In the field ofmolecular biology, theperoxisome proliferator–activated receptors (PPARs) are a group ofnuclear receptorproteins that function astranscription factors regulatinggene expression.^[1] PPARs play essential roles in regulatingcellular differentiation,development, andmetabolism (carbohydrate,lipid,protein),^[2] andtumorigenesis^[3][4][5]

Peroxisome proliferator-activated receptor gamma
Identifiers
Symbol	PPARG
NCBI gene	5468
HGNC	9236
OMIM	601487
RefSeq	NM_005037
UniProt	P37231
Other data
Locus	Chr. 3p25
Search for Structures Swiss-model Domains InterPro

Three types of PPARs have been identified: alpha,gamma, and delta (beta):^[4]

• α (alpha) - expressed inliver,kidney,heart,muscle,adipose tissue, and others^[6]
• β/δ (beta/delta) - expressed in many tissues, especially inbrain,adipose tissue, andskin
• γ (gamma) - although transcribed by the same gene, this PPAR, by way ofalternative splicing, is expressed in three forms:
  • γ1 - expressed in virtually all tissues, includingheart,muscle,colon,kidney,pancreas, andspleen
  • γ2 - expressed mainly inadipose tissue; it is 30amino acids longer than γ1
  • γ3 - expressed inmacrophages,large intestine,white adipose tissue

These agents,pharmacologically related to thefibrates, were discovered in the early 1980s.

PPARs were originally identified inXenopus frogs as receptors that induce the proliferation ofperoxisomes in cells in 1992.^[7] The first PPAR (PPARα) was discovered in 1990 during the search for a molecular target of a group of agents then referred to asperoxisome proliferators, as they increased peroxisomal numbers in rodent liver tissue, apart from improvinginsulin sensitivity.^[8]

When it turned out that PPARs played a versatile role in biology, the agents were in turn termedPPAR ligands. The best-known PPAR ligands are thethiazolidinediones.

After PPARδ (delta) was identified in humans in 1992,^[9] it turned out to be closely related to PPARβ (beta), previously described during the same year in anamphibian,Xenopus. The term "PPARδ" is generally used in the US, while "PPARβ" has remained in Europe, where this receptor was initially discovered.

PPARs were named because they induce peroxisome proliferation in rodents, but this induction has not been verified in humans.^[10][11]

All PPARsheterodimerize with theretinoid X receptor (RXR) and bind to specific regions on theDNA of target genes. These DNA sequences are termed PPREs (peroxisome proliferatorhormone response elements). The DNAconsensus sequence is AGGTCANAGGTCA, with N being anynucleotide. In general, this sequence occurs in the promoter region of agene, and, when thePPAR binds its ligand,transcription of target genes is increased or decreased, depending on the gene. The RXR also forms aheterodimer with a number of other receptors (e.g.,vitamin D andthyroid hormone).

The function of PPARs is modified by the precise shape of their ligand-binding domain (see below) induced by ligand binding and by a number ofcoactivator andcorepressor proteins, the presence of which can stimulate or inhibit receptor function, respectively.^[12]

Endogenous ligands for the PPARs includefree fatty acids,eicosanoids andVitamin B3.PPARγ is activated by PGJ₂ (aprostaglandin) and certain members of the5-HETE family ofarachidonic acid metabolites including 5-oxo-15(S)-HETE and 5-oxo-ETE.^[13] In contrast, PPARα is activated byleukotriene B₄. Certain members of the15-hydroxyeicosatetraenoic acid family of arachidonic acid metabolites, including 15(S)-HETE, 15(R)-HETE, and 15-HpETE activate to varying degrees PPAR alpha, beta/delta, and gamma. In addition,PPARγ was reported to be involved in cancer pathogenesis and growth.^[14][15]PPARγ activation by agonist RS5444 may inhibit anaplastic thyroid cancer growth.^[16] See^[17] for a review and critique of the roles of PPAR gamma in cancer.

The three main forms of PPAR are transcribed from differentgenes:

• PPARα -chromosome 22q12-13.1 (OMIM170998^{[dead link]})
• PPARβ/δ -chromosome 6p21.2-21.1 (OMIM600409^{[dead link]})
• PPARγ -chromosome 3p25 (OMIM601487^{[dead link]}).

Hereditary disorders of all 3 of these PPARs have been described, generally leading to a loss in function and concomitantlipodystrophy,insulin resistance, and/oracanthosis nigricans.^[18] OfPPARγ, a gain-of-functionmutation has been described and studied:Pro12Ala, which decreases the risk ofinsulin resistance. It is quite prevalent, with anallele frequency of 0.03 - 0.12 in some populations.^[19] In contrast,pro115gln is associated withobesity. Certain otherpolymorphisms in PPAR show a high incidence in populations with elevatedbody mass indexes.

Like other nuclear receptors, PPARs are modular in structure and contain the followingfunctional domains:

• (A/B) -N-terminal region
• (C)DBD -DNA-binding domain
• (D) - flexiblehinge region
• (E)LBD -ligand binding domain
• (F)C-terminal region

The DBD contains twozinc finger motifs, which bind to specific sequences of DNA known ashormone response elements when the receptor is activated.

The LBD has an extensivesecondary structure consisting of 13alpha helices and abeta sheet.^[20] Both natural and synthetic ligands can bind to the LBD, eitheractivating orrepressing the receptor's activity.

PPARα and PPARγ are the molecular targets of a number of marketeddrugs.

For instance thehypolipidemicfibrates activate PPARα.^{[citation needed]}

Theanti diabeticthiazolidinediones activate PPARγ.^{[citation needed]}

The synthetic chemicalperfluorooctanoic acid activates PPARα whileperfluorononanoic acid activates both PPARα and PPARγ.^{[citation needed]}

Berberine inactivates PPARγ.^[21]

Other natural compounds from different chemical classes activate or inactivate PPARγ.^[22][23][24]

• Metabolic syndrome
• Endocannabinoid system

• [1] (PPAR Resource Page, Penn State University).
• CakhiaTV - Link Xem Trực Tiếp Bóng Đá Ngay Sắc Nét Full HD (Nuclear Receptor Resource).
• PPAR reference outlineArchived 2020-02-14 at theWayback Machine (Rutgers University).
• Peroxisome+Proliferator-Activated+Receptors at the U.S. National Library of MedicineMedical Subject Headings (MeSH)
• ProteopediaPeroxisome_Proliferator-Activated_Receptors - the Peroxisome Proliferator-Activated Receptor Structure in Interactive 3D

• Genes on human chromosome 22
• Genes on human chromosome 3
• Genes on human chromosome 6
• Nuclear receptors

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