Peroxisome Proliferator-Activated Receptors: Difference between revisions
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[[Image: 3dzy2.png| | <StructureSection load='' size='450' side='right' caption='Crystal Structure of Human PAPRα complex with agonist ([[1i7g]])' scene='Peroxisome_Proliferator-Activated_Receptors/Ppar_opening_2/2'> | ||
{{ | [[Image: 3dzy2.png|320px|left|thumb| Human PPARγ bound to RXRα and PPRE DNA strand, [[3dzy]]]] | ||
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==Function== | |||
The [[Peroxisome Proliferator-Activated Receptors]] (PPAR) α, γ, and δ are members of the [[Nuclear receptors|nuclear receptor family]]. Since their discovery in the early 90s, it has become clear that the PPARs are essential modulators of external stimuli, acting as transcription factors to regulate mammalian metabolism, cellular differentiation, and tumorigenesis. The PPARs are the targets of numerous pharmaceutical drugs aimed at treating hypolipidemia and [[diabetes]] among other diseases.<ref name="Berger"/> See also [[Diabetes & Hypoglycemia]]. | |||
*'''PPARα''' regulates the expression of genes involved in fatty acid β oxidation<ref>PMID:15497675</ref>. | |||
<br /> | *'''PPARγ''' regulates the expression of genes involved a variety of physiological processes like development of adipose cells, cell proliferation, macrophage function and immunity<ref>PMID:18518822</ref>. For details see [[PPAR-gamma]]. For details on PPARγ drugs see [[Pioglitazone]].<br /> | ||
*'''PPARδ''' regulates the expression of genes involved in fatty acid burning in adipose tissue and skeletal muscle<ref>PMID:15733739</ref>. | |||
==Biological Role== | ==Biological Role== | ||
[[Image: PPAR_Mechanism.png|400px|left|thumb| PPAR Mechanism of Action in the Human Body]] | [[Image: PPAR_Mechanism.png|400px|left|thumb| PPAR Mechanism of Action in the Human Body]] | ||
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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>. | 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>. | ||
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==Natural Ligands== | ==Natural Ligands== | ||
PPARγ binds polyunsaturated fatty acids like linoleic acid, linolenic acid, and eicosapentaenoic acid at affinities that are in line with serum levels found in the blood. PPARα binds a variety of saturated and unsaturated fatty acids including palmitic acid, oleic acid, linoleic acid, and arachidonic acid.<ref>PMID:1316614</ref> PPAR's ligand selectivity is intermediate between that of the other isotypes and is activated by palmitic acid and a number of eicosanoids.<ref>PMID:7836471</ref> | |||
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==PPAR Structure== | ==PPAR Structure== | ||
===Ligand Binding Domain=== | ===Ligand Binding Domain=== | ||
The structures of the PPARs are very similar over each isotype. All PPAR isotypes have a ligand binding domain (LBD). The LBD, which is located in the C-terminal half of the receptor, is composed of 13 α-helices and a four-stranded ß-sheet. <scene name='Peroxisome_Proliferator-Activated_Receptors/Ligand_binding_pocket/2'>The ligand binding pocket</scene> ([[2f4b]]) is Y-shaped and consists of an <scene name='Peroxisome_Proliferator-Activated_Receptors/Y_shaped/4'>entrance and two pockets, Arm I and Arm II, along with a "charge-clamp"</scene>.<ref name="Nolte">PMID:9744270</ref> The ligand binding pocket of PPARs is quite large (about 1400 cubic angstroms) in comparison to that of other nuclear receptors which allows the PPARs to interact with numerous structurally distinct ligands.<ref name="Nolte"/>. Within Arm I, four polar resides are conserved over all PPAR isotypes, <scene name='Peroxisome_Proliferator-Activated_Receptors/4_conserved_residues/1'>namely Ser280, Tyr314, His440, and Tyr464</scene> in the case of PPARα. These residues are part of a hydrogen bonding network that interacts with the carboxylate group of fatty acids and other ligands upon binding.<ref>PMID:16405912</ref> The <scene name='Peroxisome_Proliferator-Activated_Receptors/Helix_h12/4'>ligand-dependent activation domain (AF-2) helix H12</scene> ([[1kkq]]), whose function is to generate the receptors’ co-activator binding pocket, is located at the C-terminal end of the LBD.