Peroxisome proliferator-activated receptor delta (PPAR-delta), or (PPAR-beta), also known as Nuclear hormone receptor 1 (NUC1) is a nuclear receptor that in humans is encoded by the ''PPARD''

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

. This gene encodes a member of the

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. PPARs play essential roles in the regu ...

(PPAR) family. It was first identified in ''

Xenopus ''Xenopus'' () (Gk., ξενος, ''xenos''=strange, πους, ''pous''=foot, commonly known as the clawed frog) is a genus of highly aquatic frogs native to sub-Saharan Africa. Twenty species are currently described within it. The two best-know ...

'' in 1993.

Function

PPAR-delta is a

nuclear hormone 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 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 Expression may refer to: Linguistics * Expression (linguistics), a word, phrase, or sentence * Fixed expression, a form of words with a specific meaning * Idiom, a type of fixed expression * Metaphorical expression, a particular word, phrase, o ...

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 ...

agonists are regarded as exercise

mimetics Mimesis (; grc, μίμησις, ''mīmēsis'') is a term used in literary criticism and philosophy that carries a wide range of meanings, including '' imitatio'', imitation, nonsensuous similarity, receptivity, representation, mimicry, the ...

. In

adipose tissue Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular ...

PPAR-β/δ increases both oxidation as well as uncoupling of oxidative phosphorylation. 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 Pyruvate dehydrogenase lipoamide kinase isozyme 4, mitochondrial is an enzyme that in humans is encoded by the ''PDK4'' gene. It codes for an isozyme of pyruvate dehydrogenase kinase. This gene is a member of the PDK/BCKDK protein kinase family a ...

, ANGPTL4, PLIN2, and

CD36 CD36 (cluster of differentiation 36), also known as platelet glycoprotein 4, fatty acid translocase (FAT), scavenger receptor class B member 3 (SCARB3), and glycoproteins 88 (GP88), IIIb (GPIIIB), or IV (GPIV) is a protein that in humans is enco ...

. The expression of this gene is found to be elevated in colorectal cancer cells. The elevated expression can be repressed by adenomatosis polyposis coli ( APC), a tumor suppressor protein involved in the APC/

beta-catenin Catenin beta-1, also known as beta-catenin (β-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene. Beta-catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcrip ...

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 ...

of the

corpus callosum The corpus callosum (Latin for "tough body"), also callosal commissure, is a wide, thick nerve tract, consisting of a flat bundle of commissural fibers, beneath the cerebral cortex in the brain. The corpus callosum is only found in placental m ...

epidermal The epidermis is the outermost of the three layers that comprise the skin, the inner layers being the dermis and hypodermis. The epidermis layer provides a barrier to infection from environmental pathogens and regulates the amount of water relea ...

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 Keratinocytes are the primary type of cell found in the epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells. Basal cells in the basal layer (''stratum basale'') of the skin are sometimes referre ...

Role in cancer

Studies into the role of PPAR-delta in

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

have produced contradictory results and there is no scientific consensus 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 GW501516 (also known as GW-501,516, GW1516, GSK-516, Cardarine, and on the black market as Endurobol) is a PPARδ receptor agonist that was invented in a collaboration between Ligand Pharmaceuticals and GlaxoSmithKline in the 1990s. It entere ...

and GW0742, 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,

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...

and

keratinocytes Keratinocytes are the primary type of cell found in the epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells. Basal cells in the basal layer (''stratum basale'') of the skin are sometimes referre ...

, as well as in

heart The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide to t ...

spleen The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes .

, skeletal muscle, lung,

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a ve ...

and

thymus The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, thymus cell lymphocytes or ''T cells'' mature. T cells are critical to the adaptive immune system, where the body adapts to specific foreign invaders. ...

Knockout studies

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

postnatal The postpartum (or postnatal) period begins after childbirth and is typically considered to end within 6 weeks as the mother's body, including hormone levels and uterus size, returns to a non-pregnant state. The terms puerperium, puerperal perio ...

ly. In addition, fat stores in the gonads of the mutants are smaller. The mutants also display increased epidermal hyperplasia 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 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

* GW0742 *

Telmisartan Telmisartan, sold under the brand name Micardis among others, is a medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It is a reasonable initial treatment for high blood pressure. It is taken by mouth ...

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 and NCOR2.

References

External links

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