Peroxisome proliferator-activated receptor

Molecular biology

Molecular biology is the branch of biology that deals with the molecular basis of biological activity. This field overlaps with other areas of biology and chemistry, particularly genetics and biochemistry...

, the peroxisome proliferator-activated receptors (PPARs) are a group of 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...

protein

Protein

Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

s that function as transcription factor

Transcription factor

In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...

s regulating the expression of 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...

s. PPARs play essential roles in the regulation of cellular differentiation, development

Developmental biology

Developmental biology is the study of the process by which organisms grow and develop. Modern developmental biology studies the genetic control of cell growth, differentiation and "morphogenesis", which is the process that gives rise to tissues, organs and anatomy.- Related fields of study...

, and metabolism

Metabolism

Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...

(carbohydrate

Carbohydrate metabolism

Carbohydrate metabolism denotes the various biochemical processes responsible for the formation, breakdown and interconversion of carbohydrates in living organisms....

, lipid

Lipid metabolism

Lipid metabolism refers to the processes that involve the intercourse and degradation of lipids.The types of lipids involved include:* Bile salts* Cholesterols* Eicosanoids* Glycolipids* Ketone bodies* Fatty acids - see also fatty acid metabolism...

, protein

Protein metabolism

Protein metabolism denotes the various biochemical processes responsible for the synthesis of proteins and amino acids, and the breakdown of proteins by catabolism.-Protein synthesis:Main article: Protein biosynthesis....

), and tumorigenesis of higher organisms.

Nomenclature and tissue distribution

Three types of PPARs have been identified: alpha, gamma, and delta (beta):

α (alpha)
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 :...

- expressed in 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...

, kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...

, 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...

, muscle
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...

, adipose tissue
Adipose tissue
In histology, adipose tissue or body fat or fat depot or just fat is loose connective tissue composed of adipocytes. It is technically composed of roughly only 80% fat; fat in its solitary state exists in the liver and muscles. Adipose tissue is derived from lipoblasts...

, and others
β/δ (beta/delta)
Peroxisome proliferator-activated receptor delta
Peroxisome proliferator-activated receptor beta or delta , also known as NR1C2 is a nuclear receptor that in humans is encoded by the PPARD gene....

- expressed in many tissues but markedly in 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,...

, adipose tissue
Adipose tissue
In histology, adipose tissue or body fat or fat depot or just fat is loose connective tissue composed of adipocytes. It is technically composed of roughly only 80% fat; fat in its solitary state exists in the liver and muscles. Adipose tissue is derived from lipoblasts...

, and skin
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
γ (gamma)
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...

- although transcribed by the same gene, this PPAR through alternative splicing
Alternative splicing
Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA splicing...

is expressed in three forms:
- γ1 - expressed in virtually all tissues, including 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...
  
  , muscle
  Muscle
  Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
  
  , 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...
  
  , kidney
  Kidney
  The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
  
  , pancreas
  Pancreas
  The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...
  
  , and 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...
- γ2 - expressed mainly in adipose tissue
  Adipose tissue
  In histology, adipose tissue or body fat or fat depot or just fat is loose connective tissue composed of adipocytes. It is technically composed of roughly only 80% fat; fat in its solitary state exists in the liver and muscles. Adipose tissue is derived from lipoblasts...
  
  (30 amino acid
  Amino acid
  Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
  
  s longer)
- γ3 - expressed in macrophage
  Macrophage
  Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
  
  s, large intestine
  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...
  
  , white adipose tissue
  Adipose tissue
  In histology, adipose tissue or body fat or fat depot or just fat is loose connective tissue composed of adipocytes. It is technically composed of roughly only 80% fat; fat in its solitary state exists in the liver and muscles. Adipose tissue is derived from lipoblasts...
  
  .

History

PPARs were originally 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...

frogs as receptors that induce the proliferation of peroxisome

Peroxisome

Peroxisomes are organelles found in virtually all eukaryotic cells. They are involved in the catabolism of very long chain fatty acids, branched chain fatty acids, D-amino acids, polyamines, and biosynthesis of plasmalogens, etherphospholipids critical for the normal function of mammalian brains...

s in cells.
The first PPAR (PPARα) was discovered during the search of a molecular target for a group of agents then referred to as peroxisome proliferators, as they increased peroxisomal numbers

Peroxisome

in rodent liver tissue, apart from improving insulin sensitivity

Insulin resistance

Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...

