Members of this family are divided into six structural domains (A–F). Domain A/B is also called AF-1, or the modulator region, because it is involved in activating transcription. The C domain consists of the DNA-binding domain (DBD). The D region contains the hinge, which provides flexibility between the DBD and the ligand-binding domain (LBD, region E). The amino (N) terminal part of region E contains AF-2, another domain important for transactivation. The F region is poorly defined.
Peroxisomes are found in many tissues, including liver. They are rich in oxidases and in catalase
Similar to other nuclear hormone receptores, PPAR acts as a ligand activated transcription factor. Upon binding fatty acids or hypolipidemic drugs, PPARa interacts with RXR and regulates the expression of target genes. These genes are involved in the catabolism of fatty acids. Conversely, PPARg is activated by prostaglandins, leukotrienes and anti-diabetic thiazolidinediones and affects the expression of genes involved in the storage of the fatty acids. PPARb is only weakly activated by fatty acids, prostaglandins and leukotrienes and has no known physiologically relevant ligand. However, data from PPARb null mice suggest PPARb does serve a role in fatty acid metabolism and perhaps in skin proliferation and cancer.
Differs from lysosomes in self replication and no hydrolase
In 1962, Thorp and Waring reported that ethyl chlorophenoxyisobutyrate lowered lipid levels in rats. In 1967, the ester form (clofibrate) was approved for use in the U.S. and became the most widely prescribed hypolipidemic drug.
Ref.3 Caring for diabetes>treatment and prevention> emerging therapies. Emerging therapies.www.caring for diabetes.com.
PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA RECEPTORS Reverse insulin resistance by stimulating GLUT 4 EXPRESSion and translocation and entry of glucose The first thiazolidinedione, ciglitazone, was synthesized in 1982(1). It was soon thereafter discovered that ciglitazone reduced insulin resistance in obese and diabetic animals. Because of their effects on insulin resistance, thiozolidinediones have been developed as pharmacological agents for the management of type 2 diabetes, although they were initially synthesized as potential lipid-reducing agents. Since their discovery, three thiozolidinediones have been introduced to the market in the U.S. : troglitazone (Rezulin), rosiglitazone (Avandia), and pioglitazone (Actos). In March 2000, troglitazone was withdrawn from the market because of liver toxicity. Reset glucose fatty acid cycle by reduction in circulating free fatty acids and by transcription of several genes that are imp for otimal insulin sensitivity as well as glucose and fat metabolism
[Note: Whether the adipogenic effects can be separated from those of increased insulin sensitivity is the subject of much research, particularly because of the role of obesity in this disease.] Pioglitazone and rosiglitazone can be used as monotherapy or in combination with other hypoglycemics or with insulin. The dose of insulin required for adequate glucose control in these circumstances may have to be lowered. The glitazones are recommended as a second-line alternative for patients who fail or have contraindications to metformin therapy.
FAILURE OF ORAL CONTRACEPTION CAN OCCUR WITH PIOGLITAZONE THERAPY, KETOCONAZOLE INHIBITS METABOLISM OF PIOGLITAZONE Duration of effect lasts more than 24 hours
Suppresses & Prevents TNF alfa
Risk Evaluation and Mitigation Strategy (REMS), called the Rosiglitazone REMS program. The Rosiglitazone REMS program restricted the use of rosiglitazone medicines to help ensure that their benefits outweighed the risks.
Therapeutic targets of PPARδ in the metabolic syndrome. Receptor activation improves multiple aspects of the metabolic syndrome through tissue- and cell-specific effects. In skeletal muscle, PPARδ regulates fatty acid transport and oxidation, thermogenesis, and the formation of slow-twitch muscle fibers, resulting in enhanced endurance performance. It likewise activates fatty acid transport and oxidation as well as thermogenesis in adipose tissue, retarding weight gain. PPARδ regulates the availability of BCL-6, an inflammatory suppressor protein released upon ligation of PPARδ, thereby functioning as an “antiinflammatory switch” to control macrophage-elicited inflammation and atherogenesis. In the liver, PPARδ activation suppresses glucose production by upregulating the pentose phosphate shunt. PPARδ activation also improves atherogenic dyslipidemia by raising serum HDL cholesterol levels via unclear mechanisms. Additionally, PPARδ activation in the heart enhances contractile function and may improve cardiomyopathy.
PPAR alpha activation inhibits amyloid peptide stimulated expression of tumor necrosis factor alpha and interleukin-6. PPAR gamma activation inhibits the β-amyloid stimulated expression of inflammatory cytokines. It also induces the clearance of β-amyloid peptide. Multiple sclerosisNeuroinflammation is the key to the pathophysiology of multiple sclerosis. PPAR gamma activation inhibits the production of nitric oxide, proinflammatory cytokines (tumor necrosis factor α, interleukin-1β, interleukin-6), and chemokine MCP-1 by microglia and astrocytes cells. PPAR γ activators also suppress T-cell proliferation by 40-50%. Colorectal –delta, other cancers- gamma agonists
Drugs acting on ppar
Dr Karuna Sree P
Dept. Of Pharmacology
Kamineni Institute of Medical Sciences
PPAR receptors – types
Mechanism of action
Role of PPARS
3/23/2015 2Dr Karuna Sree P, Dept. of Pharmacology, KIMS
Issemann and Green discovered Peroxisome
proliferator activated receptors (PPAR).
