Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptor transcription factors that regulate genes involved in metabolism. There are three main types of PPARs: PPARα which controls lipid metabolism and inflammation, PPARγ which regulates adipocyte differentiation and glucose metabolism, and PPARβ/δ which regulates glucose utilization and inflammation. PPARs act as receptors for fatty acids and other ligands, and regulate target genes important for metabolic processes. PPAR agonists have shown potential in treating diseases like diabetes, atherosclerosis, and cancer, though some synthetic agonists have also demonstrated toxicities. Recent research continues to explore dual and pan-PPAR agonists as well as selective mod

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