GPR120
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Free Fatty acid receptor 4 (FFAR4), also termed G-protein coupled receptor 120 (GPR120), is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that in humans is encoded (i.e., its formation is directed) by the ''FFAR4''
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
. This gene is located on the long (i.e. "q") arm of chromosome 10 at position 23.33 (position notated as 10q23.33).
G protein-coupled receptors 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 protein family, group of evoluti ...
(also termed GPRs or GPCRs) reside on their parent cells' surface membranes, bind any one of the specific set of
ligand In coordination chemistry, a ligand is an ion or molecule with a 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 el ...
s that they recognize, and thereby are activated to trigger certain responses in their parent cells. FFAR4 is a rhodopsin-like GPR in the broad family of GPRs which in humans are encoded by more than 800 different genes. It is also a member of a small family of structurally and functionally related GPRs that include at least three other
free fatty acid receptor Free fatty acid receptors (FFARs) are G-protein coupled receptors (GPRs). GPRs (also termed seven-(pass)-transmembrane domain receptors) are a large family of receptors. They reside on their parent cells' surface membranes, bind any one o ...
s (FFARs) ''viz.,''
FFAR1 Free fatty acid receptor 1 (FFAR1), also known as G-protein coupled receptor 40 (GPR40), is a rhodopsin-like G-protein coupled receptor that is coded (i.e., its synthesis is directed) by the ''FFAR1'' gene. This gene is located on the short (i.e ...
(also termed GPR40),
FFAR2 Free fatty acid receptor 2 (FFAR2), also known as G-protein coupled receptor 43 (GPR43), is a Rhodopsin-like receptor, rhodopsin-like G-protein coupled receptor (GPCR) encoded by the ''FFAR2'' gene. In humans, the ''FFAR2'' gene is located on the ...
(also termed GPR43), and
FFAR3 Free fatty acid receptor 3 (FFAR3, also termed GPR41) protein is a G protein coupled receptor (i.e., GPR or GPCR) that in humans is encoded by the ''FFAR3'' gene (i.e., ''GPR41'' gene). GPRs reside on cell surfaces, bind specific signaling molecu ...
(also termed GPR41). These four FFARs bind and thereby are activated by certain
fatty acids In chemistry, in particular in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...
. FFAR4 protein is expressed in a wide range of cell types. Studies conducted primarily on human and rodent cultured cells and in animals (mostly rodents) suggest that FFAR4 acts in these cells to regulate many normal bodily functions such as food preferences, food consumption, food tastes, body weight, blood sugar (i.e., glucose) levels,
inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
,
atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...
, and
bone remodeling 300 px, Bone tissue is removed by osteoclasts, and then new bone tissue is formed by osteoblasts. Both processes utilize cytokine ( Insulin-like_growth_factor.html" ;"title="TGF-β, Insulin-like growth factor">IGF) signalling. In osteology, bone ...
. Studies also suggest that the stimulation or suppression of FFAR4 alters the development and progression of several types of cancers. In consequence, agents that activate or inhibit FFAR4 may be useful for treating excessive fatty food consumption, obesity,
type 2 diabetes Type 2 diabetes (T2D), 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 ...
, pathological inflammatory reactions, atherosclerosis, atherosclerosis-induced
cardiovascular disease Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina, heart attack), heart failure, hypertensive heart disease, rheumati ...
, repair of damaged bones,
osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in Bone fracture, fracture risk. It is the most common reason f ...
. and some cancers. These findings have made FFAR4 a potentially attractive therapeutic
biological target A biological target is anything within a living organism to which some other entity (like an endogenous ligand or a drug) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets ...
for treating these disorders and therefore lead to the development of drugs directed at regulating FFAR4's activities. Certain
fatty acids In chemistry, in particular in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...
, including in particular the
omega-3 fatty acid Omega−3 fatty acids, also called omega−3 oils, ω−3 fatty acids or ''n''−3 fatty acids, are polyunsaturated fatty acids (PUFAs) characterized by the presence of a double bond three atoms away from the terminal methyl group in their ...
s, docosahexaenoic and
eicosapentaenoic acid Eicosapentaenoic acid (EPA; also icosapentaenoic acid) is an omega−3 fatty acid. In physiological literature, it is given the name 20:5(''n''−3). It also has the trivial name timnodonic acid. In chemical structure, EPA is a carboxylic acid wi ...
s, have been taken in
diets The Low Countries comprise the coastal Rhine–Meuse–Scheldt delta region in Western Europe, whose definition usually includes the modern countries of Luxembourg, Belgium, the Netherlands and parts of Northern France. Both Belgium and the ...
and supplements to prevent or treat the
diseases A disease is a particular abnormal condition that adversely affects the structure or function of all or part of an organism and is not immediately due to any external injury. Diseases are often known to be medical conditions that are asso ...
and tissue
injuries Injury is physiological damage to the living tissue of any organism, whether in humans, in other animals, or in plants. Injuries can be caused in many ways, including mechanically with penetration by sharp objects such as teeth or with b ...
that recent studies suggest are associated with abnormalities in FFAR4's functions. It is now known that these fatty acids activate FFAR4. While dietary and supplemental omega-3 fatty acids have had little or only marginal therapeutic effects on these disorders (see health effects of omega-3 fatty acid supplementation), many drugs have been found that are more potent and selective in activating FFAR4 than the omega-3 fatty acids and one drug is a potent inhibitor of FFAR4. This raised a possibility that the drugs may be more effective in treating these disorders and prompted initial studies testing the effectiveness of them in disorders targeted by the omega-3 fatty acids. These studies, which are mostly preclinical studies on cultured cells or animal models of disease with only a few preliminary
clinical studies Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...
, are reviewed here.