. These agents, pharmacologically

Pharmacology

Pharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...

related to the fibrate

Fibrate

In pharmacology, the fibrates are a class of amphipathic carboxylic acids. They are used for a range of metabolic disorders, mainly hypercholesterolemia , and are therefore hypolipidemic agents.- Members :...

s were discovered in the early 1980s. When it turned out that PPARs played a much more versatile role in biology, the agents were in turn termed PPAR ligands. The best-known PPAR ligands are the thiazolidinedione

Thiazolidinedione

The thiazolidinediones , also known as glitazones, are a class of medications used in the treatment of diabetes mellitus type 2. They were introduced in the late 1990s.- Mechanism of action :...

s; see below for more details.

After PPARδ (delta) was identified in humans in 1992, it turned out to be closely related to the PPARβ (beta) previously described during the same year in other animals (Xenopus

Xenopus

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

). The name PPARδ is generally used in the US, whereas the use of the PPARβ denomination has remained in Europe where this receptor was initially discovered in Xenopus.

Physiological function

All PPARs heterodimerize with the retinoid X receptor

Retinoid X receptor

The retinoid X receptor is a type of nuclear receptor that is activated by 9-cis retinoic acid. There are three retinoic X receptors : RXR-alpha, RXR-beta, and RXR-gamma, encoded by the , , genes, respectively....

(RXR) and bind to specific regions on the DNA

DNA

Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...

of target genes. These DNA sequences are termed PPREs (peroxisome proliferator hormone response element

Hormone response element

A hormone response element is a response element for hormones, a short sequence of DNA within the promoter of a gene that is able to bind a specific hormone receptor complex and therefore regulate transcription...

s). The DNA consensus sequence

Consensus sequence

In molecular biology and bioinformatics, consensus sequence refers to the most common nucleotide or amino acid at a particular position after multiple sequences are aligned. A consensus sequence is a way of representing the results of a multiple sequence alignment, where related sequences are...

is AGGTCANAGGTCA, with N being a random nucleotide

Nucleotide

Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...

. In general, this sequence occurs in the promotor region of a gene

Gene

, and, when the PPAR binds its ligand, 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...

of target genes is increased or decreased, depending on the gene. The RXR also forms a heterodimer with a number of other receptors (e.g., vitamin D

Calcitriol receptor

The calcitriol receptor, also known as the vitamin D receptor and also known as NR1I1 , is a member of the nuclear receptor family of transcription factors...

and thyroid hormone

Thyroid hormone receptor

The thyroid hormone receptor is a type of nuclear receptor that is activated by binding thyroid hormone.-Function:Amongst the most important functions of thyroid hormone receptors are regulation of metabolism and heart rate...

).

The function of PPARs is modified by the precise shape of their ligand-binding domain (see below) induced by ligand binding and by a number of coactivator

Coactivator (genetics)

A coactivator is a protein that increases gene expression by binding to an activator which contains a DNA binding domain. The coactivator is unable to bind DNA by itself....

and corepressor

Corepressor (genetics)

In molecular genetics, a corepressor is a substance that inhibits the expression of genes. A corepressor downregulates the expression of genes not through direct interaction with a gene promoter , but rather indirectly through interaction with repressor proteins that in turn bind to the...

proteins, the presence of which can stimulate or inhibit receptor function, respectively.

Endogenous ligands for the PPARs include free fatty acids and eicosanoid

Eicosanoid

In biochemistry, eicosanoids are signaling molecules made by oxidation of twenty-carbon essential fatty acids, ....

s. PPARγ is activated by PGJ₂ (a prostaglandin

Prostaglandin

A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....

). In contrast, PPARα is activated by leukotriene

Leukotriene

Leukotrienes are fatty signaling molecules. They were first found in leukocytes . One of their roles is to trigger contractions in the smooth muscles lining the trachea; their overproduction is a major cause of inflammation in asthma and allergic rhinitis...

B₄.
PPARγ activation by agonist RS5444 may inhibit anaplastic thyroid cancer growth.

Genetics

The three main forms are transcribed from different gene

Gene

PPARα - chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...

22q12-13.1 (OMIM 170998)
PPARβ/δ - chromosome 6p21.2-21.1 (OMIM 600409)
PPARγ - chromosome 3p25 (OMIM 601487).

Hereditary disorders of all PPARs have been described, generally leading to a loss in function and concomitant lipodystrophy

Lipodystrophy

Lipodystrophy is a medical condition characterized by abnormal or degenerative conditions of the body's adipose tissue. A more specific term, lipoatrophy is used when describing the loss of fat from one area...

