PPARs

The peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family of ligand-activated transcription factors that heterodimerize with retinoid X receptor (RXR) isoforms to regulate gene expression. Three subtypes of PPAR have been identified and cloned: α, δ (also known as β) and γ. Many endogenous ligands have been isolated for PPARs; these include prostacyclin, fatty acids, lysophosphatidic acid and leukotriene B4. PPARs play many important roles in the cell, including lipid homeostasis, cell proliferation, differentiation, adipogenesis and immune functions and are useful in the treatment of metabolic disease. The table below summarizes the pharmacological properties of these receptors.

Targets
Literature
Receptor Data

Literature for PPARs

Cancer

Cancer Research Product Guide

A collection of over 750 products for cancer research, the guide includes research tools for the study of:

  • Cancer Metabolism
  • Epigenetics in Cancer
  • Receptor Signaling
  • Cell Cycle and DNA Damage Repair
  • Angiogenesis
  • Invasion and Metastasis
Cardiovascular

Cardiovascular Research Product Guide

A collection of over 250 products for cardiovascular research, the guide includes research tools for the study of:

  • Hypertension
  • Thrombosis and Hemostasis
  • Atherosclerosis
  • Myocardial Infarction
  • Ischemia/Reperfusion Injury
  • Arrhythmias
  • Heart Failure
Nuclear Receptors

Nuclear Receptors Product Listing

A collection of over 150 products for key nuclear receptors, the listing includes research tools for the study of:

  • Androgen Receptors
  • Estrogen Receptors
  • Retinoic Acid Receptors
  • Retinoid X Receptors
  • Vitamin D Receptors
Retinoid Receptors

Retinoid Receptors Scientific Review

Written by Alexander Moise, this review summarizes the nature of retinoid receptors, their isotype and isoform variants and modulation of retinoid signaling. Compounds available from Tocris are listed.

PPAR Receptor Data

Receptor Subtype PPARα PPARδ PPARγ
Primary Distribution Liver, adipose tissue, kidney, heart, skeletal muscle, large intestine Ubiquitous Adipose tissue, lymphoid tissue, colon, liver, heart
Tissue Function Fatty acid synthesis and oxidation, gluconeogenesis, ketogenesis, lipoprotein assembly Placental and gut development, fatty acid oxidation, adaptive thermogenesis, control of cell proliferation and differentiation, tissue repair Adipocyte differentiation, glucose homeostasis
Human Disease Relevance Atherosclerosis Atherosclerosis Obesity and insulin resistance, type II diabetes mellitus, hypertension, atherosclerosis, cancer

Key Compounds Ki Values (nM)
Agonists Ciglitazone (1307)
Clofibrate (0824)
GW 0742 (2229)
GW 7647 (1677)
GW 1929 (1664)
L-165,041 (1856)
WY 14643 (1312)
> 1000*
50
1.1
0.006
> 10
10
5
> 1000*
> 100
0.001
6.2
> 10
0.53
60
3*
~ 500
2
1.1
0.0062
5.5
35
Antagonists BADGE (1326)
GW 9662 (1508)
>> 100
0.032
> 100
2
~ 100
0.0033

Potency values for PPAR ligands acting at human subtypes, unless otherwise stated. For full experimental details, please refer to the cited publications.

* Measured at murine receptors.

References

Nuclear Receptors Nomenclature Committee (1999) A unified nomenclature system for the nuclear receptor superfamily. Cell 97 161. Willson et al (1996) The structure-activity relationship between peroxisome proliferator receptor γ agonism and the antihyperglycemic activity of thiazolidinediones. J.Med.Chem. 39 665. Willson et al (2000) The PPARs: from orphan receptors to drug discovery. J.Med.Chem. 43 527. Brown et al (2001) Identifi cation of a subtype selective human PPARα agonist through parallel-array synthesis. Bioorg.Med.Chem.Lett. 11 1225. Wright et al (2000) A synthetic antagonist for the peroxisome proliferator-activated receptor γ inhibits adipocyte differentiation. J.Biol.Chem. 275 1873. Leesnitzer et al (2002) Functional consequences of cysteine modifi cation in the ligand binding sites of peroxisome proliferator activated receptors by GW9662. Biochemistry 41 6640. Sznaidman et al (2003) Novel selective small molecule agonist for peroxisome proliferator-activated receptor γ (PPARγ) - Synthesis and biological activity. Bioorg.Med.Chem.Lett. 13 1517.