FFAR genes

The genes for FFAR1, FFAR2, and FFAR3 are located close to each other on the short (i.e., "p") arm of
chromosome 19 Chromosome 19 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 19 spans more than 61.7 million base pairs, the building material of DNA. It is considered the most Gene density, gene-ri ...
at position 13.12 (location notated as 19p13.12); the ''FFAR4'' gene is located on the "q" (i.e., long) arm of
chromosome 10 Chromosome 10 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 10 spans about 134 million base pairs (the building material of DNA) and represents between 4 and 4.5 percent of the tota ...
at position 23.33 (location notated as 10q23.33). Humans express a long FFAR4
protein isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...
consisting of 377
amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the Proteinogenic amino acid, 22 α-amino acids incorporated into p ...
and a short
splice variant Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene may be included ...
protein isoform consisting of 361 amino acids. However, rodents, non-human primates, and other studied animals express only the short protein. The two
isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...
operate through different cell-stimulating pathways to elicit different responses. Furthermore, humans express the long FFAR4 protein only in their colon and colon cancer tissues. The consequences of these differences for the studies reported here have not been determined.


Activators and inhibitors of the free fatty acid receptors

FFARs are activated by certain straight-chain fatty acids. FFAR2 and FFAR3 are activated by short-chain fatty acids, i.e., fatty acid chains consisting of 2 to 5 carbon atoms, mainly acetic, butyric, and
propionic acid Propionic acid (, from the Greek language, Greek words πρῶτος : ''prōtos'', meaning "first", and πίων : ''píōn'', meaning "fat"; also known as propanoic acid) is a naturally occurring carboxylic acid with chemical formula . It is a ...
s. FFAR1 and FFAR4 are activated by 1) medium-chain fatty acids i.e., fatty acids consisting of 6-12 carbon atoms such as capric and
lauric acid Lauric acid, systematically dodecanoic acid, is a saturated fatty acid with a 12-carbon atom chain, thus having many properties of Medium-chain triglyceride, medium-chain fatty acids. It is a bright white, powdery solid with a faint odor of Piment ...
s; 2) long-chain
unsaturated fatty acid In chemistry, in particular in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...
s consisting of 13 to 21 carbon atoms such as myristic and steric acids; 3) monounsaturated fatty acids such as oleic and palmitoleic acids; and 4)
polyunsaturated fatty acids In biochemistry and nutrition, a polyunsaturated fat is a fat that contains a polyunsaturated fatty acid (abbreviated PUFA), which is a subclass of fatty acid characterized by a backbone with two or more carbon–carbon double bonds. Some polyunsa ...
such as the omega-3 fatty acids alpha-linolenic, eicosatrienoic, eicosapentaenoic, and
docosahexaenoic acid Docosahexaenoic acid (DHA) is an omega−3 fatty acid that is an important component of the human brain, cerebral cortex, skin, and retina. It is given the fatty acid notation 22:6(''n''−3). It can be synthesized from alpha-linolenic acid or ...
s or omega-6 fatty acids such as linoleic, gamma-linolenic, dihomo-gamma-linolenic, arachidonic, and
docosatetraenoic acid Docosatetraenoic acid designates any straight chain 22:4 fatty acid. (''See'' Essential fatty acid for nomenclature.) One isomer is of particular interest: * all-''cis''-7,10,13,16-docosatetraenoic acid is an ω-6 fatty acid with the common nam ...
s. Docosahexaenoic and eicosapentaenoic acid are commonly regarded as the main dietary fatty acids that activate FFAR4. Since all of the FFAR1- and FFAR4-activating fatty acids have similar potencies in activating FFAR4 and FFAR1 and have FAR-independent means of influencing cells, it can be difficult to determine if their actions involve FFAR4, FFAR1, both FFARs, or FFAR-independent mechanisms. The drugs which stimulate (i.e., are
agonists 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 agon ...
of) FFAR4 include: GW9508 (the first discovered and most studied FFAR agonist is about 60-fold more potent in activating FFAR1 than FFAR4; it is often used to implicate FFAR4 functions in cells that naturally or after manipulation express no or very low FFAR1 levels); TUG-891 (almost 300-fold more potent in activating FFAR4 than FFAR1 in human cells but only modestly more potent on FFAR4 than FFAR1 in mouse cells); TUG-1197 (activates FFAR4 but not FFAR1); metabolex 36 (about 100-fold more potent in activating FFAR4 than FFAR1); GSK137647A (about 50-fold more potent in activating FFAR4 than FFAR1); compound A ( Merck & Co.) and compound B (CymaBay Therapeutics) (both potently activate FFAR4 with negligible effects on FFAR1); and GPR120 III (2,000-fold more active on FFAR4 than FFAR1). AH-7614 acts as a negative
allosteric modulator In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimuli. Some of them, like benzodiazepines or alcohol, function as psychoactive drugs. The site that a ...
to inhibit FFAR4; it is >100-fold more potent in inhibiting FFAR4 than FFAR1 and the only currently available FFAR4
antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain. Most of the studies reported to date have examined the effects of two FFAR4 agonists, GW9508 and TUG-891, that have been available far longer than the other listed drugs.


