Peroxisome proliferator-activated receptor beta or delta (PPAR-β or PPAR-δ), also known as NR1C2 (nuclear receptor subfamily 1, group C, member 2) is a nuclear receptor

Nuclear receptor

In the field of molecular biology, nuclear receptors are a class of proteins found within cells that are responsible for sensing steroid and thyroid hormones and certain other molecules...

 that in humans is encoded by the PPARD gene

Gene

A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

.

This gene encodes a member of the peroxisome proliferator-activated receptor (PPAR

Peroxisome proliferator-activated receptor

In the field of molecular biology, the peroxisome proliferator-activated receptors are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes...

) family. It was first identified in Xenopus

Xenopus

Xenopus is a genus of highly aquatic frogs native to Sub-Saharan Africa. There are 19 species in the Xenopus genus...

 in 1993.

Function

PPARs are nuclear hormone receptor

Nuclear receptor

In the field of molecular biology, nuclear receptors are a class of proteins found within cells that are responsible for sensing steroid and thyroid hormones and certain other molecules...

s that bind peroxisome proliferators and control the size and number of peroxisomes produced by cells. PPARs mediate a variety of biological processes, and may be involved in the development of several chronic diseases, including diabetes, obesity, atherosclerosis, and cancer.

This protein is a potent inhibitor of ligand-induced transcription activity of PPAR-α

Peroxisome proliferator-activated receptor alpha

Peroxisome proliferator-activated receptor alpha , also known as NR1C1 , is a nuclear receptor protein that in humans is encoded by the PPARA gene.- Function :...

 and PPAR-γ

Peroxisome proliferator-activated receptor gamma

Peroxisome proliferator-activated receptor gamma , also known as the glitazone receptor, or NR1C3 is a type II nuclear receptor that in humans is encoded by the PPARG gene.Two isoforms of PPARG are detected in the human and in the mouse: PPAR-γ1 and...

. It may function as an integrator of transcription

Transcription (genetics)

Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...

 repression

Repressor

In molecular genetics, a repressor is a DNA-binding protein that regulates the expression of one or more genes by binding to the operator and blocking the attachment of RNA polymerase to the promoter, thus preventing transcription of the genes. This blocking of expression is called...

 and nuclear receptor signaling. The expression of this gene is found to be elevated in colorectal cancer

Colorectal cancer

Colorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....

 cells. The elevated expression can be repressed by adenomatosis polyposis coli (APC), a tumor suppressor protein involved in the APC/beta-catenin

Beta-catenin

Beta-catenin is a protein that in humans is encoded by the CTNNB1 gene. In Drosophila, the homologous protein is called armadillo...

 signaling pathway. Knockout studies in mice suggested the role of this protein in myelination of the corpus callosum

Corpus callosum

The corpus callosum , also known as the colossal commissure, is a wide, flat bundle of neural fibers beneath the cortex in the eutherian brain at the longitudinal fissure. It connects the left and right cerebral hemispheres and facilitates interhemispheric communication...

, epidermal cell proliferation, and glucose and lipid metabolism.

This protein has been shown to be involved in differentiation, lipid accumulation, directional sensing, polarization, and migration in keratinocyte

Keratinocyte

Keratinocytes are the predominant cell type in the epidermis, the outermost layer of the human skin, constituting 95% of the cells found there. Those keratinocytes found in the basal layer of the skin are sometimes referred to as "basal cells" or "basal keratinocytes"...

s.

Clinical significance

In one study, polymorphisms

Polymorphism (biology)

Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...

 of PPARD were found to be associated with bipolar disorder

Bipolar disorder

Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...

.

Pharmacology

Several high affinity ligands for PPAR-δ/β have been developed, including GW 501516

GW 501516

GW-501516 is a PPARδ modulator compound being investigated for drug use by GlaxoSmithKline. It activates the same pathways activated through exercise, including PPARδ and AMP-activated protein kinase...

 and GW 0742, which play an important role in research. In one study utilizing such a ligand, it has been shown that agonism of PPAR-δ changes the body's fuel preference from glucose to lipids.

