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)
Merck Compound 12
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

 

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References