Nuclear Receptors (PPARs)

Peroxisome proliferator activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that are related to retinoid, steroid and thyroid hormone receptors. PPARs play an important role in many cellular functions including lipid metabolism, cell proliferation, differentiation, adipogenesis and inflammatory signalling. PPARs have been found to interact with a number of endogenous lipids and drugs for the treatment of human metabolic diseases.

There are three distinct PPAR subtypes which are the products of different genes and are commonly designated PPARα [NR1C1], PPARδ (also known as PPARβ and NUC1) [NR1C2] and PPARγ [NR1C3]. Each receptor shows a differential pattern of tissue expression and is activated by structurally diverse compounds including endogenous long-chain fatty acids. PPARs have a highly conserved DNA binding domain (region C) and a diverse ligand-independent activation domain (region A/B) which can confer constitutive activity on the receptor. The C-terminal ligand-binding domain (regions E/F) is the site of ligand docking and has the most diversity between the pharmacologically distinct subtypes. X-ray crystallography of human PPAR isoforms has revealed important residues responsible for ligand binding, heterodimerisation and co-factor interactions.

PPARα is expressed in tissues exhibiting high rates of β-oxidation such as liver, kidney, heart and muscle. In liver, PPARα regulates lipid metabolism and in rodents, but not in man, PPARα activation induces hepatomegaly and proliferation of liver peroxisomes. PPARδ is ubiquitously expressed in tissues and has been implicated in energy metabolism in both adipose and skeletal muscle. PPARδ is abundant in many tissues during development especially in the adult rat digestive tract where a high rate of cell renewal and differentiation is required. PPARγ is highly expressed in adipose tissue and is a key transcription factor involved in the terminal differentiation of white and brown adipose tissue. There is evidence that both PPARα and PPARγ could interfere with atherogenesis, in part by exerting an anti-inflammatory activity.

PPARs regulate gene expression by heterodimeric partnering with retinoid X receptors (RXR) and subsequent binding to specific response elements (PPREs) in the promoter regions of target genes. Structurally distinct PPREs are recognized by PPARα, δ and γ. PPAR-RXR heterodimers can also be activated by ligand binding to either receptor partner independently.

A greater understanding of the mechanism of transcriptional regulation by nuclear receptors has lead to the identification of multiple accessory proteins that bind to the nuclear receptors in a ligand-dependent manner. The nuclear receptor corepressor (N-CoR) or silencing mediator of retinoid and thyroid receptors (SMRT) proteins bind and mediate repression of transcription by the unliganded receptors. Coactivator proteins such as SRC1 and CBP/p300 are recruited by agonist bound receptors and promote initiation of transcription by remodelling the chromatin structure while coactivators such as the PPAR binding protein (PBP) and TRAP220 interact directly with the transcriptional machinery. The binding of ligand triggers a series of events which result in conformational changes involving recruitment of coactivators and dissociation of corepressors. The tissue specific expression of these cofactors may be responsible for the differential transcriptional regulation and responses observed in different cell types in vivo.

PPARα agonists (fibrates) have shown therapeutic utility as lipid lowering agents whereas PPARγ agonists such as the glitazones (thiazolidinediones) are marketed as antidiabetic agents. With the involvement of PPARs in many diverse metabolic pathways there is great clinical interest in the potential utility of PPAR ligands for the treatment of cancer, inflammation, psoriasis, atherosclerosis, dyslipidaemia, neurological disorders, obesity and diabetes.

The Table below contains accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.

