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PPARsPeroxisome Proliferator Activated Receptors
Fine tuning of metabolic processes is a   hallmark of healthy organisms
PPARs• PPARs are transcriptional factors, regulating gene expression  belonging to the ligand activated nuclear receptor s...
Overview of metabolic roles of 3 PPAR isoforms
Structural features of PPARs
Molecular mechanisms of PPARs
Gene transcription machinery• In addition to activation of PPARs by natural and synthetic  ligands other factors such as R...
RXR                                                                 Vs         RXR and heterodimerisation                 ...
PPREs• Structurally, PPREs consist of direct repeat (DR)-1  elements of two hexanucleotides with the AGGTCA  sequence sepa...
Coactivators and Corepressors• Several proteins act as coactivators or corepressors that  mediate the ability of nuclear r...
PPAR -γCritical factor for adipogenesis and glucose metabolism
The PPAR-γ gene contains three promoters thatyield three isoforms, namely, PPAR-γ1, PPAR-γ2and PPAR-γ3.Tissue dependent ...
PPAR-γ mediated gene transcription• The gene transcription mechanism is identical in all PPAR  subtypes.• The process of t...
Major mechanisms ofPPAR-γ involved in the improvement of insulin                 resistance                               ...
Important biological effects of PPAR-γ
PPAR γ ligands• Exogenous Vs Endogenous. . . .
PPAR γ agonists from natural product                librarySaururus chinensis       Glycyrrhiza uralensis
Biological mechanisms of PPAR γ• Adipocyte differentiation Adipogenesis refers to the process of differentiation of the p...
 In addition to the stimulation of adipocyte  differentiation, activation of PPAR-γ also promotes apoptosis  in mature li...
Insulin SensitizationTissue necrosis factor alpha (TNF-α), a pro-inflammatorycytokine that is expressed by adipocytes, has...
Resistin, a hormone secreted by adipocytes that elevates bloodglucose levels, was inhibited by TZDs. Adipocyte-derived f...
PPAR α
PPAR- α serves as a receptor for structurally diverseclass of compounds, including hypolipidemic fibrates.PPAR- α is expr...
Biological mechanisms of PPAR α• The critical role of PPAR-α agonists in the regulation of β oxidation of  fatty acids has...
PPAR-α agonists have been reported to activatethe expression of apolipoprotein A-1.PPAR-α activation also influences the ...
PPAR β• Despite vigorous research on PPAR-γ and PPAR-α, the  functional identity of PPAR-β remains unclear.•    PPAR-β is ...
CONCLUSION• PPARs are key transcriptional factors that catalyze and  coordinate different biochemical events in order to  ...
REFERENCES• B.Desvergne, et.al, Peroxisome Prolferator-Activated  Receptor;Nuclear control of metabolism,Endocrine  review...
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PPARs

