Free Fatty acid receptor 4 (FFAR4), also termed G-protein coupled receptor 120 (GPR120), is a protein that in humans is encoded (i.e., its formation is directed) by the FFAR4 gene. This gene is located on the long (i.e. "P") arm of chromosome 10 at position 23.33 (position notated as 10q23.33). G protein-coupled receptors (also termed GPRs or GPCRs) reside on their parent cells' surface membranes, bind any one of the specific set of ligands 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 receptors (FFARs) viz., FFAR1 (also termed GPR40), FFAR2 (also termed GPR43), and FFAR3 (also termed GPR41). These four FFARs bind and thereby are activated by certain fatty acids.
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, atherosclerosis, and bone remodeling. 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, pathological inflammatory reactions, atherosclerosis, atherosclerosis-induced cardiovascular disease, repair of damaged bones, osteoporosis. and some cancers. These findings have made FFAR4 a potentially attractive therapeutic biological target for treating these disorders and therefore lead to the development of drugs directed at regulating FFAR4's activities.
Certain fatty acids, including in particular the omega-3 fatty acids, docosahexaenoic and eicosapentaenoic acids, have been taken in diets and supplements to prevent or treat the diseases and tissue injuries 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 omga-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, 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 at position 13.12 (location notated as 19p13.12); the FFAR4 gene is located on the "q" (i.e., long) arm of chromosome 10 at position 23.33 (location notated as 10q23.33). Humans express a long FFAR4 protein isoform consisting of 377 amino acids and a short splice variant protein isoform consisting of 361 amino acids. However, rodents, non-human primates, and other studied animals express only the short protein. The two isoforms 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.