The peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes.
PPARs play essential roles in the regulation of cellular differentiation, development, and metabolism carbohydrates, lipids, proteins, and tumorigenesis.
PPAR is a family of transcription factors that regulate gene expression in the liver, adipose tissue, and inflammatory cells.
Polyunsaturated fatty acids are ligands for PPAR, and their binding has been shown to affect adipose tissue metabolism and inflammatory cytokine production.
PPAR’s physiologic action is to lower fasting triglycerides and increase insulin sensitivity.
Three types of PPARs exist identified: alpha, gamma, and delta/beta
α (alpha) – expressed in liver, kidney, heart, muscle, adipose tissue, and other tissues.
β/δ (beta/delta) – expressed in many tissues but markedly in brain, adipose tissue, and skin
γ (gamma)- 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
γ3 – expressed in macrophages, large intestine, white adipose tissue.
The best-known PPAR ligands are the thiazolidinediones
All PPARs heterodimerize with the retinoid X receptor and bind to specific sequenced regions on the DNA of target genes.
The DNA consensus sequence occurs in the promoter region of a gene, and, when the PPAR binds its ligand, transcription of target genes is increased or decreased, depending on the gene.
Endogenous ligands for the PPARs include free fatty acids, eicosanoids and Vitamin B3.
Its three main forms are transcribed from different genes:
PPARα – chromosome 22
PPARβ/δ – chromosome 6
PPARγ – chromosome 3
Hereditary disorders of PPARs lead to a loss in function and concomitant lipodystrophy, insulin resistance, and/or acanthosis nigricans.
PPARγ, is a gain-of-function mutation that decreases the risk of insulin resistance.
pro115gln polymorphism is associated with obesity, and other polymorphisms have high incidence in populations with elevated body mass indexes.
PPARs contain the following functional domains:
N-terminal region
DBD (DNA-binding domain)
Flexible hinge region
LBD (ligand binding domain)
(C-terminal region
PPARα and PPARγ are the molecular targets of a number of drugs: hypolipidemic fibrates activate PPARα, and the anti diabetic thiazolidinediones activate PPARγ.