Cells and tissues expressing FFAR4

FFAR4 is expressed in a wide variety of tissues and cell types but its highest levels of expression are in certain intestinal cells (i.e., enteroendocrine K and I cells), taste bud cells,
fat cells Adipocytes, also known as lipocytes and fat cells, are the cell (biology), 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 ...
,
respiratory epithelium Respiratory epithelium, or airway epithelium, is ciliated pseudostratified columnar epithelium a type of columnar epithelium found lining most of the respiratory tract as respiratory mucosa, where it serves to moisten and protect the airways ...
cells in the lung (i.e., club cells also termed clara cells), and
macrophages Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
. It is less strongly expressed in other cell types including: various immune cells besides macrophages, cells in brain, heart, and liver tissues,
skeletal muscle Skeletal muscle (commonly referred to as muscle) is one of the three types of vertebrate muscle tissue, the others being cardiac muscle and smooth muscle. They are part of the somatic nervous system, voluntary muscular system and typically are a ...
cells, blood vessel
endothelial cells The endothelium (: endothelia) 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 res ...
, enteroendocrine L cells of the
gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the Digestion, digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascula ...
, delta cells in the islets of the pancreas, cells involved in bone development and remodeling, some cells in the
arcuate nucleus The arcuate nucleus of the hypothalamus (ARH), or ARC, is also known as the infundibular nucleus to distinguish it from the arcuate nucleus of the medulla oblongata in the brainstem. The arcuate nucleus is an aggregation of neurons in the medio ...
and
nucleus accumbens The nucleus accumbens (NAc or NAcc; also known as the accumbens nucleus, or formerly as the ''nucleus accumbens septi'', Latin for ' nucleus adjacent to the septum') is a region in the basal forebrain rostral to the preoptic area of the hypo ...
of the
hypothalamus The hypothalamus (: hypothalami; ) is a small part of the vertebrate brain that contains a number of nucleus (neuroanatomy), nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrin ...
, and in some types of cancer cells. However, in comparing animal to human studies the cells and tissues that express FFAR4 can differ and many of these studies have measured FFAR4
messenger RNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the ...
(mRNA) but not the product directed to be made by this mRNA, FFRA4 protein. The significance of these issues requires study.


FFAR4 functions and activities


Fat tissue development and thermogenesis

The two forms of
fat cells Adipocytes, also known as lipocytes and fat cells, are the cell (biology), 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 ...
, i.e.,
white White is the lightest color and is achromatic (having no chroma). It is the color of objects such as snow, chalk, and milk, and is the opposite of black. White objects fully (or almost fully) reflect and scatter all the visible wa ...
and brown fat cells, develop from precursor
stem cells In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can change into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of cell ...
. Brown fat cells promote
thermogenesis Thermogenesis is the process of heat production in organisms. It occurs in all warm-blooded animals, and also in a few species of thermogenic plants such as the Eastern skunk cabbage, the Voodoo lily ('' Sauromatum venosum''), and the giant w ...
, i.e., the generation of body heat. Studies have reported that: 1) FFAR4 levels rose in the fat tissues of mice exposed to cold; 2) TUG‐891 and GW9508 stimulated 3T3-L1 mouse stem-like cells to mature into fat cells; 3) mice lacking a functional ''ffar4'' gene (i.e., ''ffar4''
knockout A knockout (abbreviated to KO or K.O.) is a fight-ending, winning criterion in several full-contact combat sports, such as boxing, kickboxing, Muay Thai, mixed martial arts, karate, some forms of taekwondo and other sports involving striking, ...
mice; ''ffar4'' is the term for the mouse equivalent to the human ''FFAR4'' gene) had fewer brown fat cells in their subcutaneous adipose (i.e. fat) tissues in response to cold exposure, were cold intolerant, and had poor survival rates in cold temperatures; 4) GW9508 stimulated increases in the brown fat tissue of normal mice; however, in ''ffar4'' gene knockout mice it simulated
histology Histology, also known as microscopic anatomy or microanatomy, is the branch of biology that studies the microscopic anatomy of biological tissue (biology), tissues. Histology is the microscopic counterpart to gross anatomy, which looks at large ...
, i.e., microscopic, changes in fat tissue suggesting that thermogenesis was impaired; 5) TUG-891 stimulated cultured mouse fat cells to oxidize fatty acids (this oxidation underlies the development of body heat in the non-shivering form of thermogenesis); and 6) FFAR1 has not yet been reported to be expressed in the fat tissue of mice or humans. These studies suggest that FFAR4 contributes to the proliferation of brown fat cells and thermogenesis in mice. Studies are needed to determine if FFAR4 has a similar role in humans.


Obesity

Two rodent studies suggested that FFAR4 functions to limit excessive weight gains: FFAR4 deficient mice developed obesity and mice treated with the FFAR4 agonist, TUG-891, lost fat tissue. FFAR4 might play a similar obesity-suppressing role in humans. One study found that FFAR4 mRNA and protein levels were lower in the visceral fat tissues (i.e., fat around internal organs) of obese than lean individuals. However, another study found that the expression of FFAR4 mRNA was higher in the subcutaneous and omental fat tissues of obese than lean individuals. Similarly, one study reported that Europeans who carried a
single-nucleotide variant In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in ...
of the ''FFAR4'' gene which encoded a dysfunctional FFAR4 protein (it has the
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidinium, guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) a ...
rather than
histidine Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an Amine, α-amino group (which is in the protonated –NH3+ form under Physiological condition, biological conditions), a carboxylic ...
at position 270 and is notated as p.R270H) increased the risk of becoming obese. However, this relation was not found in later studies on Danish and European populations. It is possible that the loss of FFAR4 expression or activity may contribute to but by itself is insufficient to promote obesity. Other studies have implicated activated FFAR1 in having anti-obese effects in cultured cells, animal models, and possibly humans (see FFAR1 and obesity). For example, ''Ffar1'' gene knockout mice (i.e., mice made to lack ''Ffar1'' genes) became obese when fed a low-fat diet while control mice became obese only when fed a high-fat diet.