The different types of PPAR initially identified in
Belongs to nuclear receptor family.
3/23/2015 3Dr Karuna Sree P, Dept. of Pharmacology, KIMS
Nuclear Receptor Superfamily
Eg. GR, MR,
Type 2 Receptors
Eg. TR, VDR, RAR,
Eg. SF-1, HNF4
3/23/2015 4Dr Karuna Sree P, Dept. of Pharmacology, KIMS
Binds to response
elements on DNA
3/23/2015 5Dr Karuna Sree P, Dept. of Pharmacology, KIMS
*Daryl K Granner. Hormone Action & SignalTransduction. In: Robert K. Murray, Daryl K. Granner, PeterA. Mayes,VictorW. Rodwell
editors. Harper’s Illustrated Biochemistry. 26th ed. NewYork McGraw-Hill
Plays a central role in the regulation of
Storage and catabolism of dietary fats and
PPAR β / δ
3/23/2015 6Dr Karuna Sree P, Dept. of Pharmacology, KIMS
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 &
γ 2 - Adipose tissue.
γ 3 - Macrophages, large intestine, white adipose
3/23/2015 7Dr Karuna Sree P, Dept. of Pharmacology, KIMS
PPAR Partner Ligand
Active state -
PPAR - β/δ
PPAR - γ
Active state -
Lipid & CHO
3/23/2015 8Dr Karuna Sree P, Dept. of Pharmacology, KIMS
3/23/2015 9Dr Karuna Sree P, Dept. of Pharmacology, KIMS
3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 10
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
3/23/2015 11Dr Karuna Sree P, Dept. of Pharmacology, KIMS
*Robert K. Murray, Daryl K. Granner, PeterA. Mayes,VictorW. Rodwell. Harper’s Illustrated Biochemistry. 26th ed. NewYork
PPAR α agonists
3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 13
1st generation fibrates : Clofibrate
2nd generation : Gemfibrozil, Fenofibrate,
Lowers VLDL, TG by 50% & ↑ HDL-C by 15% &
↓ fibrinogen levels & LDL-C by 15-20%
Effect mediated through PPAR∝ receptor
expressed in liver, fat & muscles.
Dr Karuna Sree P, Dept. of Pharmacology, KIMS
3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 15
Activates peroxisome proliferation activated
receptor factor (PPAR-∝)
↓TG, VLDL & ↑ HDL
↑ Apo A I & II,
Dr Karuna Sree P, Dept. of Pharmacology, KIMS
Pk Dose uses
T1/2 : 1-2hrs, High efficacy
in Type III & ↓CH, Factor
VII-PL complex & promotes
in Type II
Dose reduction needed in
elderly / renal insufficiency
↑action of warfarin
T1/2 : 20 hrs
Greater ↓ in CH & ↑ HDL
Most suitable combination
Dr Karuna Sree P, Dept. of Pharmacology, KIMS
Uses : Hypertriglyceridaemias.
Fenofibrate is uricosuric - given in coexisting
ADR : GI, skin rashes, body ache, myalgia, reversible
Eosnophilia, Impotence, Blurred Vision, cholelithiasis with
↑ Aminotransferases & Alk. Phosphatase – Fenofibrate
DI : with statins increase myositis, potentiates affect of
3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 18
PPAR γ agonists
3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 19
These are insulin-sensitizing drugs
TZDs have also effects on TG, FFA, and ketone
body level in several animal models of T2DM*
3/23/2015 20Dr Karuna Sree P, Dept. of Pharmacology, KIMS
*Caring for diabetes.Treatment and prevention : Emerging therapies.
Available at www.caring for diabetes.com.
Because of Antiproliferative, Anti-inflammatory,
Have potential role
In the treatment of diabetic complications
inflammatory-proliferative diseases in non-
insulin-resistant euglycaemic individuals
Atopic and inflammatory diseases
sepsis and reperfusion injury.
3/23/2015 21Dr Karuna Sree P, Dept. of Pharmacology, KIMS
3/23/2015 22Dr Karuna Sree P, Dept. of Pharmacology, KIMS
Activate insulin responsive genes -
regulate carbohydrate & lipid metabolism
Sensitize the peripheral tissues to insulin
↑ Glucose transport
into muscle & adipose
Selective agonists of PPAR -
bind to the receptor
Pioglitazone has no effect on LDL levels, ↓
triglyceride & ↑ HDL
Rosiglitazone has inconsistent effect on lipid
profile it ↑ HDL & LDL levels
The TZDs lead to a favorable redistribution of
fat from visceral to subcutaneous tissues.
