Free fatty acid receptor 1 (FFA1), also known as GPR40, is a class A
G-protein coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
that in humans is encoded by the FFAR1
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 ...
.
It is strongly expressed in the cells of the
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 ...
and to a lesser extent in the brain.
This membrane protein binds free fatty acids, acting as a nutrient sensor for regulating energy homeostasis.
Activation/Inhibition
The protein FFA1 is activated by medium to long chain
fatty acids
In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated and unsaturated compounds#Organic chemistry, saturated or unsaturated. Most naturally occurring fatty acids have an B ...
. FFA1 is most strongly activated by eicosatrienoic acid (20:3
Δ11,14,17), but has been found to be activated by fatty acids as small as 10 carbons long. For saturated fatty acids the level of activation is dependent on the length of the carbon chain, which is not true for unsaturated fatty acids.
It has been found that three hydrophilic residues (
arginine-183,
asparagine
Asparagine (symbol Asn or N) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...
-244, and arginine-258) anchor the
carboxylate
In organic chemistry, a carboxylate is the conjugate base of a carboxylic acid, (or ). It is an ion with negative charge.
Carboxylate salts are salts that have the general formula , where M is a metal and ''n'' is 1, 2,...; ''carboxylat ...
group of a fatty acid, which activates FFA1.
In the pancreas
FFA1 is found in highest concentration in
Islets of Langerhans
The pancreatic islets or islets of Langerhans are the regions of the pancreas that contain its endocrine (hormone-producing) cells, discovered in 1869 by German pathological anatomist Paul Langerhans. The pancreatic islets constitute 1–2% of ...
, the endocrine portion of the pancreas.
Activation of FFA1 results in an increase in cytosolic
Ca2+ via the phosphoinositide pathway.
When a free fatty acid docks on FFA1, the membrane protein becomes activated. This activation causes one of its subunits to dissociate from the receptor, which then activates
phospholipase C (PLC) which is found in the cell membrane. PLC in turn hydrolyzes
phosphatidylinositol 4,5-bisphosphate
Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)''P''2, also known simply as PIP2 or PI(4,5)P2, is a minor phospholipid component of cell membranes. PtdIns(4,5)''P''2 is enriched at the plasma membrane where it is a substrate for a number o ...
(PIP
2),which is also in the membrane, to
diacyl glycerol
A diglyceride, or diacylglycerol (DAG), is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages. Two possible forms exist, 1,2-diacylglycerols and 1,3-diacylglycerols. DAGs can act as su ...
(DAG) which stays in the membrane, and
inositol 1,4,5-triphosphate (IP
3), which enters the cytosol. IP
3 can then dock on a calcium channel in the
endoplasmic reticulum which will facilitate the release of Ca
2+ into the cytosol.
![Phosphoinositide Pathway Diagram](https://upload.wikimedia.org/wikipedia/commons/a/af/Phosphoinositide_Pathway_Diagram.png)
]
The Ca
2+ that is released then initiates a
signal cascade
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a biochemical cascade, series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately re ...
, resulting in the secretion of
insulin.
A high concentration of
glucose
Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, u ...
in the blood has been found to increase the transcription of the FFA1 gene, which has made these receptors a new target for the treatment of
type II diabetes
Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urinatio ...
.
While fatty acids themselves do not elicit insulin secretion, FFA1 activation increases the amount of insulin being secreted through various linked pathways. It has also been shown that chronic exposure to high amounts of free fatty acids, like on a high fat diet, can impair the function and secretory capacity of pancreatic β-cells.
In the brain
As stated previously, FFA1 has an affinity for long chain fatty acids. Such fatty acids are also present in the brain, where FFA1 has also been found in high abundance. FFA1 receptors are present over the entire brain, but in highest numbers in the
medulla oblongata and the
substantia nigra.
Recent studies have also observed that FFA1 was present in the
olfactory bulb
The olfactory bulb (Latin: ''bulbus olfactorius'') is a neural structure of the vertebrate forebrain involved in olfaction, the sense of smell. It sends olfactory information to be further processed in the amygdala, the orbitofrontal cortex ( ...
,
striatum,
hippocampus
The hippocampus (via Latin from Greek , ' seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, ...
,
midbrain
The midbrain or mesencephalon is the forward-most portion of the brainstem and is associated with vision, hearing, motor control, sleep and wakefulness, arousal (alertness), and temperature regulation. The name comes from the Greek ''mesos'', " ...
,
hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
,
cerebellum,
cerebral cortex
The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consistin ...
and in the
spinal cord
The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the sp ...
.
Fatty acids play an important role in normal brain development as well as maintaining proper neuronal function.
It has been found that certain fatty acids that are in abundance in the brain may be linked with FFA1. These fatty acids likely activate FFA1, inducing an intracellular response.
