A presentation on PPARs for Post graduate students

1. Peroxisome proliferator-activated
receptors (PPARs)
Dr.Kavitha
Moderator: Dr.Radhika
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2. Presentation plan
• Introduction
• History
• Definition-PPAR
• Types, location, physiological role
• PPAR-genomics & proteomics
• Individual PPARs
• Toxicities related to PPARs
• Recent advances
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3. Introduction
Superfamily of
nuclear hormone
receptors
Testosterone receptor
{Androgen receptor(AR)}
Oxysterols receptor
{liver X receptor (LXR)}
Estrogen receptor (ER)
Xenobiotics receptor
{Pregnane X receptor (PXR)}
Retinoic X receptor (RXR)
Thyroid hormone receptor
(TR)
Bile acids receptor {farsenoid
X receptor (FXR)}
Vit D receptor (VDR)
PPAR
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4. History
• An attempt to delineate the mechanism-
chemicals induce peroxisome proliferation in
rhodents-Discovery of PPARs
• Peroxisome binding protein-rat liver cytosol
• Cloned receptors- structural similarities to
steroid hormone receptors
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5. Definition
PPARs are ligand-activated transcription factors that
regulate genes important in cell differentiation
and various metabolic processes, especially lipid
and glucose homeostasis.
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6. PPARs
Types Location Function Gene targets
PPAR α -Brown adipose
tissue, skeletal
muscle, heart, liver,
kidneys
-Controls lipid
metabolism and
inflammatory
processes
-β oxidation pathway
-Sterol 12-hydroxylase
-Fatty acid transport
-Fatty acid translocase
-Lipoprotein lipase
-Apolipoprotein A-I & A-II
PPAR γ -White and brown
adipose tissue,
muscle, colon and
liver
-Adipocyte
differentiation, glucose
metabolism and
inflammatory
pathways
-Genes- lipid
uptake,metabolism &
efflux
PPAR
β/δ
Brain, adipose
tissue, skin
Regulates glucose
utilization , cell
differentiation and
inflammation
-Fatty acid-binding protein
-Fatty acid transport
protein
-Fatty acid translocase 6

7. PPAR-Genomics
PPAR α -L162V , R131Q ,V227A
-PPAR L162V Polymorphism-Liver tumor progression
PPAR β/δ -+294T/C
-PPAR δ +294T/C
-Associated with increase in fasting glucose levels in women with
polycystic ovary syndrome
PPAR γ -P12A ,C1431T ,C190S ,R166W ,R194W
-PPAR γ2 Pro 12Ala variant-Reported
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8. PPAR-Proteomics
N-terminal region
(A/B domain)
DNA binding domain
(DBD, C domain)
A flexible hinge region
(D region) The C terminal region
(E/F domain)
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11. PPAR α
Natural ligands Synthetic ligands
-Unsaturated fatty
acid
-Leukotriene B4
-8-hydroxy-
eicosatetraenoic acid
-Fenofibrate
-Clofibrate
-Benfibrate
-Gemfibrozil
-GW7647
-GW9578
-LY518674
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12. Synthetic agonists of PPAR α
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13. Pharmacological role of PPAR α in human disease
Disease Role of PPARα
Dyslipidemia -Use of fibrates
Atherosclerosis -↑production of apolipoproteins,
apo-V, apo-CIII,↓TGs, ↑HDL
Obesity -Fibrate treatment-reported to
reduce weight gain in rhodents
-Benzfibrate
Diabetes -Reduce insulin resistance
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14. PPAR γ
Natural ligands Synthetic agonists Selective
Modulators
Antagonist
-Unsaturated fatty
acids
-15-hydroxy-
eicosatetraenoic
acid
-9- and 13-
hydroxy-
octadecadienoic
acid
-15 –deoxy Δ
12,14-
prostaglandin J2
-Prostaglandin
PGJ2
-Rosiglitazone
-Pioglitazone
-Troglitazone
-Ciglitazone
-Farglitazar
-S26948
-INT131
-GW1929
-GW7845
-GW0072
-Netoglitazone
-NC-2100
-GW9662
-T0070907
-PD068235
-LG100641
-BADGE
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15. Pharmacological role of PPARγ
Diabetes -↓Plasma glucose, lipid & insulin levels-T2DM
-Adipose remodeling factors
-↓ adipocyte secretion of PAI-1
-Regulate expression of genes-enhance glucose metabolism
Atherosclerosis -Anti-atherogenic
-Anti-thrombotic
Inflammation -↓TNF α, Interleukin 1β , IL-6
-Rosiglitazone-Potent anti-inflammatory
-Inflammatory bowel disease
Cancer -TZDs & 15d-PGJ-₂ : Growth inhibition of numerous tumor cancer
cell lines
-Troglitazone-inoperable lipocarcinomas
CNS -Ciglitazone- reduce cell viability & ↑apoptotic rate malignant
astrocytoma cell lines
-Pioglitazone-Delays onset & reduces severity of clinical
symptoms-experimental autoimmune encephalomyelitis (Animal
models of multiple sclerosis) 15

16. PPAR δ
Natural ligands Synthetic ligands
-Unsaturated fatty acids
-Carbaprostacyclin
-Components of VLDL
-GW501516
-GW0742
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17. Pharmacological role of PPAR δ in human disease
Lipid metabolism and
cholesterol efflux
-Reports-↑HDLc in diabetic db/db mice
-GW501516-↑HDLc, ↓LDLc, TGs & insulin levels
Adipogenesis -Adipocyte differentiation
Colorectal cancer -Potential oncogenic effector of β-catenin in colorectal
carcinogensis
-NSAIDs-Sulindac- antagonise PPAR δ activated gene
transcription
-PPAR δ null cells-↓tumorigenesis
Bone metabolism -Carbaprostacyclin- bone resorbing property
-Cathepsin K, carbonic anhydrase type II-Upregulated
-PPAR δ antagonist-potential utility in treating
osteoporosis
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18. Dual PPAR
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19. Pan PPAR co-agonism
• Bezafibrate
• α , β/δ , γ PPAR activator
• Metabolic abnormalities :Improve both insulin
sensitivity, blood lipid profile, reduces the risk
of long term C.V complications
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20. Toxicity related to PPAR
• Liver toxicity-Troglitazone
• Bladder cancer-Ragaglitazar
• Hepatocellular adenoma
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21. Recent advances
Compound Status
Dual PPAR agonist
Muraglitazar
Tesaglitazar
Aleglitazar
-Marketed
-Phase III
-Phase III
Pan Agonist
GW 677954
PLX 204
DRL-11605
-Phase II
-Phase I
-Phase I
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22. References
• Gorniak B G. Peroxisome proliferator-activated
receptors and their ligand:nutritional and
clinical implications-a review. Nutrition journal
2014, 13:17
• V.A.Javiya , J.A.Patel. The role of peroxisome
proliferator-activated receptors in human
disease. Indian J Pharmacol. Aug 2006. Vol 38.
Issue 4. 243-253
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23.   THANK YOU   23