Peroxisome proliferator-activated receptor

In the field of molecular biology, the peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes.^[1] PPARs play essential roles in the regulation of cellular differentiation, development, and metabolism (carbohydrate, lipid, and protein) of higher organisms.^[2][3]

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Nomenclature and tissue distribution

Three types of PPARs have been identified: alpha, gamma, and delta (beta):^[2]

• 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 through alternative splicing is expressed 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.^[4] 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.^[5] 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,^[6] 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 heterodimerize 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 hormone response elements). The DNA consensus sequence is AGGTCAXAGGTCA, with X being a random nucleotide. In general, 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 (e.g., vitamin D and thyroid 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 of coactivator and corepressor proteins, the presence of which can stimulate or inhibit receptor function, respectively.^[7]

Endogenous ligands for the PPARs include 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.^[8] 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).^[9] In contrast, pro115gln is associated with obesity. Some other polymorphisms have high incidence in populations with elevated body mass indexes.

Structure

  As with other nuclear receptors, PPARs are modular in structure and contain the following functional domains:

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

The DBD contains two zinc finger motifs, which bind to specific sequences of DNA known as hormone response elements when the receptor is activated. The LBD has an extensive secondary structure consisting of 13 alpha helices and a beta sheet.^[10] Natural and synthetic ligands bind to the LBD, either activating or repressing the receptor.

Pharmacology and PPAR modulators

PPARα and PPARγ are the molecular targets of a number of marketed drugs. The three main classes of PPAR drugs are:

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.

Balanced-PPAR modulators

A third class of "balanced" or "pan" PPAR ligands, which bind two or more PPAR isoforms, are currently under active investigation for treatment of a larger subset of the symptoms of the metabolic syndrome.^[11][12] These include the experimental compounds muraglitazar and tesaglitazar. In addition, there is continuing research and development of new PPAR modulators for additional therapeutic indications.

See also

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

References