Type 2 diabetes

The following studies suggest that FFAR4 regulates blood glucose levels and that FFAR4 agonists may be useful for treating individuals with
type 2 diabetes Type 2 diabetes (T2D), 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 ...
. 1) The FFAR4 agonist GSK137647 and docosahexaenoic acid stimulated the release of insulin from cultured mouse and rat
pancreatic islets 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% o ...
(sites of insulin production and storage) and improved post-feeding
hyperglycemia Hyperglycemia is a condition where unusually high amount of glucose is present in blood. It is defined as blood glucose level exceeding 6.9 mmol/L (125 mg/dL) after fasting for 8 hours or 10 mmol/L (180 mg/dL) 2 hours after eating. Blood gluc ...
in diabetic mice. 2) The FFAR1 agonist TUG-891 stimulated cultured mouse fat cells to take up glucose and lowered fasting and post-feeding blood glucose levels in diabetic rats; it also stimulated insulin secretion and lowered blood glucose levels in mice. 3) FFAR1 agonist compound A (Merck & Co.) and, with greater efficacy, a dual agonist of FFAR1 and FFAR4, DFL23916, improved blood insulin and glucose levels in mice challenged with a glucose tolerance test. 4) Fatty acid activators of FFAR4 promoted the release of
glucagon-like peptide-1 Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino-acid-long peptide hormone deriving from tissue-specific posttranslational processing of the proglucagon peptide. It is produced and secreted by intestinal enteroendocrine L-cells and cer ...
and gastric inhibitory peptide (both stimulate insulin secretion) and reduced secretion of
ghrelin Ghrelin (; or lenomorelin, INN) is a hormone primarily produced by enteroendocrine cells of the gastrointestinal tract, especially the stomach, and is often called a "hunger hormone" because it increases the drive to eat. Blood levels of ghrel ...
(which stimulates the drive to eat) in mice. 5)
Downregulation In biochemistry, in the biology, biological context of organisms' regulation of gene expression and production of gene products, downregulation is the process by which a cell (biology), cell decreases the production and quantities of its cellular ...
(i.e., forced reduction in the cellular levels) of FFAR4 impaired insulin's actions by reducing the levels of the glucose transporter GLUT4 and insulin receptor substrate in 3T3-L1 mouse fat cells. 6) FFAR4-deficient mice developed glucose intolerance (a potential form of prediabetes) when fed a high fat diet. 7) A diet rich in omega-3 fatty acids improved insulin sensitivity and glucose uptake in muscle and liver tissues in normal but not FFAR4-deficient mice. 8) FFAR4 levels in pancreas islets are higher in individuals with higher insulin and lower
HbA1c Glycated hemoglobin, also called glycohemoglobin, is a form of hemoglobin (Hb) that is chemically linked to a sugar. Most monosaccharides, including glucose, galactose, and fructose, spontaneously (that is, non-enzymatically) bond with hemoglob ...
levels (HbA1c levels rise with higher blood glucose levels averaged over the preceding 3 months). And, 9) individuals who carried the ''FFAR4'' gene variant, p.R270H, (codes a hypoactive FFAR4) who regularly consumed low-fat diets had an increased incidence of developing
type 2 diabetes Type 2 diabetes (T2D), 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 ...
; this association did not occur in p.R270H carriers who regularly consumed high-fat diets. In a phase II clinical trial (NCT02444910 https://www.clinicaltrials.gov), nine adults with previously untreated insulin-resistant type 2 diabetes were treated orally with increasing doses of KDT501 (an isohumulone derivative that is a relative weak FFAR4 activator and
partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...
of
PPARγ Peroxisome proliferator-activated receptor gamma (PPAR-γ or PPARG), also known as the glitazone reverse insulin resistance receptor, or NR1C3 (nuclear receptor subfamily 1, group C, member 3) is a type II nuclear receptor functioning as a transc ...
) for up to 29 days. After treatment, the participants had significantly lower
blood plasma Blood plasma is a light Amber (color), amber-colored liquid component of blood in which blood cells are absent, but which contains Blood protein, proteins and other constituents of whole blood in Suspension (chemistry), suspension. It makes up ...
triglyceride A triglyceride (from '' tri-'' and '' glyceride''; also TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids. Triglycerides are the main constituents of body fat in humans and other vertebrates ...
and
TNF-α Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...
levels and higher levels of adiponectin, a regulator of blood glucose levels. However, there were no significant changes in these individuals' oral glucose tolerance test results or measurements of insulin sensitivity. Further studies including the usage of more potent and selectively acting FFAR4 agonists are needed to determine their effectiveness in regulating blood glucose levels and treating type 2 diabetes. Two separate studies have reported that the selective FFAR1 agonists MK‐8666 and TAK-875 greatly improved blood glucose levels in type 2 diabetic patients but also appeared to cause unacceptable liver damage (see FFAR1 and type 2 diabetes). These studies have been regarded as proof that FFAR1 contributes to regulating glucose levels in patients with type 2 diabetes and therefore is a target for treating these patients with FFAR1 agonists that do not have significant
adverse effects An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. The term complic ...
such as
hepatotoxicity Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury (DILI) is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdr ...
. Recent preclinical studies are examining other FFAR1 agonists for their liver and other toxicities.