3/23/2015 23Dr Karuna Sree P, Dept. of Pharmacology, KIMS
Absorption : Completely absorbed from GIT
Distribution : >95% bound to plasma proteins
Metabolism : Rosiglitazone - CYP2C8
Pioglitazone - CYP2C8 & CYP3A4
Excretion : Rosiglitazone in urine
Pioglitazone in bile
Drug interactions less with rosiglitazone
3/23/2015 24Dr Karuna Sree P, Dept. of Pharmacology, KIMS
Pt who benefit most are type II DM with
substantial amount of insulin resistance
Also used in PCOD
Monotherapy – Hypoglycemia rare
Slow acting – takes 1 month for its action
Pioglitazone: 15 to 45 mg once daily orally
Rosiglitazone: 4 to 8 mg once daily orally
3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 25
Weight gain: due to fluid retention & edema
↑ Extracellular fluid volume
Worsening of CHF
↑ Deposition of subcutaneous fat
Mild anemia: due to hemodilution
Hepatotoxicity : rare
Rosiglitazone: ↑risk of fractures especially in
3/23/2015 26Dr Karuna Sree P, Dept. of Pharmacology, KIMS
3/23/2015 28Dr Karuna Sree P, Dept. of Pharmacology, KIMS
Rosiglitazone banned in India* - GSR NO. 910(E) on
12.11.2010, as well in European medicines agency
US FDA# – in Nov 2013 removed the warnings/ restrictions
on Rosiglitazone initially put in 2010 for causing heart
Pioglitazone : Banned in India & reintroduced- 2011.
^US FDA drug safety communication recommend –
Not to use / use with caution in patients with active / prior
h/o bladder cancer
3/23/2015 29Dr Karuna Sree P, Dept. of Pharmacology, KIMS
Selective PPAR Modulators gained importance
to combat the side effect profile of glitazones.
SPPARM have partially activated PPARγ target
genes involved in adipogenesis and more
agonistic activity on target genes influencing
INT131, MBX-102, antihypertensive drug -
3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 30
These are termed as glitazars, several
dual PPAR-α/γ agonists have been
3/23/2015 32Dr Karuna Sree P, Dept. of Pharmacology, KIMS
3/23/2015 33Dr Karuna Sree P, Dept. of Pharmacology, KIMS
Drug Reasons for stopping the
bladder cancer and
hyperplasia in rodent studies
Tesaglitazar renal dysfunction
Muraglitazar – completed
phase III studies
increased risk of death,
myocardial infarction, or
stroke when compared with
patients who received either
pioglitazone or placebo.
Aliglitazar Side effect proflie on kidneys
3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 34
The first Glitazar to be approved in India-2013
Indication : diabetic dyslipidemia or
hypertriglyceridemia in type-2 diabetes not
controlled by statins alone.
Development of saroglitazar
3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 35
Chemical structure : aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
Pk : well absorbed, nearly 96% plasma protein
bound, metabolism by oxidation & excreted in
Dose : 4mg oral tablet OD
Adverse effects : gastritis, asthenia and pyrexia
3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 36
PPAR δ regulates fatty acid metabolism in the brain,
skeletal muscle and adipose tissue.
Actions : improves insulin sensitivity and ↑HDL in T2DM,
dyslipidemia & obesity.
Enhance oligodendrocyte maturation and
differentiation & regulates myelination of neurons
Drugs under development for treating obesity, cancer,
3/23/2015 37Dr Karuna Sree P, Dept. of Pharmacology, KIMS
3/23/2015 38Dr Karuna Sree P, Dept. of Pharmacology, KIMS
Agonist actions on PPAR α, β/δ, γ receptors
Being developed for type 2 diabetes and
*Bezafibrate found to have pan agonist action
3/23/2015 39Dr Karuna Sree P, Dept. of Pharmacology, KIMS
*Tenenbaum A, Motro M, Fisman EZ. Dual and pan-peroxisome proliferator-activated
receptors (PPAR) co-agonism: the bezafibrate lessons. Cardiovasc Diabetol 2005 ;16:4-14.
PPARs are interesting pharmaceutical targets.
They have multiple beneficial effects.
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents.
3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 42
Guyton AC, Hall JE. Text book of Medical physiology. 11th ed.
Philadelphia (Pa): Saunders; 2006.
Laurence L. Brunton, Keith L. Parker, editors. Textbook of Goodman
and Gillman’s Manual of Pharmacology and therapeutics, 12th ed.
New York:Mac Graw Hill’s Companies;2010.
Kumar A, Hasamnis A. A clinical update on peroxisome proliferator-
activated receptors. Syst Rev Pharm 2010;1:175-81.
V. A. Javiya, J. A. Patel. The role of peroxisome proliferator –
activated receptors in human disease. Indian J Pharmacol
Taygerly JP, McGee LR, Rubenstein SM, Houze JB, Cushing TD, Li
Y. Discovery of INT131: a selective PPARγ modulator that enhances
insulin sensitivity. Bioorg Med Chem 2013;21:979-92.
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