Peroxisome proliferator-activated receptor

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Overview

In cell biology, peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor isoforms that exist across biology. They are intimately connected to cellular metabolism (carbohydrate, lipid and protein) and cell differentiation. They are transcription factors.

Nomenclature

PPAR -alpha and -gamma pathways
peroxisome proliferative activated receptor, alpha
Identifiers
Symbol	PPARA
Alt. Symbols	PPAR
Entrez	5465
HUGO	9232
OMIM	170998
RefSeq	NM_001001928
UniProt	Q07869
Other data
Locus	Chr. 22 q12-q13.1

PPAR gamma
peroxisome proliferative activated receptor, gamma
Identifiers
Symbol	PPARG
Entrez	5468
HUGO	9236
OMIM	601487
RefSeq	NM_005037
UniProt	P37231
Other data
Locus	Chr. 3 p25

peroxisome proliferative activated receptor, delta
Identifiers
Symbol	PPARD
Entrez	5467
HUGO	9235
OMIM	600409
RefSeq	NM_006238
UniProt	Q03181
Other data
Locus	Chr. 6 p21.2

Three types of PPARs have been identified: alpha, gamma and delta (beta).

• α (alpha) - expressed in liver, kidney, heart, muscle, adipose tissue, and others.
• β/δ (beta/delta) - expressed in many tissues but markedly in brain, adipose tissue and skin.
• γ (gamma) - although transcribed by the same gene, this PPAR exists in three forms:
  • γ1 - expressed in virtually all tissues, including heart, muscle, colon, kidney, pancreas and spleen.
  • γ2 - expressed mainly in adipose tissue (30 amino acids longer)
  • γ3 - expressed in macrophages, large intestine, white adipose tissue.

History

PPARs were originally identified in Xenopus frogs as receptors that induce the proliferation of peroxisomes in cells. The first PPAR (PPARα) was discovered during the search of a molecular target for a group of agents then referred to as "peroxisome proliferators", as they increased peroxisomes in rodent liver tissue, apart from improving insulin sensitivity. These agents, pharmacologically related to the fibrates were discovered in the early 1980s. When it turned out that PPARs played a much more versatile role in biology, the agents were in turn termed "PPAR ligands". The best-known PPAR ligands are the thiazolidinediones; see below for more details.

After PPARδ (delta) was identified in humans in 1992, it turned out to be closely-related to the PPARβ (beta) previously described during the same year in other animals (Xenopus). The name PPARδ is generally used in the US whereas the use of the PPARβ denomination has remained in Europe where this receptor was initially discovered in Xenopus.

Physiological function

All PPARs dimerize with the retinoid X receptor (RXR) and bind to specific regions on the DNA of target genes. These DNA sequences are termed PPREs (peroxisome proliferator response elements). The DNA consensus sequence is AGGTCAXAGGTCA with X being a random nucleotide. Generally, this sequence occurs in the promotor region of a gene, and when the PPAR binds its ligand, transcription of targets genes are increased or decreased, depending on the gene. The RXR also forms a heterodimer with a number of other receptors: the vitamin D receptor and the thyroid hormone receptor.

The function of PPARs is modified by the exact shape of their ligand-binding domain (see below) and by a number of co-activators and co-repressors, the presence of which can stimulate or inhibit receptor function.

The ligands for the PPARs are free fatty acids and eicosanoids. PPARγ is activated by PGJ₂ (a prostaglandin). In contrast, PPARα is activated by leukotriene B₄.

Genetics

The three main forms are transcribed from different genes:

• PPARα - chromosome 22q12-13.1 (OMIM 170998).
• PPARβ/δ - chromosome 6p21.2-21.1 (OMIM 600409).
• PPARγ - chromosome 3p25 (OMIM 601487).

Hereditary disorders of all PPARs have been described, generally leading to a loss in function and concomitant lipodystrophy, insulin resistance and/or acanthosis nigricans. Of PPARγ, a gain-of-function mutation has been described and studied (Pro12Ala) which decreased the risk of insulin resistance; it is quite prevalent (allele frequency 0.03 - 0.12 in some populations). In contrast, pro115gln is associated with obesity. Some other polymorphisms have high incidence in populations with elevated body mass indexes.

Structure

All PPARs have a basic structure of functional domains. The most important ones are the DBD (DNA binding domain) and the LBD (ligand binding domain). The DBD contains two zinc finger patterns which bind to the regulator region of DNA when the receptor is activated. The LBD has an extensive secondary structure of several alpha helices (13) and a beta sheet. Natural and synthetic ligands bind to the LBD, activating the receptor.

Pharmacology and PPAR modulators

PPARα and PPARγ are the targets of a number of known medications and are under continuing research for other forms of pharmacological modulation. Muraglitazar and tesaglitazar, both experimental compounds, binds to both PPAR-alpha and PPAR-gamma.

PPAR-alpha modulators

PPAR-alpha is the main target of fibrate drugs, a class of amphipathic carboxylic acids (clofibrate, gemfibrozil, ciprofibrate, bezafibrate and fenofibrate). They are used in cholesterol disorders (generally as an adjunctive to statins) and disorders that feature high triglycerides.

PPAR-gamma modulators

PPAR-gamma is the main target of the drug class of thiazolidinediones (TZDs), used in diabetes mellitus and other diseases that feature insulin resistance. It is also mildly activated by certain NSAIDs (such as ibuprofen) and indoles. Known inhibitors include the experimental agent GW-9662.

