Peroxisome Proliferator Activated

Receptors

Peroxisome Proliferator Activated

Receptors

ContentsContents1. Peroxisomes - the Discovery2. Break through with PPAR3. PPAR - Findings4. PPAR - Tissue Distribution5. Peroxisome - Functions6. PPAR Structure7. PPAR -How does it work?8. PPAR Ligands9. PPAR Types10. PPAR - a11. PPAR - b12. PPAR - g13. Role of PPAR - g in glucose metabolism14. Role of PPAR - g in cell differentiation related to adipogenesis & atherogenesis15. Role of PPAR - g in fatty acid metabolism16. Role of PPAR - g in Atherosclerosis17. PPAR - g; A target for Anti-diabetic drugs18. PPAR - g & Thiazolidinediones19. PPAR -Targetted therapy potential 20. PPAR - Looking Ahead21. PPAR - Studies

Peroxisomes - The DiscoveryPeroxisomes - The Discovery

In the 1960s Christian de Duve and his colleagues discovered small circular sack-like structures within the cells and named these Organelles as PEROXISOMES - because of their ability to produce hydrogen peroxide.

Peroxisomes gave the scientists an intriguing new puzzle - What role did these organelles play in the body?

Peroxisomes - The DiscoveryPeroxisomes - The Discovery

First clue - When testing a drug on the liver cells of rat it was observed the cells were full of peroxisomes - apparently the drug had triggered the proliferation of Peroxisomes.

In 1970s & 1980s it was discovered that peroxisomes contain more than 40 enzymes

And that a number of

compounds caused peroxisomes to multiply rapidly - sometimes as much as Hundred Folds!

How did these compounds trigger such a dramatic proliferation was the big

question???

Breakthrough with - PPARBreakthrough with - PPAR

Discovery of PPAR (Peroxisome Proliferator Activated Receptor) in 1990 by Issemann & Green was the key to the understanding of Peroxisome Proliferation

Interest on study on PPAR gained momentum when its role in human health was postulated.

Interestingly PPAR in human does not induce Peroxisome Proliferation!

PPAR - FindingsPPAR - Findings

PPARs are members of the nuclear hormone receptor family of transcription factors.

They are a diverse group of proteins that mediate ligand-dependent trannscriptional activation and repression in the genes

They modulate DNA transcription by binding to specific Peroxisome Proliferator Response Elements (PPRE) on target genes.

PPAR - Tissue DistributionPPAR - Tissue Distribution

PPARs are mostly present in tissue characterized by high rates of fatty acids catabolism such as:liver, kidney, heart ,muscles, Adipose tissues, endothelial & smooth muscle cells, monocyte/macrophages, brain, intestine, spleen, lungs, adrenal glands & mammary glands.

Peroxisome - FunctionsPeroxisome - Functions

Removal of molecular oxygen & break down of hydrogen peroxide.

Glycerolipid synthesis

Cholesterol biosynthesis and break down (bile-acid formation)

Fatty acid oxidation

Peroxisome is a subcellular organelle which performs numerous function which includes:

PPAR StructurePPAR Structure

PPAR is a proteins found in the human cells and in the cells of other animals as well.

PPAR has 5 or 6 structural regions in 4 functional domains. Which includes a :

DNA Binding Domain (DBD)

Ligand Binding Domain (LBD)

PPAR-How does it work?PPAR-How does it work?

Activation of PPAR by heat shock protein

Interaction with Ligand, Heterodimerisation with RXR (Retinoic acid receptor)

Inactive PPAR

Binding of receptor complex to DNA - PPAR responsive element (PPRE)

PPRE

Activation of gene

mRNA synthesis

PROTEIN SYNTHESIS

Ligand

RXR

DNA

PPAR LigandsPPAR Ligands

Natural Ligands:

Several fatty acids bind to the PPARs. Some derivatives of fatty acids, such as leukotrienes and prostaglandins bind to PPAR with higher affinity than fatty acids.

Pharmacological Ligands:

- Antidiabetic Thiazolidinedione class of drugs - NSAIDs like indomethacin, flufenamic acid, fenoprofen, and ibuprofen

PPAR TypesPPAR Types

Three forms of PPARs have been described till now:

PPAR

PPAR

PPAR

PPAR-PPAR-

PPAR- is expressed Expresses in tissues like skeletal muscles, liver, kidney and vascular endothelial cells.

Is involved in the control of lipoprotein metabolism, fatty acid oxidation and cellular uptake of fatty acids.

Regulates inflammatory responses in vascular endothelial cells

The transcription of PPAR- is stimulated by insulin, fibrates, phenylacetate and its analogues.

PPAR-PPAR-

PPAR- function has been demonstrated in number of different tissues in adult rats.

Although its found in human tissues, its distribution, regulation and functions is yet to be determined.

PPAR- is activated by fatty acids but its role in adipocyte differentiation remains controversial.