Taste

Human and rodent
taste buds Taste buds are clusters of 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, th ...
and other areas of their tongues contain cells that express taste receptors which detect the five taste perception elements viz.,
saltiness The gustatory system or sense of taste is the sensory system that is partially responsible for the perception of taste. Taste is the perception stimulated when a substance in the mouth biochemistry, reacts chemically with taste receptor cells l ...
,
sourness The gustatory system or sense of taste is the sensory system that is partially responsible for the perception of taste. Taste is the perception stimulated when a substance in the mouth reacts chemically with taste receptor cells located on t ...
, bitterness,
sweetness Sweetness is a basic taste most commonly perceived when eating foods rich in sugars. Sweet tastes are generally regarded as pleasurable. In addition to sugars like sucrose, many other chemical compounds are sweet, including aldehydes, ketones ...
, and
umami Umami ( from ), or savoriness, is one of the five basic tastes. It is characteristic of broths and cooked meats. People taste umami through taste receptors that typically respond to glutamates and nucleotides, which are widely present in me ...
. One well-studied site that has these receptor-bearing cells is in the mouse and human taste buds of their tongues' circumvallate papillae. TUG-891 stimulated cultured mouse and human taste bud cells to mobilize several cell activation pathways. Furthermore: 1) application of TUG-891 to the tongues of mice caused alterations in their blood levels of
cholecystokinin Cholecystokinin (CCK or CCK-PZ; from Greek ''chole'', "bile"; ''cysto'', "sac"; ''kinin'', "move"; hence, ''move the bile-sac (gallbladder)'') is a peptide hormone of the gastrointestinal system responsible for stimulating the digestion of fat a ...
(one of its functions is to mediate
satiety Satiety ( /səˈtaɪ.ə.ti/ ''sə-TYE-ə-tee'') is a state or condition of fullness gratified beyond the point of satisfaction, the opposite of hunger. Following satiation (meal termination), satiety is a feeling of fullness lasting until the next ...
) and
adipokine The adipokines, or adipocytokines (Greek ', fat; ', cell; and ', movement) are cytokines (cell signaling proteins) secreted by adipose tissue. Some contribute to an obesity-related low-grade state of inflammation or to the development of metabolic ...
s (i.e., signaling proteins secreted by fat tissues); 2) dietary fatty acids that activate FFAR4 altered the taste of and preferences for fats in rats; 3) FFAR4-deficient mice were less likely to consume fatty meals; 4) the injection of the FFAR4 agonist GPR120 III into the arcuate nucleus and nucleus accumbens brain areas of mice reduced their food intake and suppressed the rewarding effects of high-fat and high-sugar foods; and 5) TUG-891 enhanced humans' fatty orosensation (i.e., false sensation of taste obtained by tongue stimulation) when added to FFAR4-activating dietary fats but not when added to fat-free mineral oil. The latter finding suggests that in humans FFAR4 agonists enhance the sensation of fats but by themselves do not directly evoke it. However, one study found that mice with non-functional ''Ffra4'' genes retained their preferences for oily solutions and long chain fatty acids. Follow-up studies are essential to confirm the functional roles of FFAR4 in taste perceptions and preferences.


Inflammation

FFAR4 is expressed by a variety of cell types involved in
inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
such as
macrophages Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
,
dendritic cells A dendritic cell (DC) is an antigen-presenting cell (also known as an ''accessory cell'') of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system ...
,
eosinophils Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. Along wi ...
,
neutrophils Neutrophils are a type of phagocytic white blood cell and part of innate immunity. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in different ...
, and
T cells T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their ce ...
. FFAR4 activators inhibited: human eosinophils from secreting a pro-inflammatory
cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
,
interleukin 4 The interleukin 4 (IL4, IL-4) is a cytokine that induces differentiation of naive helper T cells ( Th0 cells) to Th2 cells. Upon activation by IL-4, Th2 cells subsequently produce additional IL-4 in a positive feedback loop. IL-4 ...
; mouse RAW 264.7 and
peritoneal The peritoneum is the serous membrane forming the lining of the abdominal cavity or coelom in amniotes and some invertebrates, such as annelids. It covers most of the intra-abdominal (or coelomic) organs, and is composed of a layer of mesotheli ...
macrophages from secreting the pro-inflammatory cytokines
tumor necrosis factor-α Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors ...
(i.e., TNF-α) and interleukin-6; bone marrow-derived mouse dendritic cells from secreting the pro-inflammatory cytokines monocyte chemoattractant protein 1, TNF-α, interleukin 6, interleukin-12 subunit alpha, and
interleukin-12 subunit beta Subunit beta of interleukin 12 (also known as IL-12B, natural killer cell stimulatory factor 2, cytotoxic lymphocyte maturation factor p40, or interleukin-12 subunit p40) is a protein subunit that in humans is encoded by the IL12B gene. IL-12B is ...
; and mouse helper and
cytotoxic T cell A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular ...
s from releasing the pro-inflammatory cytokines interferon gamma, interleukin 17,
interleukin-2 Interleukin-2 (IL-2) is an interleukin, which is a type of cytokine signaling molecule forming part of the immune system. It is a 15.5–16  kDa protein that regulates the activities of white blood cells (leukocytes, often lymphocytes) ...
, and TNF-α. These findings suggest that FFAR4 acts to suppress inflammation, a view supported by the following studies. FFAR4-deficient mice have increased levels of inflammation in their fat tissues. Furthermore, FFAR4 agonist drugs and/or omega-3 fatty acids reduced: 1) the chronic inflammation that develops in the fat and liver tissues of db/db mice; 2)
cyclophosphamide Cyclophosphamide (CP), also known as cytophosphane among other names, is a medication used as chemotherapy and to suppress the immune system. As chemotherapy it is used to treat lymphoma, multiple myeloma, leukemia, ovarian cancer, breast cancer ...
-induced
interstitial cystitis Interstitial cystitis (IC), a type of bladder pain syndrome (BPS), is chronic pain in the Urinary bladder, bladder and pelvic floor of unknown cause. Symptoms include urinary urgency, feeling the need to urinate right away, urinary frequency, ...
(i.e., urinary bladder inflammation) in rats; 3) the liver inflammation which follows transient blockage of its blood supply in mice; 4) chronic
sleep deprivation Sleep deprivation, also known as sleep insufficiency or sleeplessness, is the condition of not having adequate duration and/or quality of sleep to support decent alertness, performance, and health. It can be either Chronic (medicine), chronic ...
-induced inflammation of visceral fat tissues in mice; 5) diet-induced inflammation in the
islets An islet ( ) is generally a small island. Definitions vary, and are not precise, but some suggest that an islet is a very small, often unnamed, island with little or no vegetation to support human habitation. It may be made of rock, sand and ...
of the
pancreas The pancreas (plural pancreases, or pancreata) is an Organ (anatomy), organ of the Digestion, digestive system and endocrine system of vertebrates. In humans, it is located in the abdominal cavity, abdomen behind the stomach and functions as a ...
in mice (this reduction did not occur in mice lacking a functional ''FFAR4'' gene); 6) 2,4-dinitrochlorobenzene-induced mouse
contact dermatitis Contact dermatitis is a type of acute or chronic inflammation of the skin caused by exposure to chemical or physical agents. Symptoms of contact dermatitis can include itchy or dry skin, a red rash, bumps, blisters, or swelling. These rashes ...
(this reduction did not occur in ''FFAR4'' gene-deficient mice); 7) dextran sodium sulfate-induced
colitis Colitis is swelling or inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and ...
in mice; and 8) brain inflammation due to the reduction of blood flow to the brains of mice caused by experimentally induced
cerebral infarction Cerebral infarction, also known as an ischemic stroke, is the pathologic process that results in an area of necrotic tissue in the brain (cerebral infarct). In mid to high income countries, a stroke is the main reason for disability among peo ...
. The short-term (i.e., less than 29 days) phase II clinical trial (NCT02444910 https://www.clinicaltrials.gov) found that nine diabetic adults treated with the FFAR4 agonist KDT501 developed higher plasma levels of adiponectin. Biopsied specimens of these individual's subcutaneous fat tissues obtained up to 3 days after the end of KDT501 treatment released greater amounts of adiponectin than biopsies obtained before KDT501 treatment. Adiponectin has various anti-inflammatory actions.


