increased postexercise, and activating transcription factor 2 (ATF2) binding increased at 3 h of recovery. These data indicate no difference in PGC-1α mRNA or transcriptional control after exercise in cold versus room temperature and 3 h of recovery. However, the observed reductions in the mRNA of select transcription factors downstream of PGC-1α indicate a potential influence of exercise in the cold on the transcriptional response related to mitochondrial biogenesis.

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