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PPARs

  1. 1. PPARsPeroxisome Proliferator Activated Receptors
  2. 2. Fine tuning of metabolic processes is a hallmark of healthy organisms
  3. 3. PPARs• PPARs are transcriptional factors, regulating gene expression belonging to the ligand activated nuclear receptor superfamily.• PPARs play essential roles in the regulation of cellular differentiation, development and metabolism (carbohydrate, lipid, protein),• Activation by endogenously secreted prostaglandins, fatty acids and eicasanoids.• On activation, initiate transcription of an array of genes that are involved in energy homeostasis.
  4. 4. Overview of metabolic roles of 3 PPAR isoforms
  5. 5. Structural features of PPARs
  6. 6. Molecular mechanisms of PPARs
  7. 7. Gene transcription machinery• In addition to activation of PPARs by natural and synthetic ligands other factors such as RXR,PPRE and cofactors play a pivotal role in acheiving desired transcription.
  8. 8. RXR Vs RXR and heterodimerisation RAR. .• The LBD domain facilitates the heterodimerisation of PPARs with the RXR and the resultant heterodimer subsequently binds to PPRE with the recruitment of cofactors
  9. 9. PPREs• Structurally, PPREs consist of direct repeat (DR)-1 elements of two hexanucleotides with the AGGTCA sequence separated by a single nucleotide spacer.• The DR-1 pattern is specific for PPAR–RXR heterodimer, which distinguishes it from the DR- 3, DR-4 patterns of other nuclear receptor responsive element patterns.
  10. 10. Coactivators and Corepressors• Several proteins act as coactivators or corepressors that mediate the ability of nuclear receptors to initiate or suppress the transcription process.• Unliganded state – corepression – histone deacetylase activity• Liganded state – coactivation- histone acetylase activity• NCoR & SMRT• SRC-1 & PPAR-BP
  11. 11. PPAR -γCritical factor for adipogenesis and glucose metabolism
  12. 12. The PPAR-γ gene contains three promoters thatyield three isoforms, namely, PPAR-γ1, PPAR-γ2and PPAR-γ3.Tissue dependent expressionPPAR-γ1 is found in a broad range oftissues, whereas PPAR-γ2 is restricted to adiposetissue.PPAR-γ3 is abundant in macrophages, largeintestine and white adipose tissue.
  13. 13. PPAR-γ mediated gene transcription• The gene transcription mechanism is identical in all PPAR subtypes.• The process of transcription begins with the binding of ligands (endogenous or exogenous) to the PPAR-γ receptor.• Ligand-bound PPAR heterodimerises with RXR, this heterodimer binds to the promoter region of PPRE, with the recruitment of co-activators.• This results in the increase in transcription activities of various genes involved in diverse biological processes .
  14. 14. Major mechanisms ofPPAR-γ involved in the improvement of insulin resistance Lipid metabolism Glucose homeostasis Adipogenesis
  15. 15. Important biological effects of PPAR-γ
  16. 16. PPAR γ ligands• Exogenous Vs Endogenous. . . .
  17. 17. PPAR γ agonists from natural product librarySaururus chinensis Glycyrrhiza uralensis
  18. 18. Biological mechanisms of PPAR γ• Adipocyte differentiation Adipogenesis refers to the process of differentiation of the pre- adipocyte precursor cells into adipocytes that are capable of lipid filling, as well as the expression of hormones and cytokines. PPAR γ and C/EBP are important transcription factors involved in the process of cell growth and arrest, followed by progression into the fully differentiated adipocyte phenotype.
  19. 19.  In addition to the stimulation of adipocyte differentiation, activation of PPAR-γ also promotes apoptosis in mature lipid-filled adipocytes. This ligand-induced apoptosis in mature cells causes the stimulation of adipogenesis from pre-adipocyte precursors, resulting in an increased number of small, relatively insulin-sensitive adipocytes.
  20. 20. Insulin SensitizationTissue necrosis factor alpha (TNF-α), a pro-inflammatorycytokine that is expressed by adipocytes, has been linked toinsulin resistance.In vivo investigations showed that PPAR- γ agonists improveinsulin resistance by opposing the effect of TNF-α in adipocytes.Expression of the glucose transporter protein GLUT4 by PPAR-γ agonists in adipocytes is also pivotal in the process of glucoseuptake..
  21. 21. Resistin, a hormone secreted by adipocytes that elevates bloodglucose levels, was inhibited by TZDs. Adipocyte-derived factors such as 11β-hydroxysteroiddehydrogenase 1 and adiponectin were influenced by PPAR-γactivation, improving insulin resistance and glucose homeostasis.
  22. 22. PPAR α
  23. 23. PPAR- α serves as a receptor for structurally diverseclass of compounds, including hypolipidemic fibrates.PPAR- α is expressed in numerous tissues in rodentsand humans including liver, kidney, heart, skeletalmuscle and brown fat.
  24. 24. Biological mechanisms of PPAR α• The critical role of PPAR-α agonists in the regulation of β oxidation of fatty acids has been well documented.• They stimulate the cellular uptake of fatty acids by increasing the expression of the fatty acid transport protein (FATP) and fatty acid translocase (FAT).• Exogenous ligands of PPAR-α such as fibrates and other peroxisome proliferator agents promote the expression of cytochrome P4504A (CYP4A).• In the heart, PPAR-α primarily supplies energy to the myocardium by regulating the genes responsible for fatty acid uptake and oxidation.• This is achieved by decreasing fatty acid oxidation and inhibiting lipoprotein lipase.
  25. 25. PPAR-α agonists have been reported to activatethe expression of apolipoprotein A-1.PPAR-α activation also influences the expressionof the cholesterol efflux “pump” known as ATPbinding cassette A1 (ABCA1) in macrophages, animportant component of the apolipoprotein A1-mediated RCT pathway.
  26. 26. PPAR β• Despite vigorous research on PPAR-γ and PPAR-α, the functional identity of PPAR-β remains unclear.• PPAR-β is expressed in a wide range of tissues and cells, with relatively higher levels in the brain, adipose tissue and skin.
  27. 27. CONCLUSION• PPARs are key transcriptional factors that catalyze and coordinate different biochemical events in order to achieve energy homeostasis.• To date, three main types of PPARs have been identified, namely α,β, and γ.• Each isoform varies in ligand specificity and tissue distribution and hence serve different biological purposes.
  28. 28. REFERENCES• B.Desvergne, et.al, Peroxisome Prolferator-Activated Receptor;Nuclear control of metabolism,Endocrine reviews:649-688:1999;20[5].• K.Bhavani , et . al, An overview of Biological Mechanisms of PPARs, Pharmacological research:51[2005],85-94.

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