Atherosclerosis and cardiovascular disease

Arterial An artery () is a blood vessel in humans and most other animals that takes oxygenated blood away from the heart in the systemic circulation to one or more parts of the body. Exceptions that carry deoxygenated blood are the pulmonary arteries in ...
atherosclerosis is initiated by damage to these blood vessels'
endothelial The endothelium (: endothelia) 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 res ...
cells, i.e., their single layers of cells which face the blood. This damage opens a passage for circulating low-density lipoproteins to enter the vessel and move to its innermost layer, the
tunica intima The tunica intima (Neo-Latin "inner coat"), or intima for short, is the innermost tunica (biology), tunica (layer) of an artery or vein. It is made up of one layer of endothelium, endothelial cells (and macrophages in areas of disturbed blood flo ...
, where they are metabolized to oxidized low-density lipoproteins (i.e., oxLDL). Circulating
monocytes Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and monocyte-derived dendritic cells. As a part of the vertebrate innate immune system monocytes also i ...
attach to the damaged endothelium, move to the tunica intima, ingest the oxLDL, and differentiate into M1 macrophages, i.e., macrophages that promote inflammation. These M1 cells continue to ingest oxLDL and may eventually become
cholesterol Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils. Cholesterol is biosynthesis, biosynthesized by all anima ...
-laden foam cells that promote the development of
atheromatous plaque An atheroma, or atheromatous plaque, is an abnormal accumulation of material in the inner layer of an arterial wall. The material consists of mostly macrophage cells, or debris, containing lipids, calcium and a variable amount of fibrous conne ...
s, i.e., hardened accumulations of macrophages, lipids, calcium, and fibrous
connective tissue Connective tissue is one of the four primary types of animal tissue, a group of cells that are similar in structure, along with epithelial tissue, muscle tissue, and nervous tissue. It develops mostly from the mesenchyme, derived from the mesod ...
. Over time, the plaques may grow to sizes that narrow or occlude the arteries in which they reside to cause
peripheral artery disease Peripheral artery disease (PAD) is a vascular disorder that causes abnormal narrowing of arteries other than those that supply the heart or brain. PAD can happen in any blood vessel, but it is more common in the legs than the arms. When narr ...
,
hypertension Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...
,
coronary artery disease Coronary artery disease (CAD), also called coronary heart disease (CHD), or ischemic heart disease (IHD), is a type of cardiovascular disease, heart disease involving Ischemia, the reduction of blood flow to the cardiac muscle due to a build-up ...
s, and heart damage. The following studies suggest that the suppression of vascular inflammation by FFAR4 agonists reduces the development of atherosclerosis and its associated disorders. 1) The FFAR1/FFAR4 activating drug, GW9508, stimulated cultured human THP-1 macrophage foam cells and RAW264.7 mouse macrophages to secrete their cholesterol and reduce their levels of
cholesteryl ester 300px, Cholesteryl oleate, a member of the cholesteryl ester family Cholesteryl esters are a type of dietary lipid and are ester derivatives of cholesterol. The ester bond is formed between the carboxylate group of a fatty acid and the hydroxyl g ...
s. 2) In cell cultures, GW9508 and TUG-891 inhibited THP-1 monocytes from attaching to human aortic endothelial cells. 3) Long-term administration of GW9508 or TUG-891 to APOE−/− mice (these mice develop atherosclerosis due to lack of the
apolipoprotein E Apolipoprotein E (Apo-E) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in Alzheimer's disease and cardiovascular diseases. It is encoded in humans by the gene ''APOE''. Apo-E belongs to a family ...
gene) converted M1 macrophages to inflammation-suppressing M2-macrophages and resulted in less vascular inflammation and smaller atherosclerotic plaques (TUG-891's actions were reversed by the FFAR4 antagonist, AH-7614). 4) Following constriction of their aortas (using an experimental procedure termed transverse aortic constriction which forces the heart to beat against excessively high blood pressures), the hearts of FFAR4-deficient male but not female mice had pathologically thickened ventricle walls which contracted dysfunctionally compared to mice with normal FFAR4 levels. 5) Cardiac tissue FFAR4 levels were lower in humans with
congestive heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to fill with and pump blood. Although symptoms vary based on which side of the heart is affected, HF typically pr ...
. And, 6) compared to women, men carrying the defective p.R270H ''FFAR4'' gene had several cardiac abnormalities including larger
left ventricle A ventricle is one of two large chambers located toward the bottom of the heart that collect and expel blood towards the peripheral beds within the body and lungs. The blood pumped by a ventricle is supplied by an atrium, an adjacent chamber in t ...
masses, larger left ventricle diameters as measured at the end of
diastole Diastole ( ) is the relaxed phase of the cardiac cycle when the chambers of the heart are refilling with blood. The contrasting phase is systole when the heart chambers are contracting. Atrial diastole is the relaxing of the atria, and ventricul ...
, increased maximum left cardiac atrium sizes, and a trend toward somewhat lower minimum cardiac
ejection fraction An ejection fraction (EF) is the volumetric fraction (or portion of the total) of fluid (usually blood) ejected from a chamber (usually the heart) with each contraction (or heartbeat). It can refer to the cardiac atrium, cardiac ventricle, gall ...
s. Many but not all clinical trials have found that dietary regimens enriched with eicosapentaenoic and docosahexaenoic acids lower the risk of coronary artery heart disease,
congestive heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to fill with and pump blood. Although symptoms vary based on which side of the heart is affected, HF typically pr ...
, and sudden death due to cardiac disease. Further studies are needed to determine if the therapeutic effects of omega-3 fatty acids in mice and humans involve FFAR4 activation and if potent, selectively acting FFAR4 drugs are more effective than omega-3 fatty acids in preventing and/or treating these and the other cited atherosclerosis-associated disorders.


