Apelin (also known as APLN) is a peptide that in humans is encoded by the ''APLN'' gene.
Apelin is one of two endogenous
ligand
In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's ele ...
s for the
G-protein
G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their ...
-coupled
APJ receptor that is expressed at the surface of some cell types.
It is widely expressed in various organs such as the heart, lung, kidney, liver,
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 ...
,
gastrointestinal tract
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans a ...
, brain, adrenal glands,
endothelium
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the ve ...
, and human
plasma.
Discovery
Apelin is a peptide hormone that was identified in 1998 by Masahiko Fujino and his colleagues at
Gunma University
, abbreviated to , is a national university in Japan. The main campus is located in Aramaki-machi, Maebashi City, Gunma Prefecture.
History
Gunma University was established in 1949 by integrating the national colleges in Gunma Prefecture: , ...
and
Takeda Pharmaceutical Company
The is a Japanese multinational pharmaceutical company, with partial American and British roots. It is the largest pharmaceutical company in Asia and one of the top 20 largest pharmaceutical companies in the world by revenue (top 10 followin ...
.
In 2013, a second peptide hormone named
Elabela was found by
Bruno Reversade to also act as an endogenous
ligand
In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's ele ...
to the
APLNR.
Biosynthesis
The apelin gene encodes a pre-proprotein of 77 amino acids,
with a
signal peptide
A signal peptide (sometimes referred to as signal sequence, targeting signal, localization signal, localization sequence, transit peptide, leader sequence or leader peptide) is a short peptide (usually 16-30 amino acids long) present at the N-ter ...
in the
N-terminal
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...
region. After translocation into the
endoplasmic reticulum
The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...
and cleavage of the signal peptide, the proprotein of 55 amino acids may generate several active fragments: a 36 amino acid peptide corresponding to the sequence 42-77 (apelin 36), a 17 amino acid peptide corresponding to the sequence 61-77 (apelin 17) and a 13 amino acid peptide corresponding to the sequence 65-77 (apelin 13). This latter fragment may also undergo a pyroglutamylation at the level of its N-terminal glutamine residue. However the presence and/or the concentrations of those peptides in human plasma has been questioned.
Recently, 46 different apelin peptides ranging from apelin 55 () to apelin 12 have been identified in bovine colostrum, including C-ter truncated isoforms.
Physiological functions
The sites of receptor expression are linked to the different functions played by apelin in the organism.
Vascular
Vascular expression of the
receptor participates in the control of
blood pressure
Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressur ...
and its activation promotes the formation of new blood vessels (
angiogenesis).
The blood pressure-lowering (
hypotensive
Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the dia ...
) effect of apelin results from the activation of receptors expressed at the surface of
endothelial cells
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the ves ...
.
This activation induces the release of
nitric oxide
Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its ...
(NO),
a potent vasodilator, which induces relaxation of the smooth muscle cells of artery wall. Studies performed on mice knocked out for the apelin receptor gene
have suggested the existence of a balance between
angiotensin II
Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the adr ...
signalling (which increases blood pressure)e and apelin signalling (which lowers it). The
angiogenic activity is the consequence of apelin action on the proliferation and migration of the endothelial cells. Apelin activates
signal transduction
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellular ...
cascades inside the cell, including
extracellular signal-regulated kinases
In molecular biology, extracellular signal-regulated kinases (ERKs) or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules that are involved in functions including the regulation of meiosis, mitosis, and ...
(ERKs),
protein kinase B
Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, t ...
(PKB, also known as Akt), and p70
s6 kinase
In molecular biology, ribosomal s6 kinase (rsk) is a family of protein kinases involved in signal transduction. There are two subfamilies of rsk, p90rsk, also known as MAPK-activated protein kinase-1 (MAPKAP-K1), and p70rsk, also known as S6-H1 K ...
phosphorylation
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, ...
,
which lead to the proliferation of endothelial cells and the formation of new blood vessels.
Genetic knockout
A gene knockout (abbreviation: KO) is a genetic technique in which one of an organism's genes is made inoperative ("knocked out" of the organism). However, KO can also refer to the gene that is knocked out or the organism that carries the gene kno ...
of the apelin gene is associated with a delay in the development of the retinal vasculature.
Cardiac
The apelin receptor is expressed early during the
embryonic development
An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...
of the heart, where it regulates the migration of cell progenitors fated to differentiate into
cardiomyocytes
Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle tha ...
, the contractile cells of the heart.
