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Fat and Beyond: The Diverse Biology of PPAR gamma


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Fat and Beyond: The Diverse Biology of PPAR gamma

  1. 1. WELCOME
  2. 2. Credit Seminar on SPEAKER P.RAMESH PH.D (ABC)
  3. 3. PPARs (peroxisome proliferator-activated receptors ) are nuclear receptors & function as “Transcription factor” Essential roles in regulation of cellular differentiation, atherosclerosis & macrophage function 3 types have been identified: Alpha α, Gamma , and Delta  (Beta β) 3 α (alpha) - expressed in
  4. 4. Cont… β/δ (beta/delta) - expressed in many tissues but markedly in brain, adipose tissue, and skin γ (gamma) - although transcribed by the same gene, this PPAR through alternative splicing is expressed in 3 isoforms: γ1 - expressed in virtually all tissues γ2 - expressed mainly in adipose tissue (30 A.As longer) 4
  5. 5. PPAR is a ligand-activated transcriptional factor have a dominant role in development of adipose cells It is subfamily of structurally similar to nuclear receptor PPAR functions as an obligate heterodimer with RXRs High affinity binding to DNA by PPAR requires absolute dimerization with RXR (Tontonoz P, et al., 1994) Domains of PPAR proteins present nearly all nuclear hormone receptor Retinoid X Receptor 5
  6. 6. Cont… C N PPAR has two N-terminal variants formed by alternative splicing (Adams M, et al., 1997)  PPAR 2 is expressed in more adipose selective manner N-terminal region influences the response to ligand 6 binding of LBD by phosphorylation at ser112 al., 1996) (Hu E, et
  7. 7. N C DNA-binding domain (DBD): Highly conserved domain containing two zinc fingers which binds to specific sequences of DNA called hormone response elements (HRE) 7 C-terminal region is responsible for dimerization with RXR (Ren D, et al., & contains Transcriptional activation domain (AF2) 2002)
  8. 8. Cont… C-terminal region also form ligand binding pocket, with many hydrophobic residuces occuring inside the pocket Crystal structure of PPAR LBD 8 (Gampe RT, et al., 2000)
  9. 9. Cont…  PPAR activation induced by ligand dependent and independent mechanisms  Absence of ligand, corepressors bind to heterodimers & recruit Histone deacetylases to repress transcription  After ligand binding, increase PPAR affinity for number of co-activators  N-terminal regulatory domain: Contains the activation function 1 (AF-1) whose action is independent of the 9 presence of ligand (Tontonoz P, et al., 1994)
  10. 10.  Co-activators: These are not themselves regulated at expression level CBP/p300 SRC family TRAP220 PGC-1α Co-repressors: SMART NCoR RIP140 10
  11. 11. Cont… Biological Ligands: Polyunsaturated fatty acids Prostanoids (15-deoxy-12,14 prostaglandin-J2) Leukotriene LTB4 Oxidized fattyacids (9-HODE & 13-HODE) Lysophosphatidic acid Synthetic Ligands: Thiazolidinedion (TZD) Anti-Diabetic Drug Fibrates (Hyperlipidemia) 11 (Debevec D, et al., 2007)
  12. 12. Adipocyte is central player in control of energy balance & whole body lipid homeostasis PPAR is dominant or “master” regulator of Adipogenesis It induces differentiation of pre-adipocytes into adipocytes & expressed in BAT and WAT (Sears I, et al., 1996) C/EBP-β/ bind to PPAR promoter & activates PPAR 12 Upon ligand activation, PPAR induces many target genes involved in Lipogenesis & Adipogenesis
  13. 13. KLF5 CHOP KLF1 5 SREBP1 C KLF2 C/EBP PPAR KROX20 C/EBP C/EBP C/EBP GATA2 /3 Genes of Adipocyte differentiation Anti-adipogenic factors Activation Inhibition 13 (Evan D, et al., 2006)
  14. 14. INSULIN IGF-1 WNT10b TGF SHH FGF BMPs SMO PTC Testosterone IRS -Catenin AR SMAD3 P ? SMAD3 + SHN2 SMAD1 P13K AKT/PKB C/EBP CREB FOXO1/A2 ? TCF/LEF GATA2/3 ? PPAR OTHERS 14 (Evan D, et al., 2006)
  15. 15. Anti-Diabetic drugs Dietary fattyacids PPAR Intracellular fattyacids Prostaglandins PGJ2 Ap2 CBP RXR SRC LPL CD36 p300 RNA pol-II PEPCK Aquaporin7 GLUT4 Perilipin PGAR GlyK Fig: Role of PPAR pathway for Adipogenesis 15
  16. 16. 16
  17. 17. Triacylglycerols (Chylomicrons) Glucose (Liver) CD36 GLUT4 Liver Fattyacids Glucose Glycerol-3-P PEPCK LPL Aquaporin7 FattyacylcoA Perilipin Triacylglycerols HSL Glycerol Adipocyte Fattyacids 17
  18. 18. Triacylglycerols (Chylomicrons) Glucose (Liver) LPL CD36 GLUT4 Liver Fattyacids Glucose Glycerol-3-P Aquaporin7 FattyacylcoA PEPCK Perilipin Triacylglycerols HSL Glycerol Adipocyte Fattyacids 18
  19. 19. PPAR extensively studied in WAT differentiation & same receptor is also important in BAT development & function Thermogenic effect of PPAR in BAT is mediated by PGC1α, induced by cold exposure of animals (Sears I, et al., 1996) PGC-1α regulates activation of PPAR on thermogenesis & fattyacid oxidation by interacting with PPAR/RXR Stimulation of uncoupling protein (UCP-1), responsible 19 for uncoupling β-oxidation PPAR Coactivator-1
