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==PPARδ Bound to GW074==
==PPARδ Bound to GW074==
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Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors that regulate metabolism. They are divided into three families: α, γ, and δ. PPARδ is activated by endogenous lipids, and plays a role in the regulation of lipid metabolism. Synthetic PPARδ agonists hold significant promise for treatment of metabolic and cardiovascular diseases. (Note: In the literature, PPARδ is sometimes also called PPARβ).
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== Introduction ==
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Peroxisome proliferator activated receptors ([[PPAR]]s) are ligand-activated transcription factors that regulate metabolism. They are divided into three families: α, γ, and δ. PPARδ is activated by endogenous lipids, and plays a role in the regulation of lipid metabolism. Synthetic PPARδ agonists hold significant promise for treatment of metabolic and cardiovascular diseases. (Note: In the literature, PPARδ is sometimes also called PPARβ). In this structure, PPARδ is bound to a synthetic agonist, GW074, which binds PPARδ 300-fold more tightly than PPARα and PPARγ<ref>DOI 10.1371/journal.pone.0033643</ref>.
<StructureSection load='3tkm' size='340' side='right' caption='PDB ID: 3TKM' scene=''>
<StructureSection load='3tkm' size='340' side='right' caption='PDB ID: 3TKM' scene=''>
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== Function ==
== Function ==
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PPARs are ligand-activated transcription factors. These receptors are activated by a number of endogenous lipids, but synthetic ligands have also been developed for therapeutic use<ref>DOI 10.1016/j.phrs.2004.07.012</ref>. After activation, PPAR forms a heterodimer with the retinoid X receptor, and the complex binds to DNA, either stimulating or repressing transcription of genes involved in glucose or lipid metabolism.
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PPARs are ligand-activated transcription factors. These receptors are activated by a number of endogenous lipids, but synthetic ligands have also been developed for therapeutic use<ref>DOI 10.1016/j.phrs.2004.07.012</ref>. After activation, PPAR forms a heterodimer with the [[Retinoid X receptor]], and the complex binds to DNA, either stimulating or repressing transcription of genes involved in glucose or lipid metabolism.
PPARδ is found in many tissues, but is most highly expressed in the gut, kidney, and heart<ref>DOI 10.1210/edrv.20.5.0380</ref>. It is activated by fatty acids, triglycerides, prostacyclin, and retinoic acid<ref>DOI doi.org/10.1016/j.pharmthera.2009.12.001</ref>. Though it is the least studied PPAR, its known functions include regulating acyl-CoA synthetase 2 expression and mediating embryo implantation<ref>DOI 10.1074/jbc.274.50.35881</ref><ref>DOI 10.1101/gad.13.12.1561</ref>.
PPARδ is found in many tissues, but is most highly expressed in the gut, kidney, and heart<ref>DOI 10.1210/edrv.20.5.0380</ref>. It is activated by fatty acids, triglycerides, prostacyclin, and retinoic acid<ref>DOI doi.org/10.1016/j.pharmthera.2009.12.001</ref>. Though it is the least studied PPAR, its known functions include regulating acyl-CoA synthetase 2 expression and mediating embryo implantation<ref>DOI 10.1074/jbc.274.50.35881</ref><ref>DOI 10.1101/gad.13.12.1561</ref>.
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== Disease ==
== Disease ==
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PPARδ agonists are being investigated as treatments for a number of metabolic disorder and cardiovascular disorders, but have not yet been deployed clinically. Current literature suggests that PPARδ agonists could enhance fatty acid oxidation in skeletal muscle, reduce serum triglycerides, increase serum high density lipoprotein (HDL) cholesterol and stimulate aspects of reverse cholesterol transport, improve glucose homeostasis, and trigger thermogenesis and weight loss. Though there are some health benefits associates with PPARα and γ agonists, these drugs also have undesirable side effects including such as edema and weight gain for PPARα, and carcinogenicity for PPARγ<ref>DOI 10.1038/35013000</ref>. If PPARδ agonists are to be used clinically, it is thus important to develop a ligand that does not also bind to the other PPARs.
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PPARδ agonists are being investigated as treatments for a number of metabolic disorder and cardiovascular disorders, but have not yet been deployed clinically. Current literature suggests that PPARδ agonists could enhance fatty acid oxidation in skeletal muscle, reduce serum triglycerides, increase serum HDL levels, and enhance weight loss<ref>DOI 10.1210/edrv.20.5.0380</ref>. Though there are some health benefits associated with PPARα and γ agonists, these drugs also have undesirable side effects including such as edema and weight gain, and carcinogenicity in rodents<ref>DOI 10.1371/journal.pone.0033643</ref><ref>DOI 10.1038/35013000</ref>. If PPARδ agonists are to be used clinically, it is thus important to develop a ligand that does not also bind to the other PPARs.
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== Relevance ==
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</StructureSection>
</StructureSection>
== References ==
== References ==
<references/>
<references/>

Current revision

PPARδ Bound to GW074

Introduction

Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors that regulate metabolism. They are divided into three families: α, γ, and δ. PPARδ is activated by endogenous lipids, and plays a role in the regulation of lipid metabolism. Synthetic PPARδ agonists hold significant promise for treatment of metabolic and cardiovascular diseases. (Note: In the literature, PPARδ is sometimes also called PPARβ). In this structure, PPARδ is bound to a synthetic agonist, GW074, which binds PPARδ 300-fold more tightly than PPARα and PPARγ[1].

PDB ID: 3TKM

Drag the structure with the mouse to rotate

References

  1. ↑ Batista FA, Trivella DB, Bernardes A, Gratieri J, Oliveira PS, Figueira AC, Webb P, Polikarpov I. Structural Insights into Human Peroxisome Proliferator Activated Receptor Delta (PPAR-Delta) Selective Ligand Binding. PLoS One. 2012;7(5):e33643. Epub 2012 May 11. PMID:22606221 doi:10.1371/journal.pone.0033643
  2. ↑ Batista FA, Trivella DB, Bernardes A, Gratieri J, Oliveira PS, Figueira AC, Webb P, Polikarpov I. Structural Insights into Human Peroxisome Proliferator Activated Receptor Delta (PPAR-Delta) Selective Ligand Binding. PLoS One. 2012;7(5):e33643. Epub 2012 May 11. PMID:22606221 doi:10.1371/journal.pone.0033643
  3. ↑ doi: https://dx.doi.org/10.1016/j.phrs.2004.07.012
  4. ↑ doi: https://dx.doi.org/10.1210/edrv.20.5.0380
  5. ↑ doi: https://dx.doi.org/doi.org/10.1016/j.pharmthera.2009.12.001
  6. ↑ doi: https://dx.doi.org/10.1074/jbc.274.50.35881
  7. ↑ doi: https://dx.doi.org/10.1101/gad.13.12.1561
  8. ↑ doi: https://dx.doi.org/10.1210/edrv.20.5.0380
  9. ↑ Batista FA, Trivella DB, Bernardes A, Gratieri J, Oliveira PS, Figueira AC, Webb P, Polikarpov I. Structural Insights into Human Peroxisome Proliferator Activated Receptor Delta (PPAR-Delta) Selective Ligand Binding. PLoS One. 2012;7(5):e33643. Epub 2012 May 11. PMID:22606221 doi:10.1371/journal.pone.0033643
  10. ↑ Kersten S, Desvergne B, Wahli W. Roles of PPARs in health and disease. Nature. 2000 May 25;405(6785):421-4. PMID:10839530 doi:10.1038/35013000

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