Its expression is also detected in the cardiomyocytes of the adult where apelin behaves as one of the most potent stimulator of cardiac contractility.
Aged apelin knockout mice develop progressive impairment of cardiac contractility.
Apelin acts as a mediator of the cardiovascular control, including for blood pressure and blood flow. It is one of the most potent stimulators of cardiac
contractility
Contractility refers to the ability for self-contraction, especially of the muscles or similar active biological tissue
*Contractile ring in cytokinesis
*Contractile vacuole
*Muscle contraction
**Myocardial contractility
*See contractile cell for ...
yet identified, and plays a role in cardiac tissue remodeling. Apelin levels are increased in left ventricles of patients with chronic heart failure and also in patients with
chronic liver disease
Chronic liver disease in the clinical context is a disease process of the liver that involves a process of progressive destruction and regeneration of the liver parenchyma leading to fibrosis and cirrhosis. "Chronic liver disease" refers to diseas ...
.
Exercise
The plasma concentration of apelin is shown to increase during exercise.
Paradoxically, exogenous apelin in healthy volunteers reduced VO2 peak (peak oxygen consumption) in an endurance test.
Brain
Apelin receptor is also expressed in the neurons of brain areas involved in regulating water and food intake.
[De Mota et al., 2000] Apelin injection increases water intake
and apelin decreases the
hypothalamic secretion of the
antidiuretic
An antidiuretic is a substance that helps to control fluid balance in an animal's body by reducing urination, opposing diuresis. Its effects are opposite that of a diuretic. The major endogenous antidiuretics are antidiuretic hormone (ADH; also ...
hormone
A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...
vasopressin
Human vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin, is a hormone synthesized from the AVP gene as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It then ...
.
This
diuretic
A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics in ...
effect of apelin in association with its hypotensive effect participates in the homeostatic regulation of body fluid. Apelin is also detected in brain areas which control appetite, but its effects on food intake are very contradictory.
Adipose tissue
Apelin is expressed and secreted by
adipocyte
Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesi ...
s, and its production is increased during adipocyte differentiation and is stimulated by
insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabol ...
.
Most obese people have elevated levels of insulin, which may therefore be the reason why obese people have been reported to also have elevated levels of apelin.
Digestive
Apelin receptor is expressed in several cell types of the
gastro-intestinal tract
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans an ...
:
stomach
The stomach is a muscular, hollow organ in the gastrointestinal tract of humans and many other animals, including several invertebrates. The stomach has a dilated structure and functions as a vital organ in the digestive system. The stomach i ...
enterochromaffine-like cells;
unknown cells of endocrine
pancreas
The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an en ...
,
[Sorhede Winzell et al., 2005] colon epithelial cells.
In stomach, activation of receptors on enterochromaffine-like cells by apelin secreted by
parietal cells
Parietal cells (also known as oxyntic cells) are epithelial cells in the stomach that secrete hydrochloric acid (HCl) and intrinsic factor. These cells are located in the gastric glands found in the lining of the fundus and body regions of th ...
can inhibit histamine release by enterochromaffine-like cells, which in turn decreases acid secretion by parietal cells.
In pancreas, apelin inhibits the insulin secretion induced by glucose.
This inhibition reveals the functional interdependency between apelin signalling and insulin signalling observed at the adipocyte level where insulin stimulate apelin production.
Recently, receptor expression was also detected in skeletic muscle cells. Its activation is involved in glucose uptake and participates in the control of glucose blood levels
glycemia.
Bone
Receptor expression is also observed at the surface of osteoblasts, the cell progenitors involved in bone formation.
Muscle aging
Muscle apelin expression decreases with age in rodents and humans.
By supplementing aged mice with exogenous apelin, Cedric Dray, Philippe Valet, and their colleagues demonstrated that the peptide was able to promote muscle hypertrophy and consequently induced a gain in strength.
This study also demonstrated that apelin targets muscle cells during aging by different and complementary pathways: it acts on muscle metabolism by activating an AMPK-dependent mitochondria biogenesis, it promotes autophagy and decreases inflammation in aged mice.
Moreover, apelin receptor is also present on muscle stem cells and promotes in vitro and in vivo proliferation and differentiation of these cells into mature muscle cells participating to muscle regeneration. Finally, muscle apelin could be used a biomarker of physical exercise success in aged individual since its production is correlated to the benefit of a chronic physical exercise in aged individuals.
References
Further reading
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External links
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* {{UCSC gene info, APLN
Proteins