<ref>PMID:11027271</ref> The conserved hydrogen bonding network in <scene name='Peroxisome_Proliferator-Activated_Receptors/Helix_h12_in_place/1'>Arm I also helps hold the AF2-helix in the active conformation</scene>, promoting co-activator binding.<ref name="Zoete"/> <scene name='Peroxisome_Proliferator-Activated_Receptors/Arm_ii_hydrophobic/3'>Arm II is highly hydrophobic </scene>and is thus ideal for binding the hydrophobic tail of fatty acids via Van der Waals interactions. | The structures of the PPARs are very similar over each isotype. All PPAR isotypes have a ligand binding domain (LBD). The LBD, which is located in the C-terminal half of the receptor, is composed of 13 α-helices and a four-stranded ß-sheet. <scene name='Peroxisome_Proliferator-Activated_Receptors/Ligand_binding_pocket/2'>The ligand binding pocket</scene> ([[2f4b]]) is Y-shaped and consists of an <scene name='Peroxisome_Proliferator-Activated_Receptors/Y_shaped/4'>entrance and two pockets, Arm I and Arm II, along with a "charge-clamp"</scene>.<ref name="Nolte">PMID:9744270</ref> The ligand binding pocket of PPARs is quite large (about 1400 cubic angstroms) in comparison to that of other nuclear receptors which allows the PPARs to interact with numerous structurally distinct ligands.<ref name="Nolte"/>. Within Arm I, four polar resides are conserved over all PPAR isotypes, <scene name='Peroxisome_Proliferator-Activated_Receptors/4_conserved_residues/1'>namely Ser280, Tyr314, His440, and Tyr464</scene> in the case of PPARα. These residues are part of a hydrogen bonding network that interacts with the carboxylate group of fatty acids and other ligands upon binding.<ref>PMID:16405912</ref> The <scene name='Peroxisome_Proliferator-Activated_Receptors/Helix_h12/4'>ligand-dependent activation domain (AF-2) helix H12</scene> ([[1kkq]]), whose function is to generate the receptors’ co-activator binding pocket, is located at the C-terminal end of the LBD.<ref>PMID:11027271</ref> The conserved hydrogen bonding network in <scene name='Peroxisome_Proliferator-Activated_Receptors/Helix_h12_in_place/1'>Arm I also helps hold the AF2-helix in the active conformation</scene>, promoting co-activator binding.<ref name="Zoete"/> <scene name='Peroxisome_Proliferator-Activated_Receptors/Arm_ii_hydrophobic/3'>Arm II is highly hydrophobic </scene>and is thus ideal for binding the hydrophobic tail of fatty acids via Van der Waals interactions. | ||
Despite over 80% of the ligand binding cavity residues being conserved over all PPAR isotypes, it is the remaining 20% that creates the ligand specificity seen between isotypes. A few examples illustrate this point. In PPARδ, the cavity is significantly narrower adjacent to the AF-2 helix and Arm I. This prevents PPARδ from being able to accommode large headed TZDs and L-tyrosine based agonsists. In the case of PPARα, PPARα does not bind ligands with large carboxylate head groups because of <scene name='Peroxisome_Proliferator-Activated_Receptors/Tyr_314/4'> Tyrosine 314</scene> as compared to PPARγ which has a smaller equivalent residue in His323.<ref name="Zoete"/> Or in the case of binding some benzenesulfonamide derivatives, the <scene name='Peroxisome_Proliferator-Activated_Receptors/Pi_stacking/2'>pi stacking of Phe363 and the aromatic moiety</scene> ([[2g0g]]) in the case of PPARγ is lost in PPARα (Ile354) and PPARδ(Ile 363)<ref name="Zoete"/> | Despite over 80% of the ligand binding cavity residues being conserved over all PPAR isotypes, it is the remaining 20% that creates the ligand specificity seen between isotypes. A few examples illustrate this point. In PPARδ, the cavity is significantly narrower adjacent to the AF-2 helix and Arm I. This prevents PPARδ from being able to accommode large headed TZDs and L-tyrosine based agonsists. In the case of PPARα, PPARα does not bind ligands with large carboxylate head groups because of <scene name='Peroxisome_Proliferator-Activated_Receptors/Tyr_314/4'> Tyrosine 314</scene> as compared to PPARγ which has a smaller equivalent residue in His323.<ref name="Zoete"/> Or in the case of binding some benzenesulfonamide derivatives, the <scene name='Peroxisome_Proliferator-Activated_Receptors/Pi_stacking/2'>pi stacking of Phe363 and the aromatic moiety</scene> ([[2g0g]]) in the case of PPARγ is lost in PPARα (Ile354) and PPARδ(Ile 363)<ref name="Zoete"/> | ||