It has been found that
docosahexaenoic acid
Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is a primary structural component of the human brain, cerebral cortex, skin, and retina. In physiological literature, it is given the name 22:6(n-3). It can be synthesized from alpha-lin ...
(DHA) has a higher affinity than other fatty acids for FFA1.
DHA makes up 30% and
arachidonic acid, another fatty acid found in the brain, makes up 20% of the fatty acids in the brain.
Both of these fatty acids must be obtained from the diet because the body cannot make them. A correct balance of these fatty acids is vital to normal brain function and structure.
DHA is supplied to the brain via
astrocytes
Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of endo ...
, which release DHA so that it reaches a high enough concentration to act as an extracellular signal on FFA1.
The abundance of FFA1 in the brain and the high affinity for DHA suggest that FFA1 may play a role in neuronal function in the brain. It is hypothesized that DHA and arachidonic acid could improve memory function by interacting with FFA1 in the hippocampus neurons.
This hypothesis is based on the idea that once FFA1 is activated by these fatty acids, the resulting signal is related to
progenitor cell
A progenitor cell is a biological cell that can differentiate into a specific cell type. Stem cells and progenitor cells have this ability in common. However, stem cells are less specified than progenitor cells. Progenitor cells can only differ ...
proliferation.
This implies that FFA1 signaling could stimulate the production of new memory cells in the brain. More research needs to be done in proving these suggestions, but if proven to be true FFA1 could be a target in producing new memory cells that are destroyed by diseases like
Alzheimer's and
Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
.
Additionally, FFA1 abundance in the brain has been suggested to play a role in pain. DHA has been reported to induce an increased tolerance for pain without binding to
opioid receptors.
Researchers have hypothesized that stimulation of FFA1 by DHA could accelerate the release of
endorphins, which is how DHA could induce an increased tolerance to pain.
DHA binds to FFA1, which could activate a signaling cascade that leads to Ca
2+ influx, which then leads to accelerated endorphin release and novel pain control.
Again, additional research must be done to fully understand the mechanism and to prove these hypotheses, but the implications could provide additional targets for pain control in individuals.
Oral Fat Detection
FFA1(GPR40) has been implicated in the ability to
taste
The gustatory system or sense of taste is the sensory system that is partially responsible for the perception of taste (flavor). Taste is the perception produced or stimulated when a substance in the mouth reacts chemically with taste receptor ...
fats. It is expressed in
taste bud
Taste buds contain the taste receptor cells, which are also known as gustatory cells. The taste receptors are located around the small structures known as papillae found on the upper surface of the tongue, soft palate, upper esophagus, the c ...
cells (specifically cell type I), and its absence leads to reduced preference to two types of fatty acid (
linoleic acid
Linoleic acid (LA) is an organic compound with the formula COOH(CH2)7CH=CHCH2CH=CH(CH2)4CH3. Both alkene groups are ''cis''. It is a fatty acid sometimes denoted 18:2 (n-6) or 18:2 ''cis''-9,12. A linoleate is a salt or ester of this acid.
...
and
oleic acid
Oleic acid is a fatty acid that occurs naturally in various animal and vegetable fats and oils. It is an odorless, colorless oil, although commercial samples may be yellowish. In chemical terms, oleic acid is classified as a monounsaturated omeg ...
), as well as decreased neuronal response to fatty acids administered orally.
Mediator role in pathologic fibrotic pathways
GPR40 was discovered to be a major mediator in pathologic fibrotic pathways in 2018.
Drugs under investigation
FFA1 in Breast Cancer
FFA1 has been found to be expressed in the human
breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a r ...
cell line
MCF-7
MCF-7 is a breast cancer cell line isolated in 1970 from a 69-year-old White woman. MCF-7 is the acronym of Michigan Cancer Foundation-7, referring to the institute in Detroit where the cell line was established in 1973 by Herbert Soule and co-wor ...
. An increase in
2+">a2+ which is a consequence of FFA1 activation, has been shown to modulate processes required for breast cancer cell proliferation. This suggests that FFA1 plays a crucial role in breast cancer proliferation. To further demonstrate this connection,
pertussis toxin
Pertussis toxin (PT) is a protein-based AB5-type exotoxin produced by the bacterium ''Bordetella pertussis'', which causes whooping cough. PT is involved in the colonization of the respiratory tract and the establishment of infection. Rese ...
, which is a very specific inhibitor of GPCRs like FFA1, was found to diminish cancer cell proliferation. Also, using a PLC inhibitor diminished proliferation.
See also
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Free fatty acid receptor
References
Further reading
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{{DEFAULTSORT:Free Fatty Acid Receptor 1
G protein-coupled receptors