  20. 20. Cont… Phosphorylated PGC-1α is recruited PPAR binding site on UCP-1 promoter PGC-1α is stabilized & activated by p38 MAP kinases PGC-1α binds to PPAR by its LBD in a ligand independent manner LXXLL motif containing co-activator binds to PPAR Insulin/akt pathway shutdown hepatic gluconeogenesis, phosphorylation of PGC-1 (McInerney E, et al., 1998) 20
  21. 21. G protein ATP cAMP MAP kinas e PGC1 P PPAR UCP-1 (Sears I, et al., 1996)
  22. 22. Cont… 22 Fig: Thermogenesis by UCP-1 in BAT
  23. 23. Insulin Resistance: is a condition in which body cells become less sensitive to the glucose-lowering effects of the hormone insulin Type2 Diabetes mellitus: Pancreas secrete normal or even greater than normal amount of insulin Hallmark of type2 Diabetes is Insulin Resistance In type2 Diabetes, plasma levels of FFAs & Glucose are 23 increased
  24. 24. In T2DM inappropriate deposition of lipids in liver & skeletal muscle Thiazolidinedione (TZD), Rosiglitazone & Pioglitazone are used for treatment of type2 Diabetes (Haris P, et al., 1994) Activation of PPAR target gene expression enhance to store dietary fattyacids Target genes contributing to this include AP2, LPL, CD36, PEPCK & Aquaporin 7 24 (Kishida K, et al., 2001)
  25. 25. Cont… Adipose tissue is primary target for effects of TZD It also promotes many signaling molecules called Adipokines from adipocytes Adiponectin Resistin TNFα INFLAMMATORY RESPONSE MCP-1 IL-6, IL-1β (Bouskila M, et al., 2005) 25
  26. 26. Ligand activation (TZD) of PPAR in adipocytes is associated with decreased production of TNFα, Resistin & MCP-1 Increase of Adiponectin gene Decreased Insulin Resistance Suppression of Hepatic glucose uptake & stimulates muscle glucose uptake 26
  27. 27. ADIPONECTINS:  It is a protein hormone abundantly expressed in adipocytes  Adiponectin affects:  Decreased gluconeogenesis  Increased glucose uptake  β-oxidation  Triglyceride clearance  Protection from endothelial dysfunction  insulin sensitivity 27
  28. 28. TNF-α: Cont… It is an inflammatory cytokine released in obese & insulin resistance Also propagates atherosclerotic lesion formation It also promotes apoptosis in endothelial cells by dephosphorylating protein kinase B or Akt & contribute endothelial injury 28
  29. 29. Cont… RESISTIN:  It is recently discovered fat-specific hormone, directly induces insulin resistance in muscle & liver  Neutralization of resistin by specific antibodies results in decreased blood glucose level  It also express cell adhesion molecule (VCAM-1), chemokine MCP-1(Atherosclerotic lesion formation) with insulin resistance patients 29
  30. 30. Insulin Muscle Liver Adipocyte Hypertrophy ? RESISTIN Diet induced Obesity Adipocyte 30 (Olavi U, et al., 2002)
  31. 31. Adipokines & Inflammation:  Increased in adipose tissue (WAT) with obesity during inflammation (TNF-α, IL-6,IL-18, MIF, CRP & PAI-1)  Circulatory inflammatory markers are raised in obese  IL-6 released from adipose tissue stimulates hepatic synthesis of CRP in obese  Similary IL-18 is acivated by TNF-α 31 (Trayhurn P, et al., 2005)
  32. 32. Cont…  Why Obese should be accompanied by Inflammation???  It is mainly due to HYPOXIA  Adipose tissue (WAT) mass is very large in Obese & Type-II diabetes are linked to inflammation (Sears I, et al., 1996) 32
  33. 33. TZD effects on Skeletal Muscle and Liver: Skeletal Muscle is largest glucose utilizing organ, ability of TZD is to improve whole body insulin resistance PPARγ expression is very low in Skeletal muscle compare to fat Effect of PPARγ ligands on skeletal muscle for glucose uptake are likely to be indirect Direct of effect of PPARγ activation in muscle is still 33 unclear (Castrillo A, et al., 2004)
  34. 34. Cont… In liver also expression of PPARγ is very low, activation of PPARγ signaling promotes lipid accumulation (Hepatic Steatosis) in rodents But does not appear in human hepatic steatosis TZD is beneficial in treating nonalcoholic fatty liver disease in humans (Castrillo A, et al., 2004) 34
  35. 35. PPARγ is induced differentiation of monocytes into macrophages & highly expressed in Macrophages It also differentiates of monocytes into dendritic cells Oxidized ligands (9-HODE & 13-HODE) & lipoproteins responsible for PPARγ signaling in myeloid cells Upon ligand activation, it promotes expression of genes CD36, LXR, Arg-1& IL-10 (Sears I, et al., 1996) 35
  36. 36. 36
  37. 37.  PPARγ is a lipid-activated member of the nuclear receptor superfamily of transcription factors  Biological receptor for the TZD class of antidiabetic drugs  Master transcriptional regulator of adipocyte differentiation & controls expression of a genes involved in lipid metabolism  PPARγ action in myeloid cells, such as macrophages and 37 DCs, has been linked to the modulation of immune and
  38. 38. 38