===AF-2 Domain: Structure and Function=== | ===AF-2 Domain: Structure and Function=== | ||
As briefly mentioned before, the AF-2 domain is essential for ligand binding and <scene name='Peroxisome_Proliferator-Activated_Receptors/Ppar_opening3/2'>PPAR</scene> ([[2prg]]) function. Upon ligand binding, helix H12 of AF-2 closes on the ligand-binding site, reducing conformational flexibility of the LBD and assuming a structure that is ideal for co-activator binding. Using Molecular Dynamic simulations, it has been determined that residues <scene name='Peroxisome_Proliferator-Activated_Receptors/H_bonding_network/3'>Glu324, Arg397, Arg443, and Tyr 477</scene> (in PPARγ) are involved in a hydrogen bond network that stabilizes the AF-2 helix in the active conformation upon ligand binding.<ref name="Zoete"/> | |||
As briefly mentioned before, the AF-2 domain is essential for ligand binding and <scene name='Peroxisome_Proliferator-Activated_Receptors/Ppar_opening3/2'>PPAR</scene> function. Upon ligand binding, helix H12 of AF-2 closes on the ligand-binding site, reducing conformational flexibility of the LBD and assuming a structure that is ideal for co-activator binding. Using Molecular Dynamic simulations, it has been determined that residues <scene name='Peroxisome_Proliferator-Activated_Receptors/H_bonding_network/3'>Glu324, Arg397, Arg443, and Tyr 477</scene> (in PPARγ) are involved in a hydrogen bond network that stabilizes the AF-2 helix in the active conformation upon ligand binding.<ref name="Zoete"/> | |||
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===Co-Activator & Co-Repressor Binding=== | ===Co-Activator & Co-Repressor Binding=== | ||
[[Image: SRC_binding.png| | [[Image: SRC_binding.png|250px|left| Human PPARγ Co-Activator Binding Site. PPARγ bound to SRC-1, [[3dzy]]]] | ||
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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> | 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> | ||
When PPAR is bound to a co-repressor, the <scene name='Peroxisome_Proliferator-Activated_Receptors/H12_in_alpha/4'>hydrogen bond between Tyr 464 in PPAR alpha in AF-2 and other AF-2 stabilizing helices is destroyed</scene>, preventing the AF-2 H12 helix from occupying its active state. This in turn eliminates the charge clamp between PPAR and a prospective co-activator.<ref name="Gampe"/> Notice the <scene name='Peroxisome_Proliferator-Activated_Receptors/H12_in_alpha_active/2'>position of H12 when bound to a co-activator.</scene> | When PPAR is bound to a co-repressor, the <scene name='Peroxisome_Proliferator-Activated_Receptors/H12_in_alpha/4'>hydrogen bond between Tyr 464 in PPAR alpha in AF-2 and other AF-2 stabilizing helices is destroyed</scene>, preventing the AF-2 H12 helix from occupying its active state. This in turn eliminates the charge clamp between PPAR and a prospective co-activator.<ref name="Gampe"/> Notice the <scene name='Peroxisome_Proliferator-Activated_Receptors/H12_in_alpha_active/2'>position of H12 when bound to a co-activator.</scene> | ||
===Formation of Heterodimer with RXR=== | ===Formation of Heterodimer with RXR=== | ||
The interface of PPAR and RXR is composed of an intricate <scene name='Peroxisome_Proliferator-Activated_Receptors/Dimer_interface/1'>network of hydrophobic </scene>and <scene name='Peroxisome_Proliferator-Activated_Receptors/Dimer_interface_polar/2'>polar interactions </scene>which show remarkable complementarity. For the PPARγ-RXRα dimer the dimmer interface interactions are particularly extensive. <ref name="Gampe"/> | The interface of PPAR and RXR is composed of an intricate <scene name='Peroxisome_Proliferator-Activated_Receptors/Dimer_interface/1'>network of hydrophobic </scene>and <scene name='Peroxisome_Proliferator-Activated_Receptors/Dimer_interface_polar/2'>polar interactions </scene>which show remarkable complementarity. For the PPARγ-RXRα dimer the dimmer interface interactions are particularly extensive. <ref name="Gampe"/> | ||