Currently Accepted Name	PPARα	PPARδ	PPARγ
Other Names	NR1C1	NR1C2 PPARβ NUC1 FAAR	NR1C3
Structural Information	468 aa (mouse and human)	440 aa (mouse) 441 aa (human) 506 aa (human γ2)	475 aa (mouse) 475 aa (human γ1)
Tissue Expression	Liver Kidney Heart Muscle	Placenta Skeletal muscle (ubiquitously expressed)	Adipose tissue Skeletal muscle Heart Lung Ovary
Physiological Effects	Fatty acid synthesis Oxidation Ketogenesis	Fatty acid oxidation Cell cycle control	Adipocyte differentiation Glucose homeostasis
Disease Relevance	Dyslipidaemia Atherosclerosis Inflammation	Metabolic syndrome Cancer	Diabetes Psoriasis Cancer Inflammation
Subtype Selective Agonistsa	8(S)HETE (H4019) LTB4 (L0517) Tetradecylthioacetic acid (TTA) (T1698) Wy-14643 (C7081) Clofibrate (C6643) Fenofibrate (F6020) GW9578 GW7647 (G6793) Compound 12 (Merck & Co., Inc., Kenilworth, NJ) KCL 1998001079 LY518674 LY6487 NNC 61-3058	Prostaglandin A2 L-16504b L-631033 GW501516 GW0742 (G3295)	15-Deoxy-Δ 12, 14 PGJ2 (D8440) azPC (A6850) Ciglitazone (C3974) Troglitazone (CS-045) (T2573) Pioglitazone (AD-4833) (E6910) Rosiglitazone (BRL-49653) (R2408) LY171883 (L5408) L-805645 JTT-501 AD-5075 L-764406 CLX-0921 KRP-297 Farglitazar (GI262570) GW1929 (G5668) GW7845 GW0207 CDDO PAT5A Glycyrin
Non Selective Ligands	L-796449 LY465608 Bezafibrate (B9273)c	L-796449 LY465608 Bezafibrate (B9273)c	L-796449 LY465608 Bezafibrate (B9273)c
PPAR α/Γ Selective Ligands	SB-213068 SB-219994 LY1099 AZ242 (Tesaglitazar, Galida) BMS298585 (Muraglitazar) 9-HODE 13-HODE (H9146) GW2331 NNC 61-0029 ((-) DRF-2725, Ragaglitazar) NNC 61-4424 NNC 61-4718 NNC 61-4705		SB-213068 SB-219994 LY1099 AZ242 (Tesaglitazar, Galida) BMS298585 (Muraglitazar) 9-HODE 13-HODE (H9146) GW2331 NNC 61-0029 ((-) DRF 2725, Ragaglitazar) NNC 61-4424 NNC 61-4718 NNC 61-4705
PPAR α/Δ Selective Ligand	GW2433	GW-2433	Not Known
Partial Agonists and Antagonists	Antagonist GW6471 (G5045)	Antagonist Sulindac (NSAID)d (S8139)	Partial Agonists NC-2100 Netoglitazone MCC-555 FMOC-leucine (47633) Agonist LG100754 (SML0771)k Antagonists LG100641 PD068235 GW0072e BADGE (D3415)f L-764406g GW9662 (M6191)g T0070907 (T8703)i SR-202 (Mifobate) (S1320)j Diclofenac (D6899)l
Coactivators	PGC-1 CBP CREB-binding protein/p300 interacting transactivator with ED-rich tail 2	SRC-2	PGC-1 PGC-2 SRC-1 (NCoA-1) PBP (DRIP205/ TRAP220)
Corepressors	Not Known	N-CoR SMRT	SMRT/TRAC-2
Interacting Proteinsh	RIP140 TRAP220 TRAP100	RIP140	TRAP100 DRIP
Radioligands	[3H]-GW 2331 [125I]-SB-236636	[3H]-GW 2433 [3H]-L-783483	[3H]-BRL-49653 (rosiglitazone) [125I]-SB-236636 [3H]-GW 2331 [3H]-AD-5075

Footnotes

a) This data is compiled from multiple literature and from different human assays - binding assays and transactivation assays. Many compounds are known agonists at multiple PPARs with different isoform selectivities. Selectivity > 5 fold unless indicated otherwise.

b) L-165041 has 2.6-fold selectivity for murine PPARδ/PPARγ but is 10-fold selective for human PPARδ/PPARγ and PPARα.

c) Human PPARδ/PPARα 2.5 fold selectivity and murine PPARδ/PPARγ selectivity 2-fold.

d) Antagonist activity of compound under review.

e) Antagonist but partial agonist in transactivation assays but inhibitor of adipocyte differentiation. Has reduced ability to recruit coactivators to the transcription complex.

f) Antagonist inhibiting adipocyte differentiation but binds to PPARγ in a binding assay.

g) Irreversible PPARγ ligand.

h) Interaction only demonstrated in vitro.

i) Increased NCoR recruitment.

j) Decreased SRC-1 recruitment.

k) RXR/PPARγ agonist.

l) Antagonist but can also act as a partial agonist.

Abbreviations

8(S)HETE: 8(S) Hydroxyeicosa-tetraenoic acid
9-HODE: 9-Hydroxy-octadecadienoic acid
13-HODE: 13-Hydroxy-octadecadienoic acid
azPC: Hexadecyl azelaoyl phosphatidylcholine
BADGE: Bisphenol A diglycidyl ether
CBP: CREB-binding protein
CDDO: 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic acid
DRIP: Vitamin D receptor-interacting proteins
LTB4: Leukotriene B-4
N-CoR: Nuclear receptor corepessor
NSAID: Non steroidal anti inflammatory
NCoA-1: Nuclear receptor coactivator
PBP: PPAR binding protein
PGC: Peroxisome proliferator-activated receptor gamma coactivator
RIP: Retinoid X receptor interacting protein
SMRT: Silencing mediator of retinoid and thyroid receptors
SRC-1: Steroid receptor coactivator-1
TRAC: Thyroid hormone receptor-associating cofactor
TRAP: Thyroid receptor-associated proteins