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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 steroid hormone, steroids, thyroid hormone, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to ...
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 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 ...
(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 ag ...
s are regarded as exercise mimetics. 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 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 t ...
. PPAR-delta may function as an integrator of transcription 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, 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 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 ...
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 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 ...
s.


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 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 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 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 r ...
, 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 (anatomy), organ in the human gastrointestinal tract, gastrointestinal tract where most of the #Absorption, absorption of nutrients from food takes place. It lies between the stomach and large intes ...
,
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 i ...
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 (biology), 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 ca ...
,
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 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 m ...
,
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 ...
,
brain A brain is an organ (biology), 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 Visual perception, vision. I ...
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 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
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
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 sp ...
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 proliferatio ...
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 ''ara ...
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 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 ...
*
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 r ...
* Telmisartan


Interactions

Peroxisome proliferator-activated receptor delta has been shown to
interact Advocates for Informed Choice, doing business as, 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 trai ...
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


Further reading

* * * * * *


External links

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