See also

• Thiazolidinedione
• Anti-diabetic drug
• Diabetes mellitus
• Insulin resistance
• Metabolic syndrome

Sources

• Berger J, Moller DE (2002). "The mechanisms of action of PPARs". Annu. Rev. Med. 53: 409-35. doi:10.1146/annurev.med.53.082901.104018. PMID 11818483.
• Feige JN, Gelman L, Michalik L, Desvergne B, Wahli W (2006). "From molecular action to physiological outputs: peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions". Prog. Lipid Res. 45 (2): 120-59. doi:10.1016/j.plipres.2005.12.002. PMID 16476485.
• Michalik L, Auwerx J, Berger JP, Chatterjee VK, Glass CK, Gonzalez FJ, Grimaldi PA, Kadowaki T, Lazar MA, O'Rahilly S, Palmer CN, Plutzky J, Reddy JK, Spiegelman BM, Staels B, Wahli W (2006). "International Union of Pharmacology. LXI. Peroxisome proliferator-activated receptors". Pharmacol. Rev. 58 (4): 726-41. doi:10.1124/pr.58.4.5. PMID 17132851.

External links

• PPAR resource (Penn State University).
• PPAR reference outline (Rutgers University).
• MeSH Peroxisome+Proliferator-Activated+Receptors

v • d • e Transcription factors and intracellular receptors
(1) Basic domains	(1.1) Basic leucine zipper (bZIP) Activating transcription factor (1, 2, 3, 4, 5, 6) • AP-1 (c-Fos, FOSB, FOSL1, FOSL2, c-Jun, JUNB, JUND) • BACH (1, 2) • C/EBP (α, β, γ, δ, ε, ζ) • CREB (1, 3) • GABPA • MAF (B, F, G, K) • NRL • NRF1 • XBP1 (1.2) Basic helix-loop-helix (bHLH) ATOH1 • AhR • AHRR • ARNT • ASCL1 • BMAL (ARNTL, ARNTL2) • CLOCK • HIF (1A, 3A) • Myogenic regulatory factors (MyoD, Myogenin, MYF5, MYF6) • NEUROD1 • Twist • USF1 (1.3) bHLH-ZIP Myc • MITF • SREBP (1, 2) (1.6) Basic helix-span-helix (bHSH) AP-2
(2) Zinc finger DNA-binding domains	(2.1) Nuclear receptor (Cys4) subfamily 1 (Thyroid hormone (α, β), CAR, FXR, LXR (α, β), PPAR (α, β/δ, γ), PXR, RAR (α, β, γ), ROR (α, β, γ), Rev-ErbA (α, β), VDR) • subfamily 2 (COUP-TF (I, II), Ear-2, HNF4 (α, γ), PNR, RXR (α, β, γ), Testicular receptor (2, 4), TLX) • subfamily 3 (Steroid hormone (Estrogen (α, β), Estrogen related (α, β, γ), Androgen, Glucocorticoid, Mineralocorticoid, Progesterone)) • subfamily 4 NUR (NGFIB, NOR1, NURR1) • subfamily 5 (LRH-1, SF1) • subfamily 6 (GCNF) • subfamily 0 (DAX1, SHP) (2.2) Other Cys4 GATA (1, 2, 3, 4, 5, 6) (2.3) Cys2His2 General transcription factors (TFIIA, TFIIB, TFIID, TFIIE, TFIIF, TFIIH: 1, 2) • GLI-Krüppel family (1, 2, 3, YY1) • KLF (2, 4, 5, 6, 10, 11, 12, 13) • Sp1 • zinc finger (3, 35, 43, 146, 148, 165, 217, 268, 281, 350) • Zbtb7 (7A) • ZBT (16, 17, 33) (2.4) Cys6 HIVEP1
(3) Helix-turn-helix domains	(3.1) Homeo domain ARX • Homeobox (A1, A3, A4, A5, A7, A9, A10, A11, A13, B1, B2, B3, B4, B5, B6, B7, B8, B9, B13, C4, C6, C8, C9, C13, D1, D3, D4, D9, D10, D11, D12, D13) • NANOG • NKX (2-1, 2-5, 3-1) • POU domain (PIT-1, BRN-3: 1, 2, Octamer transcription factor: 1, 2, 3/4, 6, 7) (3.2) Paired box PAX (1, 2, 3, 4, 5, 6, 7, 8, 9) (3.3) Fork head / winged helix E2F (1, 2, 3, 4, 5) • FOX proteins (C1, C2, E1, G1, H1, L2, M1, N3, O3, O4, P1, P2, P3) (3.4) Heat Shock Factors HSF1 (3.5) Tryptophan clusters ELF (4, 5) • Interferon regulatory factors (1, 2, 3, 4, 5, 6, 7, 8) • MYB (3.6) TEA domain transcriptional enhancer factor 1, 2
(4) β-Scaffold factors with minor groove contacts	(4.1) Rel homology region NF-κB (NFKB1, NFKB2, REL, RELA, RELB) • NFAT (5, C1, C2, C3, C4) (4.2) STAT STAT (1, 2, 3, 4, 5, 6) (4.3) p53 p53 (4.4) MADS box Mef2 (A, B, C, D) • SRF (4.7) High mobility group HNF (1A, 1B) • LEF1 • SOX (3, 4, 6, 9, 10, 13, 18) • SRY • SSRP1 (4.10) Cold-shock domain CSDA
(0) Other transcription factors	(0.2) HMGI(Y) HMGA (1, 2) (0.3) Pocket domain Rb • RBL1 • RBL2 (0.6) Miscellaneous ARID (1A, 1B, 2, 3A, 3B, 4A) • CAP • Rho/Sigma • R-SMAD