PPAR-PPAR-

PPAR- is probably the best characterized receptor

Its highly expressed in adipocytes and is known to play a critical role in adipocyte differentiation & fat deposition.

PPAR- has been also found in liver, kidney, small intestine, bladder and spleen.

Role of PPAR-in Glucose Metabolism

Role of PPAR-in Glucose Metabolism

Activation of PPAR- is responsible for insulin-sensitizing and glucose and lipid-lowering effects.

In human skeletal muscles, which is the major site of impaired insulin action in type 2 diabetes and obesity. PPAR- mRNA expression can be acutely regulated.

Role of PPAR-in cell differentiation related to Adipogenesis &

Atherogenesis

Role of PPAR-in cell differentiation related to Adipogenesis &

Atherogenesis

Therapy for Insulin resistance in NIDDM

associated with obesity

Preadipocyte

Adipocyte

Macrophage

Macrophage derived foam cell

Risk of accelerated atherosclerosis

balanced with PPAR- mediated

cardioprotection

MEDICAL RELEVANCE

PPAR - RXR

Ligand

Role of PPAR-in Fatty acid metabolism

Role of PPAR-in Fatty acid metabolism

Decreases triglyceride and free fatty acids levels by enhancing their catabolism by induction of lipoprotein lipase gene expression in adipose tissue.

Regulates oxidation of Fatty acids

Brings about degradation of lipid-derived inflammatory mediators through -oxidation pathways and thereby reduces inflammatory stress.

Role of PPAR-in Atherosclerosis

Role of PPAR-in Atherosclerosis

Atherosclerosis involves recruitment & activation of different cell types, including monocyte/macrophages, endothelial cells, smooth muscle cells & T-lymphocytes.

PPAR - activation inhibits smooth muscle cell proliferation and decreases the intima & media thickness in human carotid arteries.

In vascular wall PPAR interfere with chemo-attraction and cell adhesion of monocytes, T-lymphocytes & eosinophils.

PPAR - ; A target for Anti - Diabetic Drugs

PPAR - ; A target for Anti - Diabetic Drugs

Steps on the path linking PPAR - to type 2 diabetes was first taken by a Japanese firm called - Takeda.

Takashi Soda and his colleagues used a drug called ciglitazone on diabetic rats, it was observed that there was a decrease in insulin production & triglyceride levels along with an increase in insulin sensitivity in the animals. Unlike other drugs ciglitazone was able to address insulin resistance & insulin production.

This work pioneered the development of ‘glitazones’ or thiazolidinediones

PPAR - & ThiazolidinedionesPPAR - & Thiazolidinediones

Insulin Sensitivity

HDL Cholesterol

Triglycerides

Blood sugar levels

TZDPPAR RXR

DNA

Nucleus

Cell Membrane

Enzyme activation

PPAR - Targeted Therapy Potential

PPAR - Targeted Therapy Potential

Since the activation of PPAR- & PPAR- leads to variable reductions of plasma levels of triglycerides, glucose, and insulin levels as well as an improvement in Insulin Resistance. These receptors have potential to be used in therapeutic targets for a multitude of diseases like:

Diabetes Mellitus

Dyslipidemia

Atherosclerosis

Rheumatoid arthritis(PPARs are known to reduce IL-1, IL-6, Prostaglandins & thereby COX-2 & TNF-

Crohns Disease (Because it inhibits TNF-

Cancer (Known to inhibit tumor cell growth)

PPAR - Looking AheadPPAR - Looking Ahead

The Discovery of PPARs has opened up newer avenues for the management of a plethora of disorders and may lead to the development of novel specifically acting drugs in therapeutic areas other than diabetes & lipid metabolism.

Studies on PPAR Studies on PPAR

Soure : Cardiol Rev. 2004 May-Jun;12(3):158-70. Title : Peroxisome Proliferator Activator Receptors (PPAR), Insulin

Resistance, and Cardiomyopathy Friends or Foes for the Diabetic Patient With

Heart Failure?Authors: Nikolaidis LA, Levine TB. Division of Cardiology, Department of Medicine, Drexel University College of Medicine,

Allegheny GeneralHospital, Pittsburgh, Pennsylvania.

Peroxisome proliferator activator receptor gamma (PPARgamma) agonists are antidiabetic agents with antilipemic and insulin-sensitizing activity. Experimental studies suggest salutary effects in limiting infarct size, attenuating myocardial reperfusion injury, inhibiting hypertrophic signaling and vascular antiinflammatory actions through cytokine inhibition.

Source: J Biol Chem. 2004 Mar 15 [Epub ahead of print]

Title: Activation of peroxisome proliferator-activated receptor gamma inhibits interleukin-

1beta -Authors: Cheng S, Afif H, Martel-Pelletier J, Pelletier JP, Li X, Farrajota K, Lavigne M, Fahmi H. Osteoarthritis Research Unit, Montreal, Quebec H2L 4M1.Here, we examined the effect of PPARg ligands on interleukin-1beta (IL-1b)-induced mPGES-1 expression in human synovial fibroblasts (HSF). PPARg ligands 15-deoxy- 12,14 prostaglandin J2 (15d-PGJ2) and the thiazolidinedione troglitazone (TRO), but not PPARg ligand Wy14643, dose-dependently suppressed IL-1b-induced PGE2 production, as well as mPGES-1 protein and mRNA expression.