===DNA Binding Domain Structure=== | ===DNA Binding Domain Structure=== | ||
PPARs also contain a DNA binding domain (DBD) The <scene name='Peroxisome_Proliferator-Activated_Receptors/Zinc_fingers/1'>DBD consists of two zinc fingers</scene> ([[3dzy]]), one on PPAR and one on RXR, that bind PPREs of PPAR-responsive genes. The consensus sequence of PPREs is AGGTCA and has been found in a number of PPAR inducible genes like acyl-CoA oxidase and adipocyte fatty acid-binding protein.<ref>PMID:9383428</ref> Chandre et al. have demonstrated that the DNA PPRE allosterically contributes to its own binding via a <scene name='Peroxisome_Proliferator-Activated_Receptors/Dbd_hbonds/1'>head-to-tail interaction between the PPAR DBD and RXR DBD</scene> using residues Gln206 and Arg209 on RXRα and Asn160 on PPARγ.<ref>PMID:19043829</ref> | PPARs also contain a DNA binding domain (DBD) The <scene name='Peroxisome_Proliferator-Activated_Receptors/Zinc_fingers/1'>DBD consists of two zinc fingers</scene> ([[3dzy]]), one on PPAR and one on RXR, that bind PPREs of PPAR-responsive genes. The consensus sequence of PPREs is AGGTCA and has been found in a number of PPAR inducible genes like acyl-CoA oxidase and adipocyte fatty acid-binding protein.<ref>PMID:9383428</ref> Chandre et al. have demonstrated that the DNA PPRE allosterically contributes to its own binding via a <scene name='Peroxisome_Proliferator-Activated_Receptors/Dbd_hbonds/1'>head-to-tail interaction between the PPAR DBD and RXR DBD</scene> using residues Gln206 and Arg209 on RXRα and Asn160 on PPARγ.<ref>PMID:19043829</ref> | ||
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==Binding of Synthetic Agonists and Medical Implications== | ==Binding of Synthetic Agonists and Medical Implications== | ||
A number of synthetic agonists have been developed to bind to <scene name='Peroxisome_Proliferator-Activated_Receptors/Ppar_opening4/2'>PPAR</scene> to fight metabolic diseases like diabetes. These agonists include [http://en.wikipedia.org/wiki/troglitazone troglitazone] ([http://www.rezulin.com Rezulin]), pioglitazone ([[Actos]]), [[Fenofibrate]] (Tricor) and [[Rosiglitazone]] ([[Avandia]]). These agonists function in a similar fashion, by binding to the active site of PPARγ, activating the receptor. Rosiglitazone occupies roughly 40% of the LBD. It assumes a U-shaped conformation with the TZD head group forming a <scene name='Peroxisome_Proliferator-Activated_Receptors/Rosiglitazone_binding/3'>number of interactions that stabilize the agonist</scene>. Rosiglitazone forms hydrogen bond interactions with H323 and H449 and its TZD group, the sulfur atom of the TZD occupies a hydrophobic pocket formed by Phe363, Glu286, Phe282, Leu330, Ile326 and Leu469, and the central benzene ring occupies a pocket formed by Cys285 and Met364.<ref name="Nolte"/> | |||
A number of synthetic agonists have been developed to bind to <scene name='Peroxisome_Proliferator-Activated_Receptors/Ppar_opening4/2'>PPAR</scene> to fight metabolic diseases like diabetes. These agonists include [http://en.wikipedia.org/wiki/troglitazone troglitazone] ([http://www.rezulin.com Rezulin]), pioglitazone ([[Actos]]), and | |||
[[Image: Ciprofibrate.PNG|300px|left|thumb| Human PPARα agonist, Ciprofibrate (Modalim)]] | [[Image: Ciprofibrate.PNG|300px|left|thumb| Human PPARα agonist, Ciprofibrate (Modalim)]] | ||
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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"/> | 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"/> | ||
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See<br /> | |||
[[Glitazone Pharmacokinetics]]<br /> | |||
[[Treatments:Glitazone Pharmacokinetics References]]. | |||
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[[ | |||
== | ==3D Structures of PPAR== | ||
[[ | [[Peroxisome proliferator-activated receptor 3D structures]] | ||
</StructureSection> | |||
==Additional Resources== | ==Additional Resources== | ||