Tissue distribution

PPAR-δ/β is highly expressed in colon

Colon (anatomy)

The colon is the last part of the digestive system in most vertebrates; it extracts water and salt from solid wastes before they are eliminated from the body, and is the site in which flora-aided fermentation of unabsorbed material occurs. Unlike the small intestine, the colon does not play a...

, small intestine

Small intestine

The small intestine is the part of the gastrointestinal tract following the stomach and followed by the large intestine, and is where much of the digestion and absorption of food takes place. In invertebrates such as worms, the terms "gastrointestinal tract" and "large intestine" are often used to...

, liver

Liver

The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...

 and keratinocytes. In contrast, heart

Heart

The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...

, spleen

Spleen

The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...

, skeletal muscle

Skeletal muscle

Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...

, lung

Lung

The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...

, brain

Brain

The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...

 and thymus

Thymus

The thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....

 show low expression.

Knockout studies

Knockout mice

Knockout mouse

A knockout mouse is a genetically engineered mouse in which researchers have inactivated, or "knocked out," an existing gene by replacing it or disrupting it with an artificial piece of DNA...

 lacking the ligand binding domain of PPAR-δ/β are viable. However these mice are smaller than the wild type both neo and postnatal

Postnatal

Postnatal is the period beginning immediately after the birth of a child and extending for about six weeks. Another term would be postpartum period, as it refers to the mother...

ly. In addition, fat stores in the gonad

Gonad

The gonad is the organ that makes gametes. The gonads in males are the testes and the gonads in females are the ovaries. The product, gametes, are haploid germ cells. For example, spermatozoon and egg cells are gametes...

s of the mutants are smaller. The mutants also display increased epidermal hyperplasia

Hyperplasia

Hyperplasia means increase in number of cells/proliferation of cells. It may result in the gross enlargement of an organ and the term is sometimes mixed with benign neoplasia/ benign tumor....

 upon induction with TPA

12-O-Tetradecanoylphorbol-13-acetate

12-O-tetradecanoylphorbol-13-acetate , also commonly known as tetradecanoylphorbol acetate, tetradecanoyl phorbol acetate, and phorbol 12-myristate 13-acetate , is diester of phorbol and a potent tumor promoter often employed in biomedical research to activate the signal transduction enzyme protein...

.

Agonists

• GW-501,516
  GW 501516
  GW-501516 is a PPARδ modulator compound being investigated for drug use by GlaxoSmithKline. It activates the same pathways activated through exercise, including PPARδ and AMP-activated protein kinase...
  
  
• GW-610,742

Natural ligands of PPAR-delta are metabolites of arachidonic acid, which include 4-hydroxy-2-nonenal

4-Hydroxynonenal

4-Hydroxynonenal, or 4-hydroxy-2-nonenal or 4-HNE or HNE, , is an α,β-unsaturated hydroxyalkenal which is produced by lipid peroxidation in cells...

 (4-HNE) and 4-hydroxydodeca-(2E,6Z)-dienal (4-HDDE).

Interactions

Peroxisome proliferator-activated receptor delta has been shown to interact

Protein-protein interaction

Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...

 with HDAC3

HDAC3

Histone deacetylase 3 is an enzyme that in humans is encoded by the HDAC3 gene.-Interactions:HDAC3 has been shown to interact with HDAC9, HDAC7A, Retinoblastoma protein, RBBP4, Testicular receptor 2, MAP3K7IP2, Peroxisome proliferator-activated receptor delta, GTF2I, Histone deacetylase 5, RELA,...

 and NCOR2

Nuclear receptor co-repressor 2

The nuclear receptor co-repressor 2 is a transcriptional coregulatory protein that contains several nuclear receptor-interacting domains. In addition, NCOR2 appears to recruit histone deacetylases to DNA promoter regions. Hence NCOR2 assists nuclear receptors in the down regulation of target...

.

External links