Peroxisome Proliferator-Activated Receptors: Difference between revisions

[[Image: 3dzy2.png|320px|left|thumb| Human PPARγ bound to RXRα and PPRE DNA strand, [[3dzy]]]]

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==Biological Role==

[[Image: PPAR_Mechanism.png|400px|left|thumb| PPAR Mechanism of Action in the Human Body]]

Transcription of individual genes in eukaryotic cells is controlled very precisely at a number of different levels. One key level is the binding of specific [[DNA]] binding transcriptional factors such as nuclear receptors, to facilitate RNA polymerase function. Unliganded PPARs form a heterodimer with retinoid X receptor (RXR), specifically RXRα. This heterodimer binds to the Peroxisome Proliferator Response Element (PPRE), a specific DNA sequence present in the promoter region of PPAR-regulated genes. <ref>PMID:11330046</ref> Also associated with this unliganded heterodimer is a co-repressor complex which possesses histone deacetylation activity. This results in a tight chromatin structure, preventing gene transcription. <ref>PMID:15681609</ref> This co-repressor complex is released upon ligand binding (typical ligands include lipids and eicosanoids), allowing various co-activators and co-activator-associated proteins to be recruited. These protein complexes facilitate chromatin remodeling and [[DNA]] unwinding along with linkage to RNA polymerase II machinery, necessary steps for [[transcription]]. The genes transcribed upon activation are [[Molecular Playground/Insulin|insulin]] responsive genes involved in the control of glucose production, transport and utilization. This makes agonists of PPAR insulin sensitizers. Some PPAR related co-activators include CBP (Histone Acetylation), SRC-1,2,3 (Chromatin Acetylation), <ref>pmid:7539101</ref> PGC-1 (Recruit HAT activities), PRIC-285,320 (Chromatin Remodeling via Helicase activity)<ref>PMID:11158331</ref>and PIMT (RNA Capping via methyltransferase activity)<ref>PMID:10381882</ref>.

==Natural Ligands==

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===Co-Activator & Co-Repressor Binding===

[[Image: SRC_binding.png|250px|left| Human PPARγ Co-Activator Binding Site. PPARγ  bound to SRC-1, [[3dzy]]]]

The transcriptional activity of <scene name='Peroxisome_Proliferator-Activated_Receptors/Ppar_opening_2/2'>PPAR </scene>is regulated by its interaction with co-activators like SRC-1 or CBP and co-repressors like SMRT. <ref name="Zoete">PMID:17317294</ref>Co-activators like CBP contain a conserved LXXLL motif where X is any amino acid, and use this to bind a hydrophobic pocket on the receptor surface formed by the stabilized AF-2 helix H12.<ref name="Gampe">PMID:10882139</ref> In the case of the PPARγ/rosiglitazone/SRC-1 complex, the LXXLL motif helix of SRC-1 forms <scene name='Peroxisome_Proliferator-Activated_Receptors/Src_binding/1'>hydrophobic interactions with Leu468 and Leu318 of the LBD and hydrogen bonds between Glu471 and Lys301 and the co-activator backbone.</scene> These charged residues are conserved across PPAR isotypes and form the “charge clamp,” an essential component for co-activator stabilization in the PPAR LBD.<ref>PMID:11698662</ref>

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==Binding of Synthetic Agonists and Medical Implications==

[[Image: Ciprofibrate.PNG|300px|left|thumb| Human PPARα agonist, Ciprofibrate (Modalim)]]

Despite their structural similarities, each member of the PPAR family is localized to certain parts of the body. Location of receptor partially determines their function in the body and also the different roles they can play in medicine as drug targets. PPARγ is responsible for lipid metabolism and cellular energy homeostasis. It binds genes that transcribe proteins which act as fatty acid transporters, are critical in insulin signaling and glucose transport, catalyze glycerol synthesis from triglycerides, and catabolize lipids. This makes PPARγ an ideal target to treat Diabetes.<ref name="Berger">PMID:11818483</ref> Also, recent research has indicated that some PPAR agonists like Rosiglitazone can induce apoptosis of macrophages and would thus serve as excellent anti-inflammatory targets.<ref name="Berger2">PMID:12079620</ref> PPARα has been shown to play a critical role in the regulation of uptake and oxidation of fatty acids. This makes PPARα an excellent target for Atherosclerosis drugs which aim to reduce LDL cholesterol and increase HDL cholesterol, the two most common traits of atherosclerosis. The fibrates are a class of amphipathic carboxylic acids that are PPARα agonists used to treat hypercholesterolemia and hyperlipidemia along with the [[HMGR]] inhibitor statins. Some fibrates are Bezafibrate (Marketed by Roche as [http://www.rxmed.com/b.main/b2.pharmaceutical/b2.1.monographs/CPS-%20Monographs/CPS-%20(General%20Monographs-%20B)/BEZALIP.html Bezalip]) and Ciprofibrate ([http://www.netdoctor.co.uk/medicines/100001714.html  Modalim]).<ref name="Berger"/> PPARδ is broadly expressed across the human body and thus is suspected to play a role in a number of diseases. It has been implicated in disorders ranging from fertility problems to types of cancer. Perhaps the most important use of PPARδ agonists will be in treating central nervous system (CNS) diseases as PPARδ has been implicated in neuron myelinogenesis and neuronal signaling as well as lipid metabolism in the CNS.<ref name="Berger"/>

Most drugs target the PPARγ LBD, as ligands that bind to RXRα are likely to inadvertently act on other RXRα complexes, resulting in unexpected side effects. <ref name="Berger2"/> Sales of Avandia, marketed by GlaxoSmithKline peaked at $2.5 billion in 2006 but have since dipped dramatically due to health concerns. In response to the health concerns, sales of Actos, marketed by Takeda, have grown to block buster status.<ref>http://uk.reuters.com/article/idUKT7482820080131</ref>

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==Additional Resources==