These data define mPGES-1 and Egr-1 as novel targets of PPARg and suggest that inhibition of mPGES-1 gene transcription may be one of the mechanisms by which PPARg regulates inflammatory responses.Source: Expert Opin Ther Targets. 2004 Feb;8(1):39-48.

Title: Peroxisome proliferator-activated receptor-beta as a target for wound healing drugs.

Authors: Tan NS, Michalik L, Desvergne B, Wahli W.

Current understanding of the roles of PPARbeta in different cell types implicated in tissue repair has revealed an intriguing intercellular cross-talk that coordinates, spatially and temporally, inflammation, keratinocyte survival, proliferation and migration, which are all essential for efficient wound repair. These novel insights into the orchestrating roles of PPARbeta during wound healing may be helpful in the development of drugs for acute and chronic wound disorders.

Source: Expert Opin Investig Drugs. 2004 Mar;13(3):215-28.

Title: Peroxisome proliferator-activated receptor-gamma: therapeutic target for diseases

beyond diabetes: quo vadis?Authors: Pershadsingh HA. Department of Family Medicine, Kern Medical Center, Bakersfield, CA 93305, USA.

The discovery that the insulin-sensitising thiazolidinediones (TZDs), specific peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists, have antiproliferative, anti-inflammatory and immunomodulatory effects has led to the evaluation of their potential use in the treatment of diabetic complications and inflammatory, proliferative diseases in non-insulin-resistant, euglycaemic individuals.

Activation of PPAR-gamma may improve cardiovascular risk factors and cardiovascular outcomes in both insulin-resistant diabetic and non-diabetic individuals. Through their immunomodulatory and anti-inflammatory actions, TZDs and other PPAR-gamma agonists may prove to be effective in treating diseases unrelated to insulin resistance, such as autoimmune (e.g., multiple sclerosis), atopic (e.g., asthma, atopic dermatitis) and other inflammatory diseases (e.g., psoriasis, ulcerative colitis). Newer and safer selective PPAR-gamma agonists are presently under development. Furthermore, of considerable interest is the recent discovery that a unique subset of currently prescribed antihypertensive angiotensin II Type 1 receptor antagonists has selective PPAR-gamma-modulating activity.

Source: Circulation. 2004 Feb 24;109(7):904-10. Epub 2004 Feb 16.Title: Endothelin-1-induced cardiac hypertrophy is inhibited by activation of peroxisome

proliferator-activated receptor-alpha partly via blockade of c-Jun NH2-terminal

kinase pathway.Authors: Irukayama-Tomobe Y, Miyauchi T, Sakai S, Kasuya Y, Ogata T, Takanashi M,

Iemitsu M, Sudo T, Goto K, Yamaguchi I. Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine,

University of Tsukuba, Tsukuba, Ibaraki, Japan.

PPAR-alpha activation interferes with the signaling pathway of ET-1(Endothelin)-induced cardiac hypertrophy through negative regulation of AP-1 binding activity, partly via inhibition of the JNK pathway in cultured cardiomyocytes. Source: Front Biosci. 2004 Jan 1;9:359-69.

Title : Angiotensin II, PPAR-gamma and atherosclerosis.Authors: Kintscher U, Lyon CJ, Law RE. Institute of Pharmacology and Toxicology, Charite Hospital, Humboldt-University Berlin, D-

10117 Berlin, Germany.

Thiazolidinediones also appear to regulate angiotensin II signaling at multiple levels, significantly reducing the expression of the angiotensin II type 1 receptor and repressing signal transduction through this receptor to suppress vascular remodeling, lesion formation, and oxidative stress.

Source: Oncogene. 2004 Jan 8;23(1):100-8. Title: Peroxisome proliferator-activated receptor-gamma activation inhibits tumor progression

in non-small-cell lung cancer.in non-small-cell lung cancer.Authors:Keshamouni VG, Reddy RC, Arenberg DA, Joel B, Thannickal VJ, Kalemkerian GP,

Standiford TJ. Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, 6301 MSRB

III, 1150 W. Medical Center Drive, Ann Arbor, MI 48109, USA.

The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors and a crucial regulator of cellular differentiation. Differentiation-inducing and antiproliferative effects of PPAR-gamma suggest that PPAR-gamma agonists might be useful as effective anticancer agents.

Tro or Pio inhibited primary tumor growth by 66.7% and significantly inhibited the number of spontaneous lung metastatic lesions. Collectively, our data demonstrate that activation of PPAR-gamma impedes lung tumor progression and suggest that PPAR-gamma ligands may serve as potential therapeutic agents for NSCLC.