Peroxisomal proliferated Activated receptor

1. Bhagya Siripalli,
Dept. Of Pharmacology, SVIPS.
PEROXISOMAL
PROLIFERATOR
ACTIVATOR RECEPTORS:
ALPHA AND GAMMA

2.  Introduction
 PPAR receptors – types
 Mechanism of action
 Role of PPARS
 Clinical significance

3. INTRODUCTION
In the field of molecular biology, the peroxisome
proliferator-activated receptors (PPARs) are a group
of nuclear receptor proteins that function as transcription
factors regulating the expression of genes.
PPARs play essential roles in the regulation of cellular
differentiation, development,
and metabolism (carbohydrate, lipid, protein), and
tumorigenesis of higher organisms

4.  Issemann and Green discovered Peroxisome proliferator
activated receptors (PPAR).
 The different types of PPAR initially identified in xenopus
frog.
 Belongs to nuclear receptor family.

5. Nuclear Receptor Superfamily
Type 1
Receptors
Eg. GR, MR,
AR,ER,PR
Steroids
Type 2 Receptors
Eg. TR, VDR, RAR,
PPAR
Thyroid hormone
Vitamin D
Retinoic acid
Lipid derivatives
Orphan
receptors
Ligands not
known
Eg. SF-1, HNF4

6. Binds toresponse
elements onDNA
Ligands
bind
Co-activators
Co-regulator
proteins

7.  Plays a central role in the regulation of
 Storage and catabolism of dietary fats and
carbohydrates
 Adipocyte differentiation
 Inflammatory responses
 Cancer
 Types :
 PPAR α
 PPAR β / δ
 PPAR γ

8. Ubiquitous but predominant in
α - Liver, kidney, heart, muscle, adipose tissue.
β/ δ - Brain, adipose tissue, and skin.
γ - three forms:
γ1 - Heart, muscle, colon, kidney, pancreas & spleen.
γ 2 - Adipose tissue.
γ 3 - Macrophages, large intestine, white adipose tissue.

9. PPAR Partner Ligand
Process
affected
Related
disease process
PPAR α
Active state-
fasting
Retinoic
acid X
receptor
Fatty
acids(FA)
Fibrates Peroxisome
proliferation
Dyslipidaemia
PPAR - β/δ
FA
Proteins
Dyslipidaemi
a Obesity
PPAR - γ
Active state-
fed
FA,TZD
Lipid &CHO
metabolism
Insulin
resistance
Obesity,
Metabolic
syndrome
PCOS,NAFLD
Cardiac
steatosis

11. All PPARs heterodimerize with the retinoid X receptor (RXR) and bind to specific
regions on the DNA of target genes. These DNA sequences are termed PPREs
(peroxisome proliferator hormone response elements).
The DNA consensus sequence is AGGTCANAGGTCA, with N being
any nucleotide.
In general, this sequence occurs in the promoter region of a gene, and, when
the PPAR binds its ligand, transcription of target genes is increased or decreased,
depending on the gene.
The RXR also forms a heterodimer with a number of other receptors
(e.g., vitamin D and thyroid hormone).
The function of PPARs is modified by the precise shape of their ligand-binding
domain induced by ligand binding and by a number of co-activator and co-
repressor proteins, the presence of which can stimulate or inhibit receptor
function, respectively.
FUNCTION

13. Cellular organelle
 More than 50 enzymes are present in it, among
which catalase and oxidase are important
 Role : In the metabolism of
 fatty acids and other lipids (cholesterol, bile
acids)
 Purines
 Aminoacids
 Hydrogen peroxide

14. PPAR α agonists : Fibrates - Hyperlipidaemia
PPAR γ agonists : Thiazolidinediones -
Hyperglycaemia
PPAR dual agonists (α ,γ) : Glitazars –
Hyperlipidaemia & Hyperglycaemia
PPAR δ agonists : under investigation for
obesity, cancer

15.  Type 2 Diabetes mellitus
 Atherosclerosis, Dyslipidaemia
 Obesity
 Metabolic syndrome
 Cardiovascular diseases
 Cancers – colon, breast, prostate, lung, blood
 Assisted reproductive technology, PCOS
 Retinopathy
 Viral infections.

16.  Inflammation & Neurology
 Alzheimers disease
 Multiple sclerosis
 Parkinson's disease
 Ischemic stroke
 Spinal cord Injury
 Psoriatic arthritis
 Chronic obstructive pulmonary disease / Br. Asthma
 Inflammatory bowel disease
 Rheumatoid arthritis

17. o PPARs are interesting pharmaceutical targets.
o They have multiple beneficial effects.
o New PPAR drugs showing co agonism or pan- agonism are
expected to show synergistic effects on various metabolic
and inflammatory diseases.
o Long-term trials are needed to evaluate the efficacy and
safety of these wonder agents.