Cancer

FFAR4 has been detected in various types of cultured human cancer cells and found to promote or inhibit their proliferation,
migration Migration, migratory, or migrate may refer to: Human migration * Human migration, physical movement by humans from one region to another ** International migration, when peoples cross state boundaries and stay in the host state for some minimum le ...
, survival, and/or resistance to anti-cancer drugs. The direction of their effects depended on the type of cancer cell and response examined. Studies have reported that: 1) GW9508 (which activates FFAR1 but at higher concentrations also activates FFAR4) stimulated migration of human SW480 and HCT116 colon cancer cells (since neither
cell line An immortalised cell line is a population of cells from a multicellular organism that would normally not proliferate indefinitely but, due to mutation, have evaded normal cellular senescence and instead can keep undergoing division. The cells ...
expressed FFRA1, GW9508 appeared to stimulate this migration by activating FFAR4); 2) GW9508 inhibited the migration and proliferation of human A375 and G361
melanoma Melanoma is the most dangerous type of skin cancer; it develops from the melanin-producing cells known as melanocytes. It typically occurs in the skin, but may rarely occur in the mouth, intestines, or eye (uveal melanoma). In very rare case ...
cells but was less effective on ''FFAR4'' knockdown A375 cells (i.e. cells that have been forced to express low levels of FFAR4; this result suggests that GW5098 acted through both FFAR4 and FFAR1 in these two melanoma cell types); 3) GW9508 stimulated the migration and invasiveness of human MG-63 bone
osteosarcoma An osteosarcoma (OS) or osteogenic sarcoma (OGS) is a cancerous tumor in a bone. Specifically, it is an aggressive malignant neoplasm that arises from primitive transformed cells of mesenchyme, mesenchymal origin (and thus a sarcoma) and that exhi ...
cells but this stimulation did not occur in ''FFAR4'' gene knockdown cells and therefore appeared to involve FFAR4 activation; 4) the FFAR4 agonist TUG-891 reduced the ability of docosahexaenoic and eicosapentaenoic acids to stimulate the proliferation of human DU145 and PC-3 prostate cancer cells (this result suggests that activated FFAR1 inhibited these cells proliferation); and 5) the effects of ''FFAR4'' and ''FFAR1'' gene knockdowns and TUG-891 treatment in PANC-1 human
pancreas The pancreas (plural pancreases, or pancreata) is an Organ (anatomy), organ of the Digestion, digestive system and endocrine system of vertebrates. In humans, it is located in the abdominal cavity, abdomen behind the stomach and functions as a ...
cancer cells suggested that FFAR4 stimulated and FFAR1 inhibited these cells motility, invasiveness, and formation of colonies in cell culture assays. Activated FFAR1 also stimulates or inhibits the malignant behaviors of various cancer includend some of those discussed here (see FFAR1 and cancer). Finally, one study reported that individuals carrying a
single-nucleotide polymorphism In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a ...
, i.e. SNP, variant allele of the ''FFAR4'' gene (variant described as 9469C>A in which
adenine Adenine (, ) (nucleoside#List of nucleosides and corresponding nucleobases, symbol A or Ade) is a purine nucleotide base that is found in DNA, RNA, and Adenosine triphosphate, ATP. Usually a white crystalline subtance. The shape of adenine is ...
replaces
cytosine Cytosine () (symbol C or Cyt) is one of the four nucleotide bases found in DNA and RNA, along with adenine, guanine, and thymine ( uracil in RNA). It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attac ...
at position 9469 of the gene's
nucleic acid sequence A nucleic acid sequence is a succession of Nucleobase, bases within the nucleotides forming alleles within a DNA (using GACT) or RNA (GACU) molecule. This succession is denoted by a series of a set of five different letters that indicate the orde ...
) had increased family histories and personal risks of developing lung cancer. Further animal model, clinical, and gene studies are needed to define the roles of FFAR4 and FFAR1 in these and other cancers.


