Peroxisome proliferator-activated receptor delta (PPAR-delta), or (PPAR-beta), also known as Nuclear hormone receptor 1 (NUC1) is a

nuclear receptor In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to regulate the expression of speci ...

that in humans is encoded by the ''PPARD'' gene. This gene encodes a member of the peroxisome proliferator-activated receptor (PPAR) family. It was first identified in '' Xenopus'' in 1993.

Function

PPAR-delta is a nuclear hormone receptor that governs a variety of biological processes and may be involved in the development of several chronic diseases, including diabetes, obesity, atherosclerosis, and cancer. In muscle PPARD expression is increased by exercise, resulting in increased

oxidative Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...

(fat-burning) capacity and an increase in type I fibers. Both PPAR-delta and

AMPK AMPK may refer to: * AMP-activated protein kinase 5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme (EC 2.7.11.31) that plays a role in cellular energy homeostasis, largely to activate gl ...

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

s are regarded as exercise mimetics. In adipose tissue PPAR-β/δ increases both oxidation as well as uncoupling of

oxidative phosphorylation Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing chemical energy in order to produce adenosine tri ...

. PPAR-delta may function as an integrator of

transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, the fir ...

repression and nuclear receptor signaling. It activates transcription of a variety of target genes by binding to specific DNA elements. Well described target genes of PPARδ include PDK4,

ANGPTL4 Angiopoietin-like 4 is a protein that in human is encoded by the ''ANGPTL4'' gene. Alternatively spliced transcript variants encoding different isoforms have been described. This gene was previously referred to as ANGPTL2, HFARP, PGAR, or FIAF but ...

, PLIN2, and CD36. The expression of this gene is found to be elevated in

colorectal cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel m ...

cells. The elevated expression can be repressed by adenomatosis polyposis coli ( APC), a tumor suppressor protein involved in the APC/ beta-catenin signaling pathway. Knockout studies in mice suggested the role of this protein in

myelination Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be l ...

of the corpus callosum, 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 keratinocytes.

Role in cancer

Studies into the role of PPAR-delta in cancer have produced contradictory results and there is no

scientific consensus Scientific consensus is the generally held judgment, position, and opinion of the majority or the supermajority of scientists in a particular field of study at any particular time. Consensus is achieved through scholarly communication at confe ...

on whether it promotes or prevents cancer formation. PPAR-delta favours tumour angiogenesis.

Pharmacology

Several high affinity ligands for PPAR-delta have been developed, including GW501516 and

GW0742 GW0742 (also known as GW610742) is a PPARδ/β agonist that is investigated for drug use by GlaxoSmithKline. Pharmacology Pharmacodynamics It is mixed PPAR-B agonist antagonist depending on its dosage. It has weak activity on multiple nuclear ...

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

Tissue distribution

PPAR-delta is highly expressed in many tissues, including colon,

small intestine The small intestine or small bowel is an organ in the gastrointestinal tract where most of the absorption of nutrients from food takes place. It lies between the stomach and large intestine, and receives bile and pancreatic juice through the p ...

, liver and keratinocytes, as well as in heart, spleen,

skeletal muscle Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...

lung The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of t ...

, brain and thymus.

Knockout studies

Knockout mice A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or "knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...

lacking the ligand binding domain of PPAR-delta are viable. However, these mice are smaller than the wild type both

neo Neo or NEO may refer to: Arts and entertainment Fictional entities * Neo (''The Matrix''), the alias of Thomas Anderson, a hacker and the protagonist of the Matrix film series * Neo (''Marvel Comics'' species), a fictional race of superhumans * ...

and postnatally. In addition, fat stores in the

gonad A gonad, sex gland, or reproductive gland is a mixed gland that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gonad, the testicle, produces sper ...

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

hyperplasia Hyperplasia (from ancient Greek ὑπέρ ''huper'' 'over' + πλάσις ''plasis'' 'formation'), or hypergenesis, is an enlargement of an organ or tissue caused by an increase in the amount of organic tissue that results from cell proliferati ...

upon induction with TPA.

Ligands

PPAR-delta is activated in the cell by various fatty acids and fatty acid derivatives. Examples of naturally occurring fatty acids that bind with and activate PPAR-delta include

arachidonic acid Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the New Latin word ''arachi ...

and certain members of the

15-hydroxyicosatetraenoic acid 15-Hydroxyeicosatetraenoic acid (also termed 15-HETE, 15(''S'')-HETE, and 15''S''-HETE) is an eicosanoid, i.e. a metabolite of arachidonic acid. Various cell types metabolize arachidonic acid to 15(''S'')-hydroperoxyeicosatetraenoic acid (15(''S' ...

family of arachidonic acid metabolites including 15(''S'')-HETE, 15(''R'')-HETE, and 15-HpETE.Mol. Pharmacol. 77:171-184, 2010 Several synthetic ligands have been identified that selectively bind PPAR-delta.

Agonists

* GW501516 *

* Telmisartan

Interactions

Peroxisome proliferator-activated receptor delta has been shown to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...

with

HDAC3 Histone deacetylase 3 is an enzyme encoded by the ''HDAC3'' gene in both humans and mice. Function Histones are highly alkaline proteins that package and order DNA into structural units called nucleosomes, which comprise the major protein comp ...

and NCOR2.

References

External links

* {{PPAR modulators Intracellular receptors Transcription factors Biology of bipolar disorder