, insulin resistance

Insulin resistance

, and/or acanthosis nigricans

Acanthosis nigricans

Acanthosis nigricans is a brown to black, poorly defined, velvety hyperpigmentation of the skin. It is usually found in body folds, such as the posterior and lateral folds of the neck, the axilla, groin, umbilicus, forehead, and other areas.-Causes:...

. Of PPARγ, a gain-of-function mutation

Mutation

In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...

has been described and studied (Pro

Proline

Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...

12Ala

Alanine

Alanine is an α-amino acid with the chemical formula CH3CHCOOH. The L-isomer is one of the 20 amino acids encoded by the genetic code. Its codons are GCU, GCC, GCA, and GCG. It is classified as a nonpolar amino acid...

) which decreased the risk of insulin resistance

Insulin resistance

; it is quite prevalent (allele

Allele

An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...

frequency 0.03 - 0.12 in some populations). In contrast, pro

Proline

115gln

Glutamine

Glutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...

is associated with obesity

Obesity

Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...

. Some other polymorphisms have high incidence in populations with elevated body mass indexes.

Structure

Like other nuclear receptors, PPARs are modular in structure and contain the following functional domains:

(A/B) N-terminal region
(C) DBD (DNA-binding domain
DNA-binding domain
A DNA-binding domain is an independently folded protein domain that contains at least one motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence or have a general affinity to DNA...

)
(D) flexible hinge region
(E) LBD (ligand binding domain)
(F) C-terminal region

The DBD contains two zinc finger

Zinc finger

Zinc fingers are small protein structural motifs that can coordinate one or more zinc ions to help stabilize their folds. They can be classified into several different structural families and typically function as interaction modules that bind DNA, RNA, proteins, or small molecules...

motifs, which bind to specific sequences of DNA known as hormone response element

Hormone response element

s when the receptor is activated. The LBD has an extensive secondary structure

Secondary structure

In biochemistry and structural biology, secondary structure is the general three-dimensional form of local segments of biopolymers such as proteins and nucleic acids...

consisting of 13 alpha helices

Alpha helix

A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...

and a beta sheet

Beta sheet

The β sheet is the second form of regular secondary structure in proteins, only somewhat less common than the alpha helix. Beta sheets consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet...

. Natural and synthetic ligands bind to the LBD, either activating

Agonist

An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...

or repressing

Receptor antagonist

A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...

the receptor.

Pharmacology and PPAR modulators

PPARα and PPARγ are the molecular targets of a number of marketed drug

Drug

A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...

s. For instance the hypolipidemic

Hypolipidemic agent

Hypolipidemic agents, or antihyperlipidemic agents, are a diverse group of pharmaceuticals that are used in the treatment of hyperlipidemias. They are called lipid-lowering drugs or agents.- Classes of hypolipidemic drugs :...

fibrate

Fibrate

s activate PPARα, and the anti diabetic thiazolidinediones activate PPARγ. The synthetic chemical perfluorooctanoic acid

Perfluorooctanoic acid

Perfluorooctanoic acid , also known as C8 and perfluorooctanoate, is a synthetic, stable perfluorinated carboxylic acid and fluorosurfactant. One industrial application is as a surfactant in the emulsion polymerization of fluoropolymers. It has been used in the manufacture of such prominent...

activates PPARα while the synthetic perfluorononanoic acid

Perfluorononanoic acid

Perfluorononanoic acid, or PFNA, is a synthetic perfluorinated carboxylic acid and fluorosurfactant that is also an environmental contaminant found in people and wildlife along with PFOS and PFOA.-Chemistry and properties:...

activates both PPARα and PPARγ. Berberine

Berberine

Berberine is a quaternary ammonium salt from the protoberberine group of isoquinoline alkaloids. It is found in such plants as Berberis Berberine is a quaternary ammonium salt from the protoberberine group of isoquinoline alkaloids. It is found in such plants as Berberis Berberine is a quaternary...

activates PPARγ.

External links

http://ppar.cas.psu.edu (PPAR Resource Page, Penn State University).
http://nrresource.org (Nuclear Receptor Resource).
PPAR reference outline (Rutgers University). - the Peroxisome Proliferator-Activated Receptor Structure in Interactive 3D

The source of this article is wikipedia, the free encyclopedia. The text of this article is licensed under the GFDL.

Nomenclature and tissue distribution

History

Physiological function

Genetics

Structure

Pharmacology and PPAR modulators

See also

External links