Breast cancer

Breast cancer studies on FFAR4 have been more extensive than those on other cancers. Cell culture studies showed that the knockdown of FFAR4 levels in cultured human
MCF-7 MCF-7 is a breast cancer cell line isolated in 1970 from a 69-year-old 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-workers ...
,
MDA-MB-231 Scientists study the behaviour of isolated cells grown in the laboratory for insights into how cells function in the body in health and disease. Experiments using cell culture are used for developing new diagnostic tests and new treatments for dise ...
, and SKBR3 breast cancer cells slowed their proliferation and increased their death by
apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
and that GW9508 and TUG-891 inhibited the proliferation and migration of MCF-7 and MDA-MB-231 cells. Animal studies found that ''Ffar4'' gene knockdown MBA-MB-231 cells transplanted into mice formed more rapidly growing and larger tumors than those formed by normal MBA-MB-231 cell transplants; and that GW9508-treated mice transplanted with ''FFAR4'' gene knockdown MBA-MB-231 cells had more lung
metastases Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...
than mice transplanted with normal MBA-MB-231-cells. These findings suggest that FFAR4 and FFAR1 contribute to inhibiting breast tumor growth but FFAR1, not FFAR4, inhibits these cell's metastasis. Clinical observation studies reported that: 1) FFAR4 was expressed in patients' breast cancers but not in the normal
epithelium Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...
lining their breasts' ducts and
lobules In anatomy, a lobe is a clear anatomical division or extension of an organ (as seen for example in the brain, lung, liver, or kidney) that can be determined without the use of a microscope at the gross anatomy level. This is in contrast to the mu ...
; 2) the proportions of five fatty acids which activate FFRA4 and FFAR1 (viz., stearic, dihomo-gamma-linolenic, docosatetraenoic, docosapentaenoic, and docosahexaenoic acids) were higher in patients' cancerous than adjacent normal breast tissues; 3) patients with ER(+) breast cancer, (i.e., breast cancers containing cells that express estrogen receptors) had higher cancer tissue levels of FFAR4 than patients with estrogen receptor negative, i.e., ER(-), breast cancer; 4) among all ER(+) breast cancer patients who were treated with
tamoxifen Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and men. It is also being studied for other types of cancer. It has been used for Albright syndrome ...
(a
selective estrogen receptor modulator Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonists/antagonists (ERAAs), are a class of drugs that act on estrogen receptors (ERs). Compared to pure ER agonists–antagonists (e.g., full agonists and silent ...
commonly used to treat breast cancer), those with high cancer cell FFAR4 levels had a significantly lower 10 year recurrence-free survival rate (percentage of individuals disease-free 10 years after diagnosis) and lower 10 year breast cancer-specific survival rate (percentage of individuals alive 10 years after diagnosis) than those with lower FFAR4 expression levels or ER(-) breast cancer patients; 5) individuals with higher cancer tissue FFAR4 levels who had a luminal A, luminal B HER2(–), or luminal B HER(2+) breast cancer subtype (see breast cancer subtypes) had worse prognoses than individuals with low FFAR4 levels in these respective cancer subtypes (individuals with non-luminal HER2(+) or triple-negative breast cancer subtypes did not show this relationship). These clinical findings allow that one or more of the five FFAR4/FFAR1-activating fatty acids in breast cancer tissues contributes to this cancers development and/or progression; that high levels of FFAR4 in ER(+) breast cancers confer resistance to tamoxifen therapy and thereby reduce survival; and that high levels of FFAR4 are associated with poorer survival in certain breast cancer subtypes. Studies are needed to determine if a high FFAR4 level can be a clinically useful marker for predicting the severity and prognosis of breast cancers, a contraindication to using tamoxifen to treat breast cancers, and a
target Target may refer to: Warfare and shooting * Shooting target, used in marksmanship training and various shooting sports ** Bullseye (target), the goal one for which one aims in many of these sports ** Aiming point, in field artille ...
for treating ER(+) breast cancers with, e.g., a FFAR4 inhibitor.


Bone remodeling

Osteoclast An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and bone remodeling, remodeling of bones of the vertebrate, vertebral skeleton. The osteoclast disassembles and digests th ...
s absorb bone tissue in a physiological process needed to maintain, repair, and remodel bones. Osteoclasts develop by a process of
cellular differentiation Cellular differentiation is the process in which a stem cell changes from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellula ...
termed osteoclastogenesis from cells in the
mononuclear phagocyte system In immunology, the mononuclear phagocyte system or mononuclear phagocytic system (MPS), also known as the macrophage system, is a part of the immune system that consists of the Phagocyte, phagocytic cells located in reticular connective tissue. T ...
. In a mouse
bone marrow Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...
culture model of bone reabsorption, GW9508 inhibited osteoclast activity by reducing the differentiation of cells to osteoclasts as well as the survival and function of the osteoclasts. Since FFAR4 expression was 100-fold higher than FFAR1 in the osteoclasts and knockdown of FFAR4 in the osteoclasts blocked GW9508's effects, studies suggest that activated FFAR4 functions to block osteoclast-mediated
bone resorption Bone resorption is resorption of bone tissue, that is, the process by which osteoclasts break down the tissue in bones and release the minerals, resulting in a transfer of calcium from bone tissue to the blood. The osteoclasts are multi-nuclea ...
. In support of this view, ''Ffar4'' gene knockdown mice developed osteoarthritis more rapidly than control mice in a model of knee osteoarthritis; docosahexaenoic acid inhibited the expression of inflammatory factors in cultured human
chondrocyte Chondrocytes (, ) are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteoglycans. Although the word '' chondroblast'' is commonly used to describe an immatu ...
s; and the levels of FFAR4 protein in the osteoarthritic and/or nearby fat tissue of humans with osteoarthritis were higher than those with non-osteoarthritic bone disease. These studies suggest that FFAR4 inhibits bone resorption and may prove to be useful for treating excessive bone resorption, i.e., osteoporosis.


References


See also

*
Free fatty acid receptor Free fatty acid receptors (FFARs) are G-protein coupled receptors (GPRs). GPRs (also termed seven-(pass)-transmembrane domain receptors) are a large family of receptors. They reside on their parent cells' surface membranes, bind any one o ...
* Free fatty acid receptor 1 {{G protein-